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It is courage based on confidence, not daring, and it is confidence based on experience. ~ Jonas Salk
Vaccination as a deliberate attempt to protect humans against disease has a short history when measured against the thousands of years that humans have sought to rid themselves of plagues and pestilence. Only in the 20th century did the practice flower into the routine vaccination of large populations. Yet, despite its relative youth, the impact of vaccination on the health of the world's peoples is hard to exaggerate. ~ Plotkin's Vaccines
Modern air travel has made prophylactic vaccination more important than ever, because this mode of transportation has greatly facilitated the spread of contagious pathogens. ~ Primer to the Immune Response
Vaccinations are a cornerstone of pediatric care. Traveling children need special attention to their vaccine status. Updating all routine vaccinations and accelerating those in the primary series should be done if possible. ~ Travel Medicine
Dr. Tom Shimabukuro said there is an increased risk of myocarditis and pericarditis with either the Moderna or Pfizer vaccine, in particular after the second dose of the vaccines. ~ Jack Davis

Vaccines are biological preparations that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. In the 2000s, vaccine misinformation developed, with opponents of vaccination spreading false claims through various media.

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  • Most of the objections made by doctors with occult tendencies are based unconsciously on a feeling that there should be higher methods of controlling diseases in man than by injecting into the human body substance taken from the bodies of animals. That is most surely and definitely correct, and some day it will be demonstrated. ... A more vital objection should be based on the suffering entailed on the animals providing the vaccine and other substances...the effect on the inner bodies is practically nil, and far less than the diseases themselves...The controlling of modern disease is being handled by modern medicine primarily in three ways: through the science of sanitation, through preventive medicine, and through inoculation.
    • Alice Bailey in Esoteric Healing (A Treatise on the Seven Rays), p.322/4, (1953).
  • The science of inoculation is purely physical in origin, and concerns only the animal body. This latter science will shortly be superseded by a higher technique, but the time is not yet.
    • Alice Bailey in Esoteric Healing (A Treatise on the Seven Rays) p.322/4 (1953).
  • How does sleep affect immunity during a genuinely ongoing immune response? There are quite a few studies that investigated the effects of sleep on the response to vaccinations used as an experimental model of infection. Intriguingly, these studies consistently demonstrate that sleep enhances the adaptive immune response against the invading antigen. Compared with subjects who stayed awake during the night after a single vaccination against hepatitis A in the morning before, subjects who regularly slept on this first night after vaccination, 4 weeks later, displayed a twofold increase in antigen-specific antibody titres. This study was the first to show in humans that a single night of normal sleep after vaccination strengthens the evolvement of a natural immune response against an invading antigen, to a clinically relevant extent. Subsequent experiments confirmed these effects for repeated inoculations with both hepatitis A and B antigens and showed that the immune-boosting effect of nocturnal sleep was also reflected by a doubling of the number of circulating antigen-specific Th cells that drive the production of hepatitis A and B-specific antibodies (Fig. 4a). The proportion of pro-inflammatory and Th1 cytokine (IL-2, IFN-γ, TNF-α) producing T cells was also profoundly reinforced by sleep. Importantly, these immuno-enhancing effects of sleep were still present at a 1-year follow-up, indicating that sleep in enhancing the initial formation of an adaptive immune response also supports the long-term maintenance of the antigenic memory, a function hallmarking the immune system.


  • The term 'natural immunity' has been often used to express post-infectious immunity and differentiate it from vaccine-induced immunity. In practice, this is not necessarily helpful. There is nothing fundamentally "unnatural" in vaccine-induced immunity, and while the minutiae of natural infection and vaccine-induced immunity might differ, this is a quintessentially unhelpful notion.


  • Edward R. Murrow: Who owns the patent on this vaccine?
    Jonas Salk: Well, the people, I would say. There is no patent. Could you patent the sun?
    • CBS Television interview, on See It Now (12 April 1955); quoted in Shots in the Dark : The Wayward Search for an AIDS Vaccine (2001) by Jon Cohen.
  • For scientific research and for the production of vaccines or other products, cell lines are at times used which are the result of an illicit intervention against the life or physical integrity of a human being. The connection to the unjust act may be either mediate or immediate, since it is generally a question of cells which reproduce easily and abundantly. This "material" is sometimes made available commercially or distributed freely to research centers by governmental agencies having this function under the law. All of this gives rise to various ethical problems with regard to cooperation in evil and with regard to scandal. It is fitting therefore to formulate general principles on the basis of which people of good conscience can evaluate and resolve situations in which they may possibly be involved on account of their professional activity.
    It needs to be remembered above all that the category of abortion "is to be applied also to the recent forms of intervention on human embryos which, although carried out for purposes legitimate in themselves, inevitably involve the killing of those embryos. This is the case with experimentation on embryos, which is becoming increasingly widespread in the field of biomedical research and is legally permitted in some countries... [T]he use of human embryos or fetuses as an object of experimentation constitutes a crime against their dignity as human beings who have a right to the same respect owed to a child once born, just as to every person". These forms of experimentation always constitute a grave moral disorder.
  • Grave reasons may be morally proportionate to justify the use of such "biological material". Thus, for example, danger to the health of children could permit parents to use a vaccine which was developed using cell lines of illicit origin, while keeping in mind that everyone has the duty to make known their disagreement and to ask that their healthcare system make other types of vaccines available. Moreover, in organizations where cell lines of illicit origin are being utilized, the responsibility of those who make the decision to use them is not the same as that of those who have no voice in such a decision.
    In the context of the urgent need to mobilize consciences in favour of life, people in the field of healthcare need to be reminded that "their responsibility today is greatly increased. Its deepest inspiration and strongest support lie in the intrinsic and undeniable ethical dimension of the health-care profession, something already recognized by the ancient and still relevant Hippocratic Oath, which requires every doctor to commit himself to absolute respect for human life and its sacredness".
  • “There is an expression out there that a failed gene therapy makes a good vaccine,” says Luk Vandenberghe, a viral vector expert at Harvard Medical School.
    One attractive feature is that adenoviruses’ inflammatory effects mean developers don’t have to use adjuvants, molecules added to conventional vaccines to direct the immune system’s attention to the viral protein. The adenoviruses themselves drive the inflammation, which is kept under control by giving the vaccines at low doses.
    And all genetic vaccines—DNA vaccines, mRNA vaccines, and adenoviral vector vaccines—mimic a natural viral infection by forcing our bodies to produce viral proteins inside our cells. That spurs the T cells of our immune system to attack these vaccinated cells, and in the process, they learn to seek and destroy cells infected with the real virus in the future.
    Traditional vaccines, made from weakened viruses or viral proteins, stimulate B cells to make antibodies against the virus. Those antibodies latch onto invading viruses and prevent them from entering our cells.
    The problem is that once the virus infiltrates our cells, the antibodies from a traditional vaccine are useless. It’s at that stage that T cells need to swoop in. Adenovirus vectors “are the best of all vaccines at inducing a T-cell response,” Wistar’s Ertl says.


  • Children are vaccinated at a very early age. The rubella vaccine, for example, is given between the ages of 12 and 15 months, with later boosters. When not provided, a child may develop a variety of serious complications, such as encephalitis, which infects 1 in 1,000 to 2,000 rubella victims. A significant percentage of these will also suffer permanent brain damage or death. Clearly a parent takes a significant risk when he refuses to have a child immunized.
    Rubella is but one of many diseases, and encephalitis but one of many complications.


  • Petri described the new study as paradigm-shifting. “It was one of those rare, seminal findings that changes the way I think about the immune response,” he said.
    Davis’ study offers hope that some of the immunity conferred by a vaccine extends beyond the specific microbe it targets, Petri said. “This adds support to the impetus to vaccinate infants in the developing world,” he said. As many as 30 different pathogens can cause diarrhea, so vaccinating small children against all of them — even if those vaccines existed — would require so many separate injections as to be logistically hopeless. Understanding the mechanism by which cross-reactivity occurs might further allow immunologists to develop “wide-spectrum vaccines” that cover a number of infectious organisms.
  • A vaccine is just exposing yourself to a little bit of the bad thing that can kill you.
  • The process of vaccination consists in injecting into the skin the liquid that is obtained by applying the discharge from the body of a small-pox patient to the udder of a cow… Vaccination is a barbarous practice, and it is one of the most fatal of all the delusions current in our time, not to be found even among the so-called savage races of the world. Its supporters are not content with its adoption by those who have no objection to it, but seek to impose it with the aid of penal laws and rigorous punishments on all people alike. ...
    • Mahatma Gandhi A Guide to Health (1921) (Part II, Chapter VI Contageous Diseases: Small-Pox) Translated from the Hindi by A. Rama Iyer, M.A. (full text multiple formats)
  • I cannot also help feeling that vaccination is a violation of the dictates of religion and morality. [Pg 108]The drinking of the blood of even dead animals is looked upon with horror even by habitual meat-eaters. Yet, what is vaccination but the taking in of the poisoned blood of an innocent living animal? Better far were it for God-fearing men that they should a thousand times become the victims of small-pox and even die a terrible death than that they should be guilty of such an act of sacrilege.
    • Mahatma Gandhi A Guide to Health (1921) (Part II, Chapter VI Contageous Diseases: Small-Pox) Translated from the Hindi by A. Rama Iyer, M.A. (full text multiple formats)


  • Effective vaccines would likely protect lives and limit disease spread in a biological weapons emergency. Licensed vaccines are currently available for a few threats, such as anthrax and smallpox, and research is underway to develop and produce vaccines for other threats, such as tularemia, Ebola virus, and Marburg virus. Many bio-weapon disease threats, however, lack a corresponding vaccine, and for those that do, significant challenges exist to their successful use in an emergency.
  • In a wide-scale emergency in which a vaccine is available or potentially available, a large supply of vaccine would be necessary and needed quickly. Currently, the U.S. Strategic National Stockpile (SNS) has enough smallpox vaccine to vaccinate every person in the country in the event of a bio-weapon attack. The stockpile also holds millions of doses of anthrax vaccine, other vaccines, antiviral medications, and other medical supplies. Quick deployment of a vaccine is essential to its success in preventing disease. For some diseases, vaccinating after exposure may have no effect on preventing disease, and for others, vaccination must occur very quickly after exposure for prophylaxis to work. In the case of smallpox, PEP is likely to be effective when given within four days of exposure to the virus. Plans provide for the smallpox vaccine to be shipped starting on the first day of an attack, and it would continue to be shipped from the stockpile to the rest of the country as needed in the five to six days following the attack.
  • Several accounts from the 1500s describe smallpox inoculation as practices in China and India (one is referred to in volume 6 of Joseph Needham’s Science and civilization in China). Glynn and Glynn, in the The Life and Death of Smallpox, note that in the late 1600s Emperor K’ang His, who had survived smallpox as a child, had his children inoculated. That method involved grinding up smallpox scabs and blowing the matter into nostril, inoculation may also have been practiced by scratching matter from a smallpox sore into the skin. It is difficult to point when the practice began, as some sources claim dates as early as 300 BCE.
  • The only human infectious disease to be eradicated through vaccination is smallpox. Polio is on the verge of being eradicated, with cases of the wild (not vaccine derived) strain only found in Central Asia. Rinderpest (a relative of measles that affected cattle) is the only animal disease to be eradicated through vaccination of cattle.
  • Second, the vaccine against the infectious agent must be highly effective and available to everyone at risk of contracting the disease. This guarantees most people getting the vaccine become immune to infection and/or disease, and that herd immunity is activated through vaccination of most of the population. For example, the effectiveness of the measles vaccine is around 99% in populations getting the two-dose series. That effectiveness drops for the whole population if a significant percentage of the population is not given the vaccine, triggering outbreaks.
    Third, and closely associated with the second point, the public must accept the vaccine and get vaccinated. The vaccine could be highly effective, have an outstanding track record of safety, and be available at little to no cost to the entire population… But all that is meaningless toward eradication if enough people in the population will not get the vaccine. This is a big problem in the era of vaccine misinformation and disinformation spreading through online sources.
  • Although the time periods have changed, the emotions and deep-rooted beliefs—whether philosophical, political, or spiritual—that underlie vaccine opposition have remained relatively consistent since Edward Jenner introduced vaccination.
  • Vaccines typically need time (weeks or months) to produce protective immunity in an individual, and may require several doses over a certain period to achieve optimum protection. Passive immunization, however, has an advantage in that it is quick acting, producing an immune response within hours or days, faster than a vaccine.
  • Military research programs throughout history have made significant contributions to medicine and, in particular, to vaccine development. These efforts have been driven primarily by the effects of infectious disease on military conflicts: smallpox devastated the Continental Army in 1776, as well as troops on both sides of the United States Civil War; typhoid fever was common among soldiers in the Spanish American War. More person-days were lost among U.S. soldiers in malaria-endemic regions to malaria than to bullets throughout the entire 20th century; indeed, malaria continues to sap military strength into the current century.
  • [I]n 1956, an adenovirus vaccine was created at WRAIR. It was an inactivated vaccine that protected against two forms of adenovirus infection, types 4 and 7, which accounted for the majority of acute respiratory diseases among trainees. (A separate vaccine developed at the National Institutes of Health protected against type 3 in addition to types 4 and 7.) Manufacturing problems led to the license for the vaccine being revoked in 1963, but two live-virus vaccines were developed just a few years later. These vaccines were unique in being produced as oral tablets with a coating that resisted stomach acid.
    After extensive military studies, both vaccines were given to new military trainees “within hours after their arrival” at basic training beginning in 1971. In 1994, however, the vaccine’s manufacturer ended production of it, and all stocks were depleted in 1999. Outbreaks of acute respiratory disease caused by adenoviruses rose among military trainees following discontinuation of the vaccination program. In 2001, the Army provided funds to re-establish an adenovirus vaccine, and the government contracted with a manufacturer to restore a production line for adenovirus type 4 and type 7 vaccine tablets. The vaccine was licensed in March 2011, and the U.S. military deployed it to training facilities beginning in October 2011. Surveillance of adenovirus illness since then shows a marked decrease in incidence of all serotypes of adenovirus after re-introduction of the vaccine.
  • Krugman was not the only researcher who experimented with institutionalized-but-otherwise-healthy people. Other notable figures in vaccine research and development used similar practices. Werner Henle, MD, at the University of Pennsylvania, conducted a test of influenza vaccine in a prison population and in a state home for the developmentally delayed. His study design required administering vaccines to his experimental group and then deliberately exposing them to influenza (he deliberately infected the placebo group with the virus). Jonas Salk, MD, conducted similar influenza studies in Michigan.
    Later, other researchers would test various vaccines, including vaccines for polio and measles, in institutionalized subjects. These tests, conducted by Salk, Hilary Koprowski, MD, and others, usually did not deliberately infect subjects with the disease agent.



  • The history of medical research and human experimentation reveals both great successes and horrible abuses. Plagues like smallpox were rampant and capable of wiping out entire cities. People were desperate for relief and would try anything that could help ward off the horrible plagues, even experimenting. English aristocrat Lady Mary Wortley Montague introduced the idea of variolation to the gentry in 1715. In variolation, ooze from the sores of smallpox victims with mild cases was scratched into the skin. During the French the Indian War, General George Washington was convinced that his most formidable for was smallpox and he subjected his men to forced variolation to stop its spread. Many of the soldiers had only mil reactions, but some became seriously ill and died. The European press, especially among the antivaccine society, bitterly criticized Washington for forcing his men into possible harm without their consent, Hessian soldiers, who fought alongside the British, were captured and imprisoned in Frederick, Maryland, where they may have been subjected to variolation experimentation—a safety precaution before Washington would order to the procedure for his own army. When British physician Edward Jenner (1749-1823) introduced the use of cowpox sores to make a vaccine against smallpox, he was subjected to the same criticism.
    In the 1700s principles of individualism, self-determination, and consent of the governed formed the establishment of the United States. Ethicists all this idea the principle of “respect for persons.” Therefore, informed consent is a human right and an outgrowth of life, liberty and the pursuit of happiness.
  • During the French Indian War, General George Washington was convinced that his most formidable for was smallpox and he subjected his men to forced variolation to stop its spread. Many of the soldiers had only mild reactions, but some became seriously ill and died. The European press, especially among the antivaccine society, bitterly criticized Washington for forcing his men into possible harm without their consent, Hessian soldiers, who fought alongside the British, were captured and imprisoned in Frederick, Maryland, where they may have been subjected to variolation experimentation-a safety precaution before Washington would order to the procedure for his own army.
  • There is no longer any reason why American children should suffer from polio, diphtheria, whooping cough, or tetanus—diseases which can cause death or serious consequences throughout a lifetime, which can be prevented, but which still prevail in too many cases.
    I am asking the American people to join in a nationwide vaccination program to stamp out these four diseases, encouraging all communities to immunize both children and adults, keep them immunized, and plan for the routine immunization of children yet to be born. ...[O]ver the next 3 years, I am proposing legislation authorizing a program of federal assistance. This program would cover the full cost of vaccines for all children under five... It would also assist in meeting the cost of organizing the vaccination drives... and the cost of extra personnel... [T]he legislation provides continuing authority to permit a similar attack on other infectious diseases... susceptible of practical eradication as a result of new vaccines or other preventive agents. Success in this effort will require the whole-hearted assistance of the medical and public health professions, and a sustained nationwide health education effort.
    • John F. Kennedy, "Special Message to the Congress on National Health Needs" (February 27, 1962) To the Congress of the United States.
  • The history of medical research and human experimentation reveals both great successes and horrible abuses. Plagues like smallpox were rampant and capable of wiping out entire cities. People were desperate for relief and would try anything that could help ward off the horrible plagues, even experimenting. English aristocrat Lady Mary Wortley Montague introduced the idea of variolation to the gentry in 1715. In variolation, ooze from the sores of smallpox victims with mild cases was scratched into the skin. During the French and Indian War, General George Washington was convinced that his most formidable for was smallpox and he subjected his men to forced variolation to stop its spread. Many of the soldiers had only mild reactions, but some became seriously ill and died. The European press, especially among the antivaccine society, bitterly criticized Washington for forcing his men into possible harm without their consent, Hessian soldiers, who fought alongside the British, were captured and imprisoned in Frederick, Maryland, where they may have been subjected to variolation experimentation-a safety precaution before Washington would order to the procedure for his own army. When British physician Edward Jenner (1749-1823) introduced the use of cowpox sores to make a vaccine against smallpox, he was subjected to the same criticism.
    In the 1700s principles of individualism, self-determination, and consent of the governed formed the establishment of the United States. Ethicists all this idea the principle of “respect for persons.” Therefore, informed consent is a human right and an outgrowth of life, liberty and the pursuit of happiness.
  • It’s almost impossible to find a religion that has a clear anti-vaccine stance. As articles about religious schools with measles outbreaks are quick to point out, even if one spokesperson claims vaccination is against the group’s beliefs, there is always a second spokesperson who will contradict that claim. On Wednesday, WNYC quoted ultra-Orthodox Rabbi Shmuel Kamenetsky, who told a Baltimore pape this past summer that vaccines are a hoax. But, it should be noted, he didn’t raise any religious objections to them. Avi Shafran, a spokesman for Agudath Israel, of which Kamenetsky is a member of the board of rabbis, told WNYC in a wavering and inconclusive Chris Christie–style email: “It would be wrong, I think, to vilify those who opt to not vaccinate their children, or to postpone vaccinations. … But it would be equally wrong to ignore the clear science regarding the issue.” Making it pretty clear that while they don’t want to force anyone to vaccinate, they have no religious objection.
    Indeed, most religions that are dragged into this debate don’t actually oppose vaccination. In 2013, John Grabenstein, the executive director for global health and medical affairs for Merck (which may lead conspiracy theorists to claim he is just shilling for Big Pharma), wrote a paper for the journal Vaccine outlining the purported religious objections. His conclusion: The only two religions that have any possible negative stance (though it’s not even clear that they do) on vaccination are Christian Scientists and the Dutch Reformed Church.
    The Christian Scientists’ stance can be a bit tricky to ascertain, as they’re known to be excessively secretive about their thoughts on modern medicine. While they believe diseases can be cured through prayer, they don’t seem to have an official stance when it comes to preventive actions like vaccines. That being said, Grabenstein quotes Mary Baker Eddy, the founder of the Church of Christ, Scientist, as saying, “Rather than quarrel over vaccination, I recommend, if the law demand, that an individual submit to this process, that he obey the law, and then appeal to the gospel to save him from bad physical results.”
    The Dutch Reformed Church’s objections seemed to start out as fear of adverse effects, but, for some, have morphed into a belief that vaccines interfere with the relationship with God, as they make people less dependent on God. As a result of low vaccination rates in the Dutch “Bible Belt,” more than 1,200 people came down with measles in a 2013 outbreak. But there is another subset of the denomination that describes vaccinations as a gift from God that should be used with gratitude. (This interpretation is reminiscent of the famous religious joke about a drowning man who refuses help because God will save him, only to arrive in heaven to have God tell him, “I sent you a rowboat and a motorboat and a helicopter, what more did you expect?”)
    Some people cite the Catholic Church’s objection to certain vaccines, such as the rubella vaccine, that were initially developed in laboratory cell lines that were derived from aborted fetuses. (The vaccines themselves contain no fetal cells.) The church has stated that in those instances members should find alternatives when available but that there is no religious obligation to refuse these vaccines. (Catholic News Service even ends an article on this subject with the wonderful: “Children and unborn children must not pay the price for ‘the licit fight against pharmaceutical companies’ that produce immoral vaccines.”)
    Jehovah’s Witnesses have famously strict rules regarding blood transfusions, based on their interpretation of the Bible’s commandment to abstain from blood. But they don’t seem to currently oppose vaccination.
  • Of course, the state government doesn’t monitor the SATs, but for all intents and purposes it was tougher for me to take the SAT on a Sunday for religious reasons than it is to exempt a child from vaccination for religious reasons. This just goes to show that the religious exemption for vaccinations isn’t even about religion.
    Personal belief exemptions, on the other hand, require more than just the signature of the guardian. In Oregon, legislation passed in 2013 requires parents or guardians who want to claim a nonmedical exemption for their child to receive education—via a health care provider or a video—about the benefits of vaccination. If guardians are going to decide not to vaccinate, the least we can expect from them is a signed document stating that they know the repercussions of their actions instead of attempting to drag religion into a battle it doesn’t even have a real stake in.


  • Even if antibody responses seem robust, that could be misleading, cautions Melinda Beck, who studies the relationship between nutrition and immune responses at the University of North Carolina. In her studies, she says, obese people have normal initial antibody levels in response to flu vaccines, but are still twice as likely as vaccinated lean people to get the flu (that’s not to say that vaccination offers obese people no benefit). And analyses so far have focused on Western definitions of obesity. These are based on BMI, a crude measure that fails to distinguish between fat that accumulates under the skin, and fat that accumulates around organs, called visceral fat, which is more closely associated with diseases such as diabetes and high blood pressure.
    In people of European descent, a BMI of 30 kilograms per square metre or above is considered obese. But Popkin notes that people in some countries in Asia, the Middle East and Latin America, for example, tend to accumulate visceral fat at lower BMIs. China is the only country to set a lower threshold — a BMI of 28 kg m–2 — for obesity, but even then, Popkin says, some Chinese researchers will report their data using Western definitions of BMI to improve their chances of publishing.
  • A team led by vaccinologist Ofer Levy at Boston Children’s Hospital in Massachusetts is working on a COVID-19 vaccine specifically for older adults, using an in-vitro screening system to identify the best adjuvants. “Vaccines were typically developed as one-size-fits-all,” he says. But a lot of features — age, sex, and even the season — affect vaccine responses, Levy says. The best combinations of adjuvant and vaccine they find will be tested in mice and then in humans.
    But, in general, developing medications to improve immune function seems like a much smarter strategy than creating vaccines specifically for elderly people, says Claire Chougnet, an immunologist at Cincinnati Children’s Hospital Medical Center in Ohio, who is studying inflammation in aged mice. Vaccine development is costly and time-intensive. “In the case of an emerging virus, when you want a quick response, that makes things even more complicated if you have to do two types of vaccine,” she says. Plus, individual vaccines target specific pathogens, but an immune-boosting medication could be used with any vaccine. “That could work for flu, that could work for COVID-19. That would work for COVID-25,” she says. The approach is “extremely versatile”.
  • Vaccines made from mRNA can be made much faster than older vaccines could, explains Margaret Liu, a vaccine researcher who chairs the board of the International Society for Vaccines and specializes in genetic vaccines. The problem, says Liu, is that mRNA is "really easily destroyed, and that's because there are many, many enzymes that will just break it apart."


  • Vaccinations are a cornerstone of pediatric care. Traveling children need special attention to their vaccine status. Updating all routine vaccinations and accelerating those in the primary series should be done if possible. The immune system of infants and children responds differently to different types of vaccines. Safety and efficacy considerations guide vaccine recommendations for all pediatric vaccinations. Age limitations on vaccinations may be due to safety concerns (e.g., yellow fever vaccine), immune system response capability (polysaccharide vaccines), maternal antibody interference (e.g., measles, hepatitis A), or lack of data. Travel-specific recommendations may differ for vaccinating children compared with adults based on these details.
    • Sheila M. Mackell, Mike Starr, “Pediatric Travel Vaccinations”, in Travel Medicine (Fourth Edition), (2019)
  • Vaccination is a clinical application of immunization designed to artificially help the body to defend itself. A vaccine against infection is a modified form of a natural immunogen, which may be either the whole pathogen, one of its components, or a toxin. A vaccine does not cause disease when administered but induces the healthy host (the vaccinee) to mount a primary response against epitopes of the modified immunogen and to generate large numbers of memory B and T cells. In an unvaccinated individual (Fig. 14-1, left panel), naïve B and T cells capable of combatting an infecting pathogen are present in relatively low numbers when the pathogen is first encountered. A primary immune response is all that can be mounted so that, in many cases, the individual becomes sick until antibodies and/or effector T cells can act to clear the attacker. In a vaccinated individual (Fig. 14-1, right panel), a collection of circulating antibodies and an expanded army of pathogen-specific memory B and T cells have already been generated prior to a first exposure to the natural pathogen. When the natural pathogen attacks, the circulating antibodies provide a degree of immediate protection from the invader. In addition, the memory B and T cells are quickly activated, and a secondary response is mounted that rapidly clears the infection before it can cause serious illness. This type of vaccination is called prophylactic vaccination because it is intended to prevent disease.
  • NOTE: Modern air travel has made prophylactic vaccination more important than ever, because this mode of transportation has greatly facilitated the spread of contagious pathogens. For example, in 2010, an unvaccinated child who contracted measles in Europe transmitted the virus to a fellow passenger during a flight to the U.S. This passenger then attended a conference and unwittingly exposed 270 other individuals to the disease.
    Vaccination can be thought of as a form of active immunization, because the individual is administered a pathogen antigen and his/her body is responsible for activating the lymphocytes and making the antibodies necessary to provide defense against future assaults. In contrast, passive immunization is the term used to describe the transfer of protective anti-bodies from an immune individual to an unimmunized individual.
  • Today’s best known vaccination success story is the global campaign of the World Health Organization (WHO) to eradicate smallpox. In 1967, the WHO began its coordination of 200,000 health workers who took 10 years to vaccinate the world’s population in its remotest corners. Between 1976 and 1979, only one case of smallpox was recorded, leading to the declaration in 1980 that smallpox had been officially eradicated (Plate 14-1). A similar global immunization program against rinderpest is currently pushing this pathogen toward extinction (Box 14-2).



  • Vaccination as a deliberate attempt to protect humans against disease has a short history when measured against the thousands of years that humans have sought to rid themselves of plagues and pestilence. Only in the 20th century did the practice flower into the routine vaccination of large populations. Yet, despite its relative youth, the impact of vaccination on the health of the world's peoples is hard to exaggerate. With the exception of safe water, no other intervention, not even antibiotics, has had such a major effect on mortality reduction and population growth.
    Since the first vaccine was introduced by Edward Jenner (Fig. 1.1) in 1798, vaccination has controlled 14 major diseases, at least in parts of the world: smallpox, diphtheria, tetanus, yellow fever, pertussis, aemophilus influenzae type b disease, poliomyelitis, measles, mumps], rubella, typhoid, rabies, rotavirus, and hepatitis B. For smallpox, the dream of eradication has been fulfilled; naturally occurring smallpox has disappeared from the world. Cases of poliomyelitis have been reduced by 99% and this disease also is targeted for eradication. Rubella and congenital rubella syndrome have been officially declared eliminated from the Americas as of 2015. Vaccinations against many other diseases have made major headway. The path to these successes is worth examining.
    • Susan L. Plotkin, Stanley A. Plotkin, in Plotkin's Vaccines (Seventh Edition), ch.1, A Short History of Vaccination, (2018)
  • In the 7th century, some Indian Buddhists drank snake venom in an attempt to become immune to its effect. They may have been inducing antitoxin-like immunity. In the 16th century, Brahmin Hindus in India practiced a form of variolation by introducing dried pus from smallpox pustules into the skin of a patient. Writings that cite the use of inoculation and variolation in 10th-century China–make interesting reading but apparently cannot be verified. There is, however, 18th-century documentation of Chinese variolation. The Golden Mirror of Medicine, a medical text dated 1742, listed four forms of inoculation against Smallpox practiced in China since 1695: The nose plugged with powdered scabs laid on cotton wool. Powdered scabs blown into the nose. The undergarments of an infected child put on a healthy child for several days. A piece of cotton smeared with the contents of a vesicle and stuffed into the nose. This text, endorsed by the Imperial Court, raised the status of variolation in China, which previously had been considered just a folk remedy. Another Chinese text, published a century before Jenner’s work, stated that white cow fleas were used for smallpox prevention. The fleas were ground into powder and made into pills.
    • Susan L. Plotkin, Stanley A. Plotkin, in Plotkin's Vaccines (Seventh Edition), ch.1, A Short History of Vaccination, (2018)
  • A hundred and twenty million cases of the most deadly, most contagious…and least excusable…disease in medicine. For smallpox can infallibly be prevented, and only a world which had forgotten Jenner could have been taken by it unaware…or a world in which the memory of Jenner’s centuries-old prophylaxis had been systematically removed.
    • Frederik Pohl, Drunkard’s Walk (1960), Chapter 15 (ellipses as in the book)


  • In the 1970's and 1980's vaccines became, one might say, victims of their own success. They had been so effective in preventing infectious diseases that the public became much less alarmed at the threat of those diseases, and much more concerned with the risk of injury from the vaccines themselves.
  • The practice of immunisation dates back hundreds of years. Buddhist monks drank snake venom to confer immunity to snake bite and variolation (smearing of a skin tear with cowpox to confer immunity to smallpox) was practiced in 17th century China. Edward Jenner is considered the founder of vaccinology in the West in 1796, after he inoculated a 13 year-old-boy with vaccinia virus (cowpox), and demonstrated immunity to smallpox.
  • In 1798, the first smallpox vaccine was developed. Over the 18th and 19th centuries, systematic implementation of mass smallpox immunisation culminated in its global eradication in 1979.
    Louis Pasteur’s experiments spearheaded the development of live attenuated cholera vaccine and inactivated anthrax vaccine in humans (1897 and 1904, respectively). Plague vaccine was also invented in the late 19th Century. Between 1890 and 1950, bacterial vaccine development proliferated, including the Bacillis-Calmette-Guerin (BCG) vaccination, which is still in use today.
    In 1923, Alexander Glenny perfected a method to inactivate tetanus toxin with formaldehyde. The same method was used to develop a vaccine against diphtheria in 1926. Pertussis vaccine development took considerably longer, with a whole cell vaccine first licensed for use in the US in 1948.
    Viral tissue culture methods developed from 1950-1985, and led to the advent of the Salk (inactivated) polio vaccine and the Sabin (live attenuated oral) polio vaccine. Mass polio immunisation has now eradicated the disease from many regions around the world. Attenuated strains of measles, mumps and rubella were developed for inclusion in vaccines. Measles is currently the next possible target for elimination via vaccination.
    Despite the evidence of health gains from immunisation programmes there has always been resistance to vaccines in some groups. The late 1970s and 1980s marked a period of increasing litigation and decreased profitability for vaccine manufacture, which led to a decline in the number of companies producing vaccines. The decline was arrested in part by the implementation of the National Vaccine Injury Compensation programme in the US in 1986. The legacy of this era lives on to the present day in supply crises and continued media efforts by a growing vociferous anti-vaccination lobby.
  • The past two decades have seen the application of molecular genetics and its increased insights into immunology, microbiology and genomics applied to vaccinology. Current successes include the development of recombinant hepatitis B vaccines, the less reactogenic acellular pertussis vaccine, and new techniques for seasonal influenza vaccine manufacture.
    Molecular genetics sets the scene for a bright future for vaccinology, including the development of new vaccine delivery systems (e.g. DNA vaccines, viral vectors, plant vaccines and topical formulations), new adjuvants, the development of more effective tuberculosis vaccines, and vaccines against cytomegalovirus (CMV), herpes simplex virus (HSV), respiratory syncytial virus (RSV), staphylococcal disease, streptococcal disease, pandemic influenza, shigella, HIV and schistosomiasis among others. Therapeutic vaccines may also soon be available for allergies, autoimmune diseases and addictions.
  • It has been recognized for centuries that some diseases never reinfect a person after recovery. Smallpox was the first disease people tried to prevent by intentionally inoculating themselves with infected matter. Inoculation originated in India or China some time before 200 BC.
    The concept of immunization, or how to artificially induce the body to resist infection, received a big boost in 1796, when physician Edward Jenner inoculated a young boy in England and successfully prevented him from getting smallpox. Jenner used a lancet to scratch some infected material from a woman with cowpox (similar to smallpox) under the boy’s skin.
  • Lack of immunity to disease has helped to decide the fate of entire communities, from smallpox among the Indians in the New World to syphilitic soldiers in the Old. Most people have some amount of natural immunity. The human body can take care of itself in many circumstances—cuts, colds, and minor infections disappear without major upheaval. In other cases, the body has little or no naturally occurring immunity, so if you are exposed to diseases such as polio, influenza, smallpox, hepatitis, diphtheria, measles, or whooping cough, you will probably get sick with it, unless you have been immunized.
    Immunization refers to the artificial creation of immunity by deliberately infecting someone so that the body learns to protect itself. An important part of the history of immunization has been determining how to get the immunizing agent into the body. The skin, which keeps germs and mischievous substances out, is also a barrier to getting medicines and vaccines into the tissue where they can work. Physicians have used varying methods to create immunity where there is none.
  • Having an effective vaccine that could produce sufficient immunity was useless without being able to get it into the body in a harmless way. Edward Jenner used a lancet and scratched two lines on James Phipps’s arm. Fifty years after Jenner, the hypodermic syringe became available. In 1885, scientist Louis Pasteur used one to vaccinate a young boy who had been bitten by a mad dog and was sure to die of rabies—the boy lived, and immunization took another giant step forward.
    As more immunizing agents became available, people saw the benefit of immunizing large groups, such as soldiers. During World War I, they were vaccinated against diphtheria; during World War II, typhus and tetanus.
  • Hypodermic injection remains the most common method of getting through the skin. But it is not the only technology for immunization. Engineers and scientists continue to search for alternative routes into the body, such as through the moth or nose. And continuing to solve the technological problems is critical for countries in which illness and death rates are high as a result of measles, maternal tetanus, and other preventable diseases.
    A successful instrument or system must get the vaccine into the body with minimal disruption, and be cost-effective for use with billions of people. And perhaps the most important problem today—preventing reuse of syringes to avoid cross-contamination—was not even imagined in the 19th century.
  • World War II accelerated vaccine development. Fear of a repetition of the 1918–19 world epidemic of influenza focused urgent attention on all viral diseases, while commercial production of antibiotics taught researchers to grow viruses with less microbe contamination. Also, investigators paid closer attention to vaccine safety and effectiveness through clinical studies before release of a vaccine to the public, especially after the yellow fever vaccine apparently caused hepatitis B in many U.S. soldiers in 1942.
    Polio vaccine is made from the actual virus. For both research and production, vaccine makers needed to grow large quantities of virus. Influenza virus had been grown in chicken eggs, but this method did not polio. So researchers sought other materials in which to grow poliovirus.
    In 1936, Albert Sabin and Peter Olitsky at the Rockefeller Institute demonstrated that poliovirus could grow in human embryonic brain tissue, but they feared that this method might risk central nervous system damage in those who received the vaccine. The advantage of embryonic tissue, however, was that it grew quickly.
    In March 1948, John Enders, Thomas Weller, and Frederick Robbins used human embryonic skin and muscle tissue, grown in a nutrient mix with antibiotics, to prove poliovirus could infect tissue other than nerve cells. Their confirmation meant that researchers could now grow enough poliovirus to create large quantities of vaccine.
    The three scientists won the Nobel Prize in Physiology or Medicine in 1954, the year polio vaccine had its first large clinical trial. Neither Jonas Salk nor Albert Sabin received a Nobel Prize for their work in creating vaccines.


  • I started my career as a malaria researcher, and I longed for the day that we would have an effective vaccine against this ancient and terrible disease. And today is that day, an historic day. Today, the WHO is recommending the broad use of the world’s first malaria vaccine.
  • Vaccination against destination-specific diseases plays an important role in preparing a traveler, although vaccine preventable diseases (VPDs) are rare in returning persons. While mandatory vaccinations in international travel are restricted to yellow fever, meningococcal meningitis (hajj), and rarely other vaccinations in special outbreak situations, recommendation for individual precaution by vaccination is based on data from returning travelers and from the epidemiologic situation in the visiting country. Weighing risk of vaccination against the benefit for the traveler is a prerequisite for pro/con decisions and implies de-tailed evaluation of personal risk of contracting a VPD. However, the currently licensed vaccines indicated for an international traveler are considered safe, well tolerated, and efficacious.
    • Joseph Torresi, Herwig Kollaritsch, “Recommended/Required Travel Vaccines”, in Travel Medicine (Fourth Edition), (2019)
  • Healthy young child goes to doctor, gets pumped with massive shot of many vaccines, doesn't feel good and changes - AUTISM. Many such cases!


  • Back in the 2000s, we performed a series of studies in mice and people to understand how individual bouts of exercise and exercise training affect influenza infection and vaccination, respectively. In our animal studies, we found that moderate endurance exercise (30 min/day) could protect mice from death due to influenza. Mice that exercised for longer durations (∼2.5 h/day) exhibited an increase in some illness symptoms, but there was no statistically significant difference in mortality when compared to sedentary mice. We concluded that moderate exercise could be beneficial and that prolonged exercise could be detrimental to influenza-infected mice. For obvious reasons, we have not performed this experiment in people.
    We also did a large study to determine whether 10 months of regular endurance exercise could improve influenza vaccination responses in older adults, a group that is at risk for infectious disease due to immunosenescence. We found that regular, moderate cardiovascular exercise could extend the protective effect of the annual influenza vaccination so that it maintained protective levels of antibodies throughout the entire influenza season (i.e., into March and April in the northern hemisphere). We concluded that regular moderate endurance exercise might be one way to boost the protective effect of annual influenza vaccination. It is very important for all people to receive the annual influenza vaccine.

"A Vaccine for the World”: U.S. Scientists Develop Low-Cost Shot to Inoculate Global South, Peter Hotez and Amy Goodman, Democracy Now!, January 03, 2022

(multiple formats: Video, audio, text)

  • Peter Hotez: The reason why we have this situation now with Omicron... is we allowed large unvaccinated populations in low- and middle-income countries to remain unvaccinated. Delta arose out of an unvaccinated population in India in early 2021, and Omicron out of a large unvaccinated population on the African continent later in the same year. So, these two variants of concern represent failures, failures by global leaders to work with sub-Saharan Africa, Southeast Asia and Latin America to vaccinate the Southern Hemisphere, vaccinate the Global South....
  • Myself... Dr. Bottazzi... and our team of 20 scientists... make vaccines for diseases that the pharma companies won’t make... the only thing we know how to do is make low-cost, straightforward vaccines for use in resource-poor settings.... it was very difficult to get funding. We got no support from Operation Warp Speed, no support really from the G7 countries...
  • We’ve licensed our prototype vaccine, and help in the co-development, to India, Indonesia, Bangladesh and now Botswana.... it’s really exciting to show that, you know, you don’t need to be a multinational pharmaceutical company and just make brand-new technologies that will only be suitable for the Northern Hemisphere. We can really make a vaccine for the world.
  • We invite scientists from all over the world to come into our vaccine labs to learn how to make vaccines under a quality umbrella, whereas you cannot walk into Merck or GSK or Pfizer or Moderna and say, “Show me how to make a vaccine.” With our group, we can.... the biggest frustration was never really getting that support from the G7 countries... I going on cable news networks... trying to raise meager funds just to get started... fortunately, we were able to get some funding through Texas- and New York-based philanthropies, and...we raised about...$7 million...with that, we were able to pay our scientists to actually do this, transfer the technology, no patent, no strings attached, to India, now, as I said, Indonesia, Bangladesh and Botswana... we’ve been getting calls for help all over the world from ministries of science and ministries of health, and we do what we can. We could do a lot — I mean, if we had even a fraction of the support that, say, Moderna or the other pharma companies had gotten, who knows? We might have been able to have the whole world vaccinated by now....
  • It’s even a vegan vaccine... So, now our partners in Indonesia... are trying to do this as a halal vaccine for Muslim-majority countries, which is pretty exciting, as well.
Vaccines clearly have been profitable for Pfizer and Moderna... but they can still save your life. ~ Peter Hotez
  • Amy Goodman: Two hundred thousand Americans needlessly died because they believed disinformation from the far right, you tweeted. However, vaccine hesitancy seems to span the political divide, with left-leaning parents, some refusing to vaccinate themselves or their kids. Your message to those who think vaccines are a profit-making mechanism for Big Pharma that will pollute their bodies and irreversibly alter their immune system’s natural responses?
  • Peter Hotez:...Vaccines clearly have been profitable for Pfizer and Moderna... but they can still save your life. ...And we’ve seen that of those 200,000 Americans who’ve died since June 1, we now know that 85% were unvaccinated, the other 15% split between partially vaccinated and a few full vaccinated, especially if they were immunocompromised or of extremely high age. But, overwhelmingly, it’s the unvaccinated who are losing their lives.
  • And, overwhelmingly, that is coming from an aggressive campaign of disinformation, what I call anti-science aggression, coming from the conservative news outlets, coming from the members of Congress. You talked about Congresswoman Marjorie Taylor Greene just being taken off Twitter. That’s in part because she’s been out there at the CPAC conference and elsewhere discrediting vaccines, she and her colleagues. So we have about a half a dozen members of the U.S. Congress going out of their way to discredit the safety of vaccines, even saying they’re political instruments of control, or ridiculous things like, “First they’re going to vaccinate you, and then they’re going to take away your guns and your Bibles.” And as absurd as that sounds to us, there’s a fourth of the country that actually believes it, and those are the ones who are not getting vaccinated. And we even have far-right think tanks to give these far-right groups intellectual cover, academic cover. So, this is a whole ecosystem coming from political extremism on the far right, and it’s a killer. I’ve written an article called “Anti-science kills,” because now it’s killed 200,000 Americans since last June.

"As Omicron Spreads, 100+ Firms in Africa, Asia & Latin America Can Make mRNA Vaccine If Tech Shared" (16 December 2021)

"As Omicron Spreads, 100+ Firms in Africa, Asia & Latin America Can Make mRNA Vaccine If Tech Shared", Democracy Now!, (16 December 2021) (full interview video, sound file, & transcript)

  • As the coronavirus variant Omicron spreads across the world at an unprecedented rate, a group of vaccine experts has just released a list of over 100 companies in Africa, Asia and Latin America with the potential to produce mRNA vaccine. They say it is the one of the most viable solutions to fight vaccine inequity around the world and combat the spread of coronavirus variants, including Omicron. Democracy Now!
  • The new coronavirus variant Omicron is spreading across the world at an unprecedented rate. The World Health Organization warns cases of the heavily mutated variant have been confirmed in 77 countries, and likely many others that have yet to detect it.
    With international infections climbing, the Biden administration is facing renewed demands to follow through on his now seven-month-old pledge to ensure companies waive intellectual property protections on coronavirus vaccines and share them with the world.
    Now a group of vaccine experts has just released a list of over a hundred companies in Africa, Asia and Latin America with the potential to produce mRNA vaccines to fight COVID-19. They say it’s one of the most viable solutions to fight vaccine inequity around the world and combat the spread of coronavirus variants, including Omicron. ~ (Amy Goodman)
  • The backdrop to our report is Omicron. And what Omicron means, as we still figure out how infectious it is, how severe the infection that it causes is, what we know already are a few things. We know that all existing double-dose vaccines work less well against Omicron, which means that those who’ve had two doses of a Pfizer or Moderna vaccine in the United States need a booster. What we also know is that it’s highly transmissible and that it’s inevitably going to lead to a surge in cases, regardless of how severe they are.
    What that in turn means for existing vaccine inequity, which is pretty deep — Nigeria has less than 2% of its population vaccinated as compared to countries in southern Europe, where the percentage is in the eighties — what it means is that vaccine inequity suddenly becomes worse. Why? Because everyone now needs more vaccines. ~ Achal Prabhala
  • Our report is on mRNA vaccines, because they are a remarkable technology that we haven’t yet fully understood, meaning that they are not biology-based. They don’t require cells to be grown. And it means, therefore, that they can be made faster, more easily, and, therefore, by more companies than could make the previous vaccines we used to use before 2020.
    We worked on finding companies that have the facilities and the quality standards and meet the technical requirements to make mRNA vaccines. And we found, to our astonishment, that there are at least 120 companies across Africa, Asia and Latin America who could be producing millions of doses of these vaccines, which, unfortunately, in the situation that we’re in — at a precipice — is really the only way by which we can get billions more vaccines into the world in the next three to six months. ~ Achal Prabhala
  • These vaccines were created through public money — nearly $500 million of German public money from taxpayers to BioNTech, nearly a billion dollars in money from U.S. taxpayers through the government to Moderna, several billions of dollars after that in exchange for buying back vaccines at high prices. So these are very much the people’s vaccines. It’s just that they are private property.... when the Moderna CEO says, “Oh, anyone can make the Moderna vaccine,” he’s being a bit disingenuous... It’s not really possible to do that. The way vaccines work and the way regulation around vaccines work is that they need to be made with authorization and a license. Moderna and Pfizer or BioNTech... need to authorize companies to make their vaccine... to share an instruction manual as to how to do it... The problem is... it loosens Moderna and Pfizer and BioNTech’s stranglehold on these vaccines... It undercuts the massive tens of billions of dollars of profit and revenue that they can earn off selling to poor countries in the next couple of years, once they’re done with rich countries... which is why... ~ Achal Prabhala
  • We’re asking the U.S. and German governments instead to say, “Look, in the face of this intransigence, it’s time to use emergency laws... that you can use, that you have the moral and legal power to put into effect, and end this pandemic for us and bring us out of this incredible cycle of hell. ~ Achal Prabhala

“How COVID unlocked the power of RNA vaccines” (12 January, 2021)

Elie Doglin, “How COVID unlocked the power of RNA vaccines”, Nature, 589, (12 January 2021), pp.189-191.

  • It was a Friday afternoon in March 2013 when Andy Geall got the call. Three people in China had just become infected with a new strain of avian influenza. The global head of vaccines research at Novartis, Rino Rappuoli, wanted to know whether Geall and his colleagues were ready to put their new vaccine technology to the test.
    A year earlier, Geall’s team at Novartis’s US research hub in Cambridge, Massachusetts, had packaged strings of RNA nucleotides inside of small fat droplets, known as lipid nanoparticles (LNPs), and used them to successfully vaccinate rats against a respiratory virus1. Could they now do the same for the novel flu strain? And could they do it as fast as possible?
    As Geall, head of the RNA group, recalls: “I said, ‘Yeah, sure. Just send us the sequence.’” By Monday, the team had begun synthesizing the RNA. By Wednesday, they were assembling the vaccine. By the weekend, they were testing it in cells — a week later, in mice.
    The development happened at a breakneck speed. The Novartis team had achieved in one month what typically took a year or more.
    But at the time, the ability to manufacture clinical-grade RNA was limited. Geall and his colleagues would never find out whether this vaccine, and several others that they developed, would work in people. In 2015, Novartis sold its vaccines business.
  • The idea of using RNA in vaccines has been around for nearly three decades. More streamlined than conventional approaches, the genetic technology allows researchers to fast-track many stages of vaccine research and development. The intense interest now could lead to solutions for particularly recalcitrant diseases, such as tuberculosis, HIV and malaria. And the speed at which they can be made could improve seasonal-flu vaccines.
    But future applications of the technology will run up against some challenges. The raw materials are expensive. Side effects can be troubling. And distribution currently requires a costly cold chain — the Pfizer–BioNTech COVID-19 vaccine, for example, must be stored at −70 °C. The urgency of COVID-19 is likely to speed up progress on some of those problems, but many companies might abandon the strategy once the current crisis subsides. The question remains: where will it end up?
  • Vaccines teach the body to recognize and destroy disease-causing agents. Typically, weakened pathogens or fragments of the proteins or sugars on their surfaces, known as antigens, are injected to train the immune system to recognize an invader. But RNA vaccines carry only the directions for producing these invaders’ proteins. The aim is that they can slip into a person’s cells and get them to produce the antigens, essentially turning the body into its own inoculation factory.
    The idea for RNA-based vaccination dates back to the 1990s, when researchers in France (at what is now the drug firm Sanofi Pasteur) first used RNA encoding an influenza antigen in mice. It produced a response, but the lipid delivery system that the team used proved too toxic to use in people. It would take another decade before companies looking at RNA-interference therapeutics — which rely on RNA’s ability to selectively block the production of specific proteins — discovered the LNP technologies that would make today’s COVID-19 vaccines possible.
  • In 2012, around the time that Geall and his colleagues described1 the first LNP-encapsulated RNA vaccine, the US Defense Advanced Research Projects Agency (DARPA) began funding groups at Novartis, Pfizer, AstraZeneca, Sanofi Pasteur and elsewhere to work on RNA-encoded vaccines and therapeutics. None of the big-name firms stuck with the technology, however. “They were reticent about taking on any risk with a new regulatory pathway for vaccines, even though the data looked good,” says Dan Wattendorf, a former programme manager at DARPA.
  • That was the full extent of clinical development for RNA vaccines at the beginning of 2020: only a dozen candidates had gone into people; four were swiftly abandoned after initial testing; and only one, for cytomegalovirus, had progressed to a larger, follow-on study.
    Then came the coronavirus — and with it, “there’s been this enormous spotlight”, says Kristie Bloom, a gene-therapy researcher at the University of the Witwatersrand in Johannesburg, South Africa. In the past ten months alone, at least six RNA-based COVID-19 vaccines have entered human testing. Several more are nearing the clinic.
  • [W]ith RNA vaccines making headlines, Geall and many of his former colleagues have been replaying their days at Novartis. Had the company not sold off its vaccines unit, could they have helped to stamp out Ebola or Zika outbreaks in the past decade?
    “There’s always a little bit of sadness looking back,” says Christian Mandl, former head of research and early clinical development at Novartis’s vaccines unit. But he takes solace in the success of the COVID-19 vaccines today. “I am very proud that we made a valuable contribution.”

"Vaccines and Related Biological Products Advisory Committee, 154th Meeting". FDA. Food and Drug Administration. November 8, 2018. pp. 33–46. Retrieved December 8, 2020.

  • In my group, we're also working on cellsubstrate safety. Our group has been addressing, over the years, whether there are any safety concerns with the residual cell-substrate DNA that inevitably contaminates the vaccines. And also, determining whether understanding the mechanism of tumorigenesis assists in estimating risks associated with using such cells for vaccine manufacture.
    Dr. Murata, as the new PI, he is also investigating vaccine efficacy and vaccine safety, and he has established a program in human cytomegalovirus, and is measuring antibody activities against the viral glycoproteins in serum and plasma and therapeutic immune globulins. He's also developing ways to facilitate assessment of tumorigenicity.
    • p.33-34
  • The Unit of Adventitious Agent and Cell Substrate that Andrew Lewis is principal investigator. Andrew has been studying vaccine cell substrates for many years. When it was clear, in 1998, that additional cell substrates were required for the manufacture of the next generation of vaccines, these cell substrates were either tumorigenic often or derived from human tumors. The question was, for us, how does OVRR address the presumed safety issues with using such cells while retaining the public confidence in vaccines?
    This was a big issue and our scientists and DVP have been trying to wrestle with these questions; because there was a perception -- and still to some extent is -- that using tumorigenic cells represents a risk. So, we had to deal with this if we needed to use cell substrates for the new generation of vaccines. So, the potential safety issues with cell substrates; it was, could be the presence of unknown oncogenic viruses in the cells or the residual DNA, which could be an oncogenicity or infectivity. So, studies were initiated in DVP to address these issues; and Andrew and I have been working together for quite a long time on this issue.
    • pp.38-39
  • Andrew's been working on VERO cells and MCDK cells; because VERO cells are used to produce several licensed vaccines and many vaccines in the pipeline. MDCK cells are used to isolate candidate influenza virus vaccine strains. And as we hear, that MDCK cells are also used to produce the cell produced influenza vaccine.
    So, both cell lines were derived by spontaneous immortalization. VERO cells are not tumorigenic but can become tumorigenic by passage in culture. MDCK cells are tumorigenic, at least the ones used for vaccine manufacture.
    • p.39
  • I'd like to just go back to 2000, when we discussed the VERO cells to this committee; and it was recommended to us that we should set up a program on VERO cells, to understand how these cells became tumorigenic. We, at the time, thought this is rather an ambitious recommendation, but in fact we did work on this study. I think now we have a fairly good idea how VERO cells become tumorigenic.
    But because early passages of neither cell line are not available, the Lewis lab isolated new cell lines from the African green monkey kidney and dog kidney -- the precursors of these same type of cells in the VERO and MDCK respectively -- to understand the processes that bring about, affect the spontaneous immortalization, to identify any risk factors that might be there.
    It turned out that the lines from AGMK and the canine kidney cells did become tumorigenic on passage in culture. Spontaneous immortalization is accompanied by changes in microRNA expression profiles. Whether microRNA profiles can be used as biomarkers for the acquisition of a tumorigenic phenotype is being investigated by the Lewis lab.
    • pp.40-41
  • Finally, I'll give you a little bit of an overview of what we do. Our goals/objectives are to identify potential risk factors associated with the use of novel cell substrates, particularly tumorigenic cells or cells derived from human tumors. We want to develop quantitative assays to measure risk factors, determine whether these risk factors can be mitigated, for example, by testing for their presence or removal during vaccine manufacture, et cetera. And I’ll say, this has been a sustained collaboration since about 2000 with Andrew Lewis.
    Our current projects are continuing to develop animal models to assess the DNA oncogenicity, so to assess whether cell-substrate DNA can be oncogenic. Determination of whether identifying the mechanism of neoplastic transformation can assist in estimating the risk of using such cells for vaccine manufacture. If the dangers are genetic, if they are due to epititious agents or if they are epigenetic, the risk factors can be assessed from that. For example, if the cell changes are epigenetic that causes a cell to become tumorigenic, then that represents a very minimal risk, if at all, for using those cells for vaccine manufacturers, since it's not possible to transfer those events to a recipient.
    We've also been involved in establishing of high-throughput microneutralization assays, to quantify neutralizing antibodies against human pathogenic viruses, again, using these quantitative PCR readouts. We've been looking at Ebola virus and Zika virus and plan to look at dengue and perhaps MERS and SARS down the road. With Ebola, of course, we don't use the virus, we use a VSV Ebola virus hybrid. Zika, because it's a VSL2 agent, you can use that virus. But for MERS and SARS, VSL3 agents, we're attempting to use VSV as a backbone for that as well.
    • pp.43-45
  • I'd just to finish with the outcomes of the research on DNA. In vivo assays have been developed that can detect the oncogenic activity of cellular oncogenes. Several rodents have been identified that can detect the oncogenic activity of our ras/myc plasmid at below one nanogram level. Most people think that was impossible when we started this work, but it is true; you can detect one nanogram of the activated rats and make dual plasmid.
    We use newborns of CD3 epsilon mouse, SCID mouse, p53 mice, and newborn rats. And they can all detect about one nanogram of DNA or below.
    These results have been used by DVP to estimate risks from residual DNA, and to develop recommendations to sponsors for the amounts and size of DNA. But DNA oncogenic studies have reservations. For one thing, they're unlikely to detect the oncogenic activity of an activated-dominant oncogene in cellular DNA, due to the dilution. For example, the genome size of a mammalian genome is three times ten to the ninth base pairs; an oncogene might be ten to the fourth base pairs. So, there's a huge dilution up to about a million-fold difference. So, one microgram of a plasmid would be several kilogram or so of DNA. This makes the probability of detecting very, very low. And that's in fact what we found.
    But, even if this is possible detected activated oncogene and cellular DNA, only a subset of oncogenes score positive in these assays. We've assayed several oncogenes. For example, c-Myc does not score positive in an assay by itself, but it does with rats. Importantly perhaps, human papillomavirus, E6 plus E7, do not score positive in any assay, in any animal model, that we've detected. It needs rats as a complementing oncogene. Therefore, it seems possible that not all oncogenes are going to score positive. Therefore, we've decided that perhaps the best approach is to limit the size and the amount of the residual DNA in vaccines, and that's the approach we've been taking.
    • pp.45-46

"The origins of vaccination" (28 Sept, 2020)

Alexandra Flemming, “The origins of vaccination”, Nature, (28 Sept, 2020)

  • Edward Jenner (1749–1823), a physician from Gloucestershire in England, is widely regarded as the ‘father of vaccination’ (Milestone 2). However, the origins of vaccination lie further back in time and also further afield. In fact, at the time Jenner reported his famous story about inoculating young James Phipps with cowpox and then demonstrating immunity to smallpox, the procedure of ‘variolation’ (referred to then as ‘inoculation’), by which pus is taken from a smallpox blister and introduced into a scratch in the skin of an uninfected person to confer protection, was already well established.
    Variolation had been popularized in Europe by the writer and poet Lady Mary Wortley Montagu, best known for her ‘letters from the Ottoman Empire’. As wife of the British ambassador to Turkey, she had first witnessed variolation in Constantinople in 1717, which she mentioned in her famous ‘letter to a friend’. The following year, her son was variolated in Turkey, and her daughter received variolation in England in 1721. The procedure was initially met with much resistance — so much so that the first experimental variolation in England (including subsequent smallpox challenge) was carried out on condemned prisoners, who were promised freedom if they survived (they did). Nevertheless, the procedure was not without danger and subsequent prominent English variolators devised different techniques (often kept secret) to improve variolation, before it was replaced by the much safer cowpox ‘vaccination’ as described by Jenner.
  • But how did variolation emerge in the Ottoman Empire? It turns out that at the time of Lady Montagu’s letter to her friend, variolation, or rather inoculation, was practised in a number of different places around the world. In 1714, Dr Emmanuel Timmonius, resident in Constantinople, had described the procedure of inoculation in a letter that was eventually published by the Philosophical Transactions of the Royal Society (London). He claimed that “the Circassians, Georgians, and other Asiatics” had introduced this practice “among the Turks and others at Constantinople”. His letter triggered a reply from Cotton Maher, a minister in Boston, USA, who reported that his servant Onesimus had undergone the procedure as a child in what is now southern Liberia, Africa. Moreover, two Welsh doctors, Perrot Williams and Richard Wright, reported that inoculation was well known in Wales and had been practised there since at least 1600.
    Patrick Russell, an English doctor living in Aleppo (then part of the Ottoman Empire), described his investigations into the origins of inoculation in a letter written in 1786. He had sought the help of historians and doctors, who agreed that the practice was very old but was completely missing from written records. Nevertheless, it appears that at the time, inoculation was practised independently in several parts of Europe, Africa and Asia. The use of the needle (and often pinpricks in a circular pattern) was a common feature, but some places had other techniques: for example, in Scotland, smallpox-contaminated wool (a ‘pocky thread’) was wrapped around a child’s wrist, and in other places, smallpox scabs were placed into the hand of a child in order to confer protection. Despite the different techniques used, the procedure was referred to by the same name — ‘buying the pocks’ — which implies that inoculation may have had a single origin.
  • Two places in particular have been suggested as the original ‘birthplace of inoculation’: India and China. In China, written accounts of the practice of ‘insufflation’ (blowing smallpox material into the nose) date to the mid-1500s. However, there are claims that inoculation was invented around 1000 ad by a Taoist or Buddhist monk or nun and practised as a mixture of medicine, magic and spells, covered by a taboo, so it was never written down.
    Meanwhile, in India, 18th century accounts of the practice of inoculation (using a needle) trace it back to Bengal, where it had apparently been used for many hundreds of years. There are also claims that inoculation had in fact been practised in India for thousands of years and is described in ancient Sanscrit texts, although this has been contested.

”George Washington and the First Mass Military Inoculation” (February 12, 2009)

Amy Lynn Filsinger & Raymond Dwek; ”George Washington and the First Mass Military Inoculation”, Library of Congress, (February 12, 2009)

  • Traditionally, the Battle of Saratoga is credited with tipping the revolutionary scales. Yet the health of the Continental regulars involved in battle was a product of the ambitious initiative Washington began earlier that year at Morristown, close on the heels of the victorious Battle of Princeton. Among the Continental regulars in the American Revolution, 90 percent of deaths were caused by disease, and Variola the small pox virus was the most vicious of them all. (Gabriel and Metz 1992, 107)
    On the 6th of January 1777, George Washington wrote to Dr. William Shippen Jr., ordering him to inoculate all of the forces that came through Philadelphia. He explained that: "Necessity not only authorizes but seems to require the measure, for should the disorder infect the Army . . . we should have more to dread from it, than from the Sword of the Enemy." The urgency was real. Troops were scarce and encampments had turned into nomadic hospitals of festering disease, deterring further recruitment. Both Benedict Arnold and Benjamin Franklin, after surveying the havoc wreaked by Variola in the Canadian campaign, expressed fears that the virus would be the army's ultimate downfall. (Fenn 2001, 69)
    At the time, the practice of infecting the individual with a less-deadly form of the disease was widespread throughout Europe. Most British troops were immune to Variola, giving them an enormous advantage against the vulnerable colonists. (Fenn 2001, 131) Conversely, the history of inoculation in America (beginning with the efforts of the Reverend Cotton Mather in 1720) was pocked by the fear of the contamination potential of the process. Such fears led the Continental Congress to issue a proclamation in 1776 prohibiting Surgeons of the Army to inoculate.
    Washington suspected the only available recourse was inoculation, yet contagion risks aside, he knew that a mass inoculation put the entire army in a precarious position should the British hear of his plans. Moreover, Historians estimate that less than a quarter of the Continental Army had ever had the virus; inoculating the remaining three quarters and every new recruit must have seemed daunting. Yet the high prevalence of disease among the army regulars was a significant deterrent to desperately needed recruits, and a dramatic reform was needed to allay their fears.
    Weighing the risks, on February 5th of 1777, Washington finally committed to the unpopular policy of mass inoculation by writing to inform Congress of his plan. Throughout February, Washington, with no precedent for the operation he was about to undertake, covertly communicated to his commanding officers orders to oversee mass inoculations of their troops in the model of Morristown and Philadelphia (Dr. Shippen's Hospital). At least eleven hospitals had been constructed by the year's end.
    Variola raged throughout the war, devastating the Native American population and slaves who had chosen to fight for the British in exchange for freedom. Yet the isolated infections that sprung up among Continental regulars during the southern campaign failed to incapacitate a single regiment. With few surgeons, fewer medical supplies, and no experience, Washington conducted the first mass inoculation of an army at the height of a war that immeasurably transformed the international system.

“Synthetic DNA vaccines: improved vaccine potency by electroporation and co-delivered genetic adjuvants” (Nov 4, 2013)

Seleeke Flingai, Matias Czerwonko, Jonathan Goodman, Sagar B Kudchodkar, Kar Muthumani, David B Weiner; “Synthetic DNA vaccines: improved vaccine potency by electroporation and co-delivered genetic adjuvants”, Front Immunol'. 2013 Nov 4;4:354.

  • In recent years, DNA vaccines have undergone a number of technological advancements that have incited renewed interest and heightened promise in the field. Two such improvements are the use of genetically engineered cytokine adjuvants and plasmid delivery via in vivo electroporation (EP), the latter of which has been shown to increase antigen delivery by nearly 1000-fold compared to naked DNA plasmid delivery alone. Both strategies, either separately or in combination, have been shown to augment cellular and humoral immune responses in not only mice, but also in large animal models. These promising results, coupled with recent clinical trials that have shown enhanced immune responses in humans, highlight the bright prospects for DNA vaccines to address many human diseases.
  • Prevention is the most foolproof method of medical intervention, and the vaccine is its most representative example. Since Edward Jenner’s pioneering smallpox vaccine, vaccinology has followed an irregular path to its modern day form, with alternating periods of progress and stagnation. Through advances in molecular biology, vaccinology has evolved from using basic inoculations of whole microorganisms to harnessing the power and flexibility of genetic engineering. DNA vaccination, one of the latest biotechnological breakthroughs, is the beginning of a new chapter in vaccine technology.
  • The fundamental idea behind DNA vaccines (also known as genetic vaccines) is to induce immune responses against recombinant antigens encoded by genetically engineered DNA plasmids expressed in vivo. After immunization, host cellular machinery facilitates the expression of plasmid-encoded genes, which leads to the generation of foreign antigens that can be processed and presented on both major histocompatibility complex (MHC) class I and class II molecules. These host-synthesized foreign antigens can be recognized by the immune system, inducing a complete and effective immunization.
    This novel method of vaccination was engineered in response to a series of emerging diseases that remain without proper prophylactic and therapeutic treatment. More than 50 years ago, pioneering studies carried out by Atanasiu et al. and Orth et al. showed that inoculation of mouse-derived tumor DNA induced tumors and led to seroconversion in injected mice. The work of Wolff et al. showed that DNA plasmids injected intramuscularly (i.m.) could generate long-term gene expression in vivo without the need for a special delivery system; this finding helped generate much excitement for the scientific community. Within the past decade, four successful DNA plasmid products have been licensed for animal use: one for the treatment of West Nile virus in horses, one against hematopoietic necrosis virus in salmon, one for the treatment of melanoma in dogs, and a growth hormone-releasing hormone (GHRH) gene therapy for swine. However, despite promising studies in small animal models and improved efficacy in large animal models, the clinical ability of DNA vaccines still remains unproven. While the reasons for this inconsistency have yet to be fully elucidated, several attempts have been made to enhance immunogenicity in humans, resulting in studies that have provided a wealth of constructive information that may guide research efforts toward the development of improved DNA products.
  • The seeds of DNA vaccinology were planted in the mid-twentieth century, when studies by Stasney et al., Paschkis et al., and Ito demonstrated the ability to transfer DNA to animal cells by injection of crude DNA preparations isolated from tumors. These reports and others laid the groundwork for DNA vaccines by showing that DNA injection into animals can result in the expression of the delivered genes in vivo. However, perhaps the most important aspect of these early studies was that the immune system could respond to the gene products generated by DNA inoculation. For example, Atanasiu et al. and Orth et al. purified DNA extracts from polyoma viruses and demonstrated both tumor induction and the generation of anti-polyoma antibodies in injected animals. These findings were extended in studies by Israel and colleagues, who observed that injection of recombinant purified polyoma virus DNA resulted in tumor formation and anti-polyoma antibody production. Will and coworkers also observed humoral immune responses after inoculation of recombinant purified hepatitis B viral DNA into chimpanzees.
    While many of these initial studies primarily focused on studying viral DNA biology (with humoral immunity against the inoculated gene product being of secondary importance), later studies sought to specifically study plasmid gene expression in vivo for a variety of applications. For example, Benvenisty and Reshef delivered genes encoding insulin and human growth hormone (HGH) into newborn rats, resulting in their expression in vivo. Later, studies by Jon Wolff and colleagues demonstrated long-term expression of DNA plasmids injected intramuscularly in mice. And in 1992, Tang et al. directly studied the immune response in mice elicited by DNA inoculation of foreign proteins. Using a gene gun to shoot gold particles coated with HGH-encoding DNA into mouse skin, the researchers found detectable levels of antibodies against the hormone, thus reproducing the earlier work of Israel, Atanasiu and Orth but in a more controlled manner. At the annual Cold Spring Harbor Vaccine meeting in September 1992, the laboratories of Margaret Liu (Merck), Harriet Robinson (University of Massachusetts), and David Weiner (University of Pennsylvania) independently reported that plasmid delivery into small animals could induce antibodies and cytotoxic T lymphocytes (CTLs) against influenza virus or HIV. Together, these studies were instrumental in laying the groundwork for the DNA vaccine field.
  • The main advantage of DNA vaccines is their ability to stimulate both the humoral and cellular arms of the adaptive immune system. In regards to humoral immunity, the generation of antibodies by B lymphocytes against invading pathogens is one of the most effective defenses mounted by the immune system. Vaccines that utilize live-attenuated microorganisms, killed viral particles, or recombinant viral proteins elicit the production of specific antibodies that bind superficial microbial structures on the target pathogen. Unfortunately, immunological pressure or imprecise genome replication can cause certain pathogens to accumulate mutations that reduces the effectiveness of antibodies originally generated against the pathogen. Typically, antibody responses generated by traditional vaccines target only the specific antigens found in the inoculum, and are poorly able to control similar pathogens that carry either subtle or gross changes to the antigen. Due to the ability to genetically modify the antigen encoded by DNA vaccines, the vaccine can be designed to contain the most highly conserved regions of the superficial, antibody-generating structures on a pathogen, providing a means to generate broadly neutralizing antibodies against pathogens such as HIV and the influenza virus.
    Regarding cellular immunity, CTLs eradicate infected or malignant cells upon recognition of foreign antigens in complex with MHC class I molecules on the target cell. Live-attenuated microorganisms can enter cells, and their viral proteins can be processed and directed to the MHC class I pathway for presentation upon the cell surface and the subsequent induction of CTL-mediated adaptive immunity. DNA vaccines also enter cells and produce antigen that can be processed and presented via MHC class I; however, DNA vaccines eschew the reversion risks associated with live-attenuated microorganisms.
    Another major advantage of the DNA vaccine model is its versatility. In addition to the prevention of infectious diseases, DNA vaccines may also be used to treat malignancies and autoimmune or genetic disorders. When used for cancer therapy, plasmid DNA encoding a tumor-associated antigen (TAA) can be designed to induce CTL responses against cancerous cells expressing the antigen. Concerning autoimmune disorders, DNA plasmids may encode immunomodulatory proteins that could tailor the immune response to the type and intensity needed to ameliorate conditions as common as juvenile diabetes or food allergies.
  • Vaccines as a whole have maintained a very strong safety profile. Nevertheless, live-attenuated and inactivated pathogens used in traditional vaccines carry the potential to return to virulence, which may cause pathogenic infections in vivo, particularly in immunocompromised individuals. DNA vaccines, on the other hand, do not use microorganisms and therefore avoid the risk of reversion. Additionally, frequent vaccine-induced side effects such as headache, fever, and transient pain have shown reduced rates with DNA vaccines. Investigations into the possibility of DNA vaccine plasmids integrating into the host chromosome have not shown relevant levels of integration to occur. Furthermore, preclinical and clinical studies have not detected detrimental anti-vector autoimmunity (i.e., disease-causing anti-nuclear or anti-DNA antibodies) after DNA vaccination, making it possible to administer multiple doses of DNA vaccines without triggering an immune reaction to the plasmid vector; such an immunization protocol may be particularly useful for therapeutic cancer vaccination, which relies on repeated boosting of T-cell responses to be effective. This is in contrast with viral or bacterial vectors, which often induce anti-vector immunity that prevents boosting with the same vector. Lastly, while there has been evidence of anti-DNA antibodies generated as a result of epitope spreading, these antibodies were found to be transient and, most importantly, purely innocuous in animal models.
  • Of the many advancements in DNA vaccines that have drastically improved immunogenicity, plasmid delivery via in vivo EP has proven to be one of the more impactful enhancements. EP involves the application of brief electric pulses to the vaccination site after injection of plasmid DNA. Administering EP results in the formation of transient pores in the plasma membrane of cells at the injection site, which allows macromolecules such as nucleic acids to enter the cytoplasm. While the mechanisms for plasmid delivery by EP are still incompletely understood, the procedure improves plasmid delivery by a factor of 10–1,000 fold over naked DNA delivery alone. After the cessation of the electric pulses, pore closure traps the macromolecules within the cytoplasm. Not only does EP mediate enhanced plasmid uptake, but it also increases DNA distribution throughout the tissue and causes a local inflammatory reaction, both of which contribute to a stronger immune response. Importantly, the safety profile of EP after DNA vaccination is very similar to that of DNA delivered without EP, with no increased risk of toxicity or integration of the DNA plasmid into transfected cells. The most common adverse event described in clinical trials involving DNA vaccination with EP was increased pain at the application site.
    While directly translating enhanced plasmid delivery to improved gene expression and immune responses is not without difficulty, comparison studies using reporter gene systems or immunogenicity readouts have established a strong correlation between EP delivery and augmented gene expression and immune responses. Furthermore, these improvements in DNA vaccine expression and potency can be achieved at significantly lower doses than with naked DNA delivery alone. A number of preclinical studies in small and large animal models have generated a substantial profile on the application of EP with DNA vaccination. For example, administration of the HIV DNA vaccine ADVAX was shown to increase antigen-specific CD4+ and CD8+ T-cell responses in mice when delivered by EP. Additional preclinical studies in pigs, cows, rabbits, and others have had similar positive results in their respective DNA vaccine models with EP. A recent study compared protective antibody responses in chickens given a DNA vaccine containing the hemagglutinin (HA) gene of the avian influenza H5N1 virus delivered with or without EP: of the chickens that had the vaccine delivered by EP, 100% showed complete protection (low viral load and absence of clinical symptoms and mortality), while only 20% of the chickens who received the vaccine without EP developed antibodies.
  • Because low immunogenicity has been the major deterrent toward using DNA vaccines in large animals and humans, several approaches have been investigated to increase the intensity and duration of vaccine-induced immune responses. One popular strategy has been to create vaccine cocktails, which includes the DNA vaccine along with plasmids encoding immunomodulatory proteins. Such adjuvant-encoding genes can be delivered either as separate plasmids or as additional genes encoded by the antigen-encoding plasmid. Upon vaccination, cells transfected with the adjuvant-encoding plasmid can express and secrete the molecular adjuvant into the surrounding region, affecting local APCs and cells in the draining lymph node. The end result is long-lasting, low level production of immunomodulatory cytokines that can tailor the immune response to the demands of each particular pathogen. For example, protection from certain viruses, other intracellular pathogens, or tumors may benefit from the use of cytokines that induce Th1-type immunity, such as IL-2, IL-12, IL-18, and IFNγ, which all generally promote cell-mediated immune responses. Conversely, cytokines such as IL-4 and IL-5 may be useful against extracellular pathogens while IL-10 and transforming growth factor-β (TGFβ) may prove effective in treating autoimmune disorders that arise from aberrant cell-mediated immunity. And while the role of Th17 cells during infection varies from pathogen to pathogen, evidence suggests that this cell subtype assists in the resistance to a number of bacterial and parasitic infections such as Leishmania, Pseudomonas aeruginosa (107), Mycobacterium tuberculosis, and others. Cytokines such as TGFβ and either IL-6 or IL-21 are required for Th17 differentiation and may be useful for directing a Th17-type immune response during vaccination. By raising the concentration of certain immunomodulatory proteins during the initiation or boosting of an immune response, one can selectively activate or inhibit the division of the immune system that would lead to the greatest immunological benefit.
  • The early promise of DNA vaccination had been tempered by lackluster immune responses in large animal models and humans. However, technological advances in the last decade have generated renewed interest in the improved, synthetically designed, and newly formulated DNA vaccine, especially when delivered by enhanced EP systems. Improved plasmid delivery via in vivo adaptive EP and the use of genetic adjuvants (in particular as plasmid-encoded IL-12) have proven to be powerful enhancers of DNA vaccines. Not only have these strategies improved immune responses in a variety of preclinical vaccination studies, but increasing evidence is suggesting that these approaches can also augment immune responses in humans. Given the various advantages of DNA vaccines – their ease of design, strong safety record, and stability, amongst others – the enhancements in immune responses in large animal models and humans is incredibly encouraging for the viability of DNA vaccines as a competitive vaccine platform. To carry these promising results further, additional research is needed on novel adjuvants, the timing of adjuvant administration, and the combination of genetic adjuvants and EP for optimal vaccination protocols. The prospects for treatment and prevention of human and animal disease by DNA vaccines are exciting, and the continual refinement of these technologies bode well for the present and future of this vaccine field.

“Vaccines and the Right of Conscience” (Spring 2004)

Edward J. Furton, [ “Vaccines and the Right of Conscience”, National Catholic Bioethics Quarterly in spring of 2004.

  • Let us first be clear about the seriousness of these diseases—because sometimes opponents to vaccination argue that these diseases are minor. Take rubella as an example. This disease is indeed usually mild in children, causing a rash on the face and neck that usually lasts two or three days. Teenagers and young adults may also experience swollen glands in the back of the neck and some swelling and stiffness in the joints. Most people recover quickly and without any after effects following infection. The primary danger of harm from this disease, however, is to unborn babies. A woman who contracts rubella in the early stages of pregnancy has a chance of giving birth to a deformed baby. This risk is estimated at twenty percent by the Centers for Disease Control. Defects range from deafness, blindness (atrophic eyes, cataracts, chorioretinitis), and damaged hearts to unusually small brains. Mental retardation is a possibility. Miscarriages can also occur among pregnant women who contract rubella.
    The purpose of vaccinating young children, therefore, is not simply to protect them personally from the discomfort of a fairly mild disease, but also to prevent the unborn children of pregnant women from suffering through contact with infected children. Children who are immune to rubella cannot spread it to others. A girl who attains adulthood will also be protected against contracting this disease and transmitting it to her unborn child, though it is important to realize that it can still sometimes happen that one who is properly vaccinated is infected.3 This shows that the closer society comes to universal compliance against rubella, the smaller the danger will be of an outbreak of this disease. Thanks to the efforts of primary care physicians and public health officials, rubella has been nearly eradicated in the United States. The last large-scale outbreak occurred in 1964 when almost twenty thousand babies were born with severe birth defects. This is something we all hope will never happen again.
    Thus the primary reason why we should use the rubella vaccine is to protect the unborn. The issue, in essence, is one of justice, which, as Catholic theologians have defined it, is the one virtue that is directed toward the good of others. Justice implies a type of equality among human beings, Thomas Aquinas says, and he states, by way of example, that “a man’s work is said to be just when it is related to some other by way of some kind of equality, for instance, the payment of the wage due for the service rendered.” In the present case, however, we have the equality of our common human nature, which obliges each of us to respect the right to life and health that belongs to every human being. We live in a world, of course, in which many claim that human beings are not equal by nature, but that some should be accorded greater value than others. The Catholic tradition sees this as a denial of our inherent human dignity, and if it recognizes any such distinction at all, it is that preference ought to be given to the weakest and most vulnerable among us. Those who are unborn and who are subject to the possibility of contracting a serious and debilitating disease within the womb are members of this class.
    • pp.54-55
  • Daniel A. Salmon et al., “Health Consequences of Religious and Philosophical Exemptions from Immunization Laws: Individual and Societal Risk of Measles,” Journal of the American Medical Association 282.1 (July 7, 1999): 47–53. This study indicates that as the number of exemptions to vaccination increases, the incidence of infection among those who have been properly vaccinated also increases.
    • Footnote 3, p.55

“What the World’s religions teach, applied to vaccines and immune globulins” (2013)

John D. Grabenstein, “What the World’s religions teach, applied to vaccines and immune globulins”, Vaccine, 31 (2013) 2011-2023

  • For millennia, humans have sought and found purpose, solace, values, understanding, and fellowship in religious practices. Buddhist nuns performed variolation against smallpox over 1000 years ago. Since Jenner developed vaccination against smallpox in 1796, some people have objected to and declined vaccination, citing various religious reasons. This paper reviews the scriptural, canonical basis for such interpretations, as well as passages that support immunization. Populous faith traditions are considered, including Hinduism, Buddhism, Jainism, Judaism, Christianity, and Islam. Subjects of concern such as blood components, pharmaceutical excipients of porcine or bovine origin, rubella strain RA 27/3, and cell-culture media with remote fetal origins are evaluated against the religious concerns identified.
    The review identified more than 60 reports or evaluations of vaccine-preventable infectious-disease outbreaks that occurred within religious communities or that spread from them to broader communities. In multiple cases, ostensibly religious reasons to decline immunization actually reflected concerns about vaccine safety or personal beliefs among a social network of people organized around a faith community, rather than theologically based objections per se. Themes favoring vaccine acceptance included transformation of vaccine excipients from their starting material, extensive dilution of components of concern, the medicinal purpose of immunization (in contrast to diet), and lack of alternatives. Other important features included imperatives to preserve health and duty to community (e.g., parent to child, among neighbors). Concern that ‘the body is a temple not to be defiled’ is contrasted with other teaching and quality-control requirements in manufacturing vaccines and immune globulins.
    • p.2011
  • Religious concerns about immunization have a long history, reaching back to those who rejected Edward Jenner’s 1796 mode of smallpox vaccination as contrary to God’s will. In the United Kingdom, the Anti-Vaccination League formed in 1853 in London to oppose compulsory vaccination acts. Similar events occurred in the Netherlands and elsewhere. In the United States, several Boston clergymen and devout physicians formed the Antivaccination Society in 1879. In contemporary cases, such objections involve blood products, porcine or bovine pharmaceutical excipients, or the remote fetal origins of cell-culture media and rubella strain RA27/3. In contrast, it is also worth remembering that some of the earliest descriptions of variolation to prevent smallpox involved the proponency of Buddhist religious women.
    • p.2012
  • Numerous examples of vaccine-preventable outbreaks among religious schools, congregations, and communities illustrate how clusters of vulnerable people can enable epidemics, even spreading beyond those foci to neighboring, well-immunized communities. Published examples include diphtheria, Haemophilus influenzae type b, hepatitis A, measles, mumps, pertussis, poliomyelitis, and rubella. Tetanus cases have also resulted. These infections occurred in multiple countries (including transmission across borders and oceans) and among a range of cultural traditions and socioeconomic situations, leading directly to hospitalizations, disabilities, and deaths.
    In several analyses, the risk of measles or pertussis was 6–35 times higher among people claiming exemption to immunization, compared with the general population. This elevated risk applies regardless of the faith tradition involved. The infectious risk has nothing to do with religious denomination or righteousness of the objection. To paraphrase the Book of Genesis (chapter 4, verse 9), vaccine recipients are their brother’s keepers, as contributors to herd protection.
    • p.2012
  • Vaccines did not exist when the Torah, Bible, Qur’an, ¯ or major Sanskrit texts were originally written. Subsequent interpretations are fundamental to how contemporary believers approach immunization.
    • p.2012
  • Respectful consideration of religious beliefs within a clinical setting is important because medicine and religion come together to frame and enlighten choices made by patients as well as health professionals. Scientists and clinicians confront moral and ethical choices daily and often observe a religious faith that helps guide their own personal conduct. Indeed, the religious beliefs of countless historical and contemporary researchers and clinicians have been a source of motivation to help relieve human suffering by means of immunization.
    • p.2012
  • This review did not identify any canonical doctrine that has led to religious objection to vaccines or immune globulins for Bahá’í Faith, Confucianism, Daoism, Shinto, or Sikhism. Most ostensible objections to immunization attributable to religious belief fell into three categories: (a) violation of prohibitions against taking life, (b) violation of dietary laws, or (c) interference with natural order by not letting events take their course. Each is addressed further below.
    • p.2013
  • Observant Hindus who do eat meat often abstain from beef. The cow in Hindu society is traditionally identified as a caretaking and maternal figure. Verses of the Rig-Veda refer to the cow as devi (goddess), but Hindus do not worship cows, but rather venerate (deeply respect) them. This review did not identify contemporary Hindu concerns with trace bovine components of some vaccines.
    • p.2013
  • This review did not identify contemporary Buddhist concerns with trace bovine components of some vaccines.
    Buddhism does not oppose treatment of an existing illness by use of non-animal derived medicines, because treatment is an act of mercy. Antibiotics kill microorganisms, yet antibiotics are accepted because they help people get closer to reaching Enlightenment. Serious diseases separate the body from the mind. Preventing disease means preventing disharmony within the body. The Nepalese Lama Zöpa Rinpoche describes a prayer of the Healing Buddha, to prevent diseases not yet experienced [99]. He also describes Logyönma (or Loma Gyönma), “a female healing buddha in leaf-wearing aspect,” known as an opponent to epidemic diseases.
    The first written account of variolation describes a Buddhist nun (bhikkhuni) practicing around 1022–1063 CE. She ground scabs taken from a person infected with smallpox (variola) into a powder, and then blew it into the nostrils of a non-immune person to induce immunity. Continuing this tradition, the 14th Dalai Lama participated in poliovirus immunization programs personally.
    Jains may drink boiled water, cook food, use paper or soap, and take necessary antibiotics, but perhaps with some regret. When considering vaccination, Jains may benefit from an explanation of the seriousness of the diseases to be prevented, to explain the rationale for killing microorganisms in the course of vaccine production. Jains agree with Hindus that violence in self-defense can be justified.
    • p.2013-2014
  • Judaism traditionally expects certain actions of its believers to maintain health. Pikuakh nefesh, acting to save one’s own or another’s life, is a primary value, a positive commandment (mitzvah aseh). Judaic principles emphasize the community benefits of disease prevention in a manner superior to individual preference, based on scriptures such as Leviticus 19:16 (Table 1C) that counsel not to stand idly by while a neighbor is in trouble. Jewish scholars applied this directive to encourage smallpox vaccination in previous eras. Rabbi and physician Mosheh ben Maimon (also called Maimonides or Rambam) expounded: “Anyone who is able to save a life, but fails to do so, violates ‘You shall not stand idly by the blood of your neighbor”’. Indeed, in settings where vaccination services were intermittently available, several scholars stated it is permissible to set aside Sabbath restrictions on activity to allow vaccination. Similarly, there are exemptions from fasting if one is ill.
    Parental responsibilities are detailed in a number of Jewish texts, based in Proverbs 23:12–13 (Table 1C). The Talmud has long encouraged parents to teach their children to swim, as a means of preventing drowning in some unknown, but foreseeable scenario. Scholars have taken this as a metaphor for vaccination against a future infection. Maimonides wrote about prevention: “One must avoid those things which have a deleterious effect on the body, and accustom oneself to things which heal and fortify it”.
    Another metaphor related to community responsibility is elevated to the status of a paradigm: the admonition to erect a railing around one’s roof, when it was often used as a porch, to prevent harm to others who may later walk there from an anticipatable hazard (Deuteronomy 22:8, Table 1C). This paradigm has been applied as a proactive call for communal protection: vaccinating oneself and one’s family to reduce the risk of transmission of infectious diseases to neighbors and bystanders.
    • p.2014
  • In distinction to dietary laws, Jewish medical issues are judged based on concepts of medical law contained in halachic codes. The propriety of using vaccines or immune globulins within Judaism would be evaluated from a therapeutic or disease-prevention perspective. Multiple Jewish authorities agree that limitations on medications with porcine components are only an issue with oral administration (for those who observe kosher rules), not products given by injection. Thus, the teachings to avoid pork products do not apply to injectable medications, in contrast to foodstuffs.
    Permissibility of oral administration of medications with non kosher ingredients, if necessary to preserve life, is provided in the Talmud. In the case of oral medications, the transformation (ponim chadashos) of “primary” pork components into processed materials would make them more acceptable. Oral medication containing small amounts of material derived from non-kosher animals devoid of its taste could be kosher under some circumstances. According to a principle known as bitul b‘shishim, a small amount of non-kosher food mixed with a much greater quantity of kosher food may be acceptable if the non-kosher item loses its taste or is diluted beyond a 1:60 ratio. Additional conditions (e.g., intention, gentile source) need to be considered before this ruling can be made.
    • p.2014
  • Rabbi Abraham Nanzig, writing in London in 1785 in the era of smallpox outbreaks, described the halachic basis for exposing a child to variola virus (variolation) to induce immunity against smallpox: “One who undergoes this treatment while still healthy, God will not consider it a sin. Rather, it is an act of eager religious devotion, and reflects the Commandment to ‘be particularly careful of your well-being”’(Deuteronomy 4:15, Table 1C). In the 1850s, distinguished Rabbi Yisroel Lipshutz described Edward Jenner as a “righteous gentile,” for his efforts in developing smallpox vaccination.
    Jewish communities (often ultraorthodox, those who adhere meticulously to Jewish law and tend to be more isolated from others) in several countries have experienced measles and mumps outbreaks associated with declining vaccination. The transnational social networks between such communities have allowed outbreaks to spread from one country to another. Based on this review, contemporary Jewish vaccine decliners are more likely to cite concerns about vaccine safety than to invoke a specific religious doctrine that has not been considered by acknowledged Jewish scholars. Those scholars have rejected arguments that medical interventions interfere with divine providence.
    The orthodox Hasidic Jews who constitute most of the residents of the village of Kiryas Joelin Orange County, New York, volunteered for several pivotal vaccine trials. These included trials for hepatitis A vaccine and mumps vaccine.
    • p.2014
  • Most Christian denominations have no scriptural or canonical objection to use of vaccines or immune globulins per se, based on this review (Table 1C and D). These include Roman Catholicism, Eastern Orthodox and Oriental Orthodox Churches, Amish, Anglican, Baptist, the Church of Jesus Christ of Latter-day Saints (LDS), Congregational, Episcopalian, Lutheran, Methodist (including African Methodist Episcopal), Pentecostal, Presbyterian, and Seventh-Day Adventist Church.
    Exceptions appear in following sections. Roman Catholicism and some other Christian denominations have expressed concern about the aborted fetal origins of the principal formulation of rubella vaccine and some cell lines used to manufacture certain types of viral vaccines, discussed in later sections. The second half of Table 1D provides scriptural passages interpreted by a minority as contrary to vaccination.
    Within a Christian creation-fall-redemption-restoration framework, immunization advocacy can form a basis for Christian service to humanity. This is consistent with themes of being one’s brother’s keeper (Genesis 4:9, Table 1C), loving your neighbor as yourself (James 2:8, Table 1D), and acting kindly to strangers, as did the good Samaritan (Luke 10:33–35, Table 1D).
    • p.2015
  • The Amish, sometimes called old-order Amish or Amish Mennonites, are a group of Christian fellowships among Mennonite churches. Amish fellowships began with a schism within a group of Anabaptists in Switzerland in 1693 CE. Related groups in Canada and the northern US are known as Hutterites.
    Immunization is not prohibited by Amish or Hutterite religious doctrine, but vaccine acceptance varies from district to district. Districts that typically decline immunization reflect a social tradition within these religious communities, related to modernity, more than a theological objection. Low immunization rates in Amish communities have been attributed variously to limited access to care, limited disease understanding, higher priority to other activities, and concerns about vaccine safety, with variability among various communities. They tend to define illness in terms of failure to function in a work role, more than in terms of symptoms. Within Amish and related communities, multiple Haemophilus influenzae type b, measles, pertussis, poliomyelitis, rubella, and tetanus cases and outbreaks have been reported. District leaders have been more accepting of immunization at times of local outbreaks
    • p.2015
  • Spiritual healing of disease is a central tenet for members of the First Church of Christ, Scientist, founded in 1879 CE in Boston by Mary Baker Eddy. Christian Scientists frequently decline some or all medical help for disease. Individual believers often forego immunization, and church members have lobbied governments for religious exemptions from immunization.
    Eddy called believers to unmask the devil’s lies, one manifestation of which is disease. Disease, in this construct, is not fundamentally real, but rather something that can be dispelled, to reveal the perfection of God’s creation. “Sickness is part of the error which Truth casts out”. From this arose the Christian Science principle that disease is cured or prevented by prayer that affirms human perfection as God’s child and denies the reality of disease. This principle is featured in Eddy’s canon, Science and Health with Key to the Scriptures. Christian Science “practitioners” (who do not practice medicine) aid believers in focused prayer.
    • p.2015
  • In a 1901 interview with the New York Herald, Eddy said: “At a time of contagious disease, Christian Scientists endeavor to rise in consciousness to the true sense of the omnipotence of Life, Truth, and Love, and this great fact in Christian Science realized will stop a contagion.” Later, she said: “Rather than quarrel over vaccination, I recommend, if the law demand, that an individual submit to this process, that he obey the law, and then appeal to the gospel to save him from bad physical results”.
    Outbreaks of diphtheria, measles, and poliomyelitis have been reported among followers of Christian Science, including repeat measles outbreaks at Principia College and affiliated K-12 schools between 1985 and 1994. Three measles deaths and hundreds of cases occurred during those outbreaks. The Church has a policy for members to report communicable diseases to health authorities, but members have limited ability to do so. First, their practitioners and nurses are not trained in disease recognition. Second, members are taught that disease is healed by convincing oneself of its unreality. As a result, several outbreaks have been recognized only after many people were infected. In such cases, Christian Science parents were more willing to accept immunization after outbreaks were recognized by health authorities.
    • p.2015
  • Members of certain traditional reformed (bevindelijk gereformeerden) Christian denominations in the Netherlands, founded in the 1570s CE, have a tradition of declining immunization that dates back to concerns about adverse events after smallpox vaccination from 1823 onward. These communities were the epicenters of paralytic poliomyelitis, measles, congenital rubella syndrome, and mumps outbreaks between 1971 and 2008.
    Members of these denominations have familial and cultural ties to associated Christian communities in other countries (e.g., Canada, United States), where immunization rates may also be low. These ties have resulted in international transmission of vaccine-preventable diseases (e.g., measles, poliomyelitis, rubella) with multiple outbreaks in locations otherwise free of circulating disease.
    The contemporary basis for the objection of some members of these churches includes choosing to forego immunization rather than making a person less dependent on God. For a subset, avoiding interference with divine providence before infection may be paramount; another subset described immunization as a gift from God to be used with gratitude. Arguments against immunization have been refuted by other members of the traditional reformed community, for example by pointing out that using agricultural practices or raising dikes, to prevent flooding, could also be construed as contrary to divine intent, yet are common practices. Recent increases in immunization rates in Dutch communities suggest that objections to immunization may be declining.
    • p.2015
  • The Jehovah’s Witnesses is a Christian denomination tracing its roots to the late 1870s CE. The Watch Tower Bible and Tract Society is its organizing body. Since 1945, the Watch Tower Society has instructed its followers to refuse transfusions of whole blood and certain blood components (e.g., red blood cells, white blood cells, platelets, whole plasma), which they consider a violation of God’s law. This interpretation derives from several scriptural passages (Table 1E). Their blood doctrine has undergone multiple changes since 1945, principally in 1978, 2000, and 2004.
    By abstaining from blood,Witnesses express their faith that only the shed blood of Jesus can redeem them and save their life. In this view, those who respect life as a gift from God do not try to sustain life by taking in blood, even in an emergency. While albumin, antimicrobial immune globulins, Rho(D) immune globulin, and coagulation factors VIII and IX have been declared acceptable to believers since 1978, Witnesses today are taught that the use of various blood fractions are “not absolutely prohibited” and are a matter of personal choice. More recently permissible products include those derived from white blood cells (e.g., interferons, interleukins), cryoprecipitate, cryosupernatant, erythropoietin, and preparations derived from hemoglobin. It is unclear what proportion of Jehovah’s Witnesses offered such therapeutic products accept them.
    • pp.2015-2016
  • The Watch Tower Society denounced vaccination from the 1920s through the 1940s, citing scriptural passages such as those in Table 1E.
    The group banned their members from vaccination around this time, under penalty of excommunication. The Society revised this doctrine in the December 15, 1952, issue of The Watchtower, saying that those passages did not apply to vaccination. In 1961, the Society took a neutral stand, neither endorsing nor prohibiting vaccination. In the 1990s, Awake! magazine began acknowledging the clinical value of vaccination. A contemporary Watchtower web page acknowledges the efficacy of vaccination in preventing hepatitis A and hepatitis B.
    • p.2016
  • In addition to discussion above, several small Christian denominations or churches hold core beliefs that focus on healing through faith alone (Table 1D), with active avoidance of medical care (e.g., Faith Tabernacle, Church of the First Born, Faith Assembly, End Time Ministries). Several vaccine-preventable outbreaks (and associated deaths) involved faith healing to the exclusion or neglect of immunization or treatment after infection. These outbreaks involved both adults who choose not to have themselves immunized and parents who withheld routine vaccines from their children.
    • p.2016
  • According to the Qur’an, ¯ a person is not guilty of sin in a situation where the lack of a halal alternative creates an undesired necessity to consume that which is otherwise haram (Qur’an¯ 2:173). This is the basis for the “law of necessity” in Islamic jurisprudence: “That which is necessarymakes the forbidden permissible” in exceptional circumstances (Table 1F).
    • p.2016
  • Opposition to immunization programs among selected Muslim communities has occurred during poliovirus immunization programs in Nigeria, Pakistan, and Afghanistan. The opposition within northern Nigeria, notably in the state of Kano, was particularly long-lasting and an impediment to the global eradication effort. Detailed consideration of the Nigerian situation revealed that what was described as ostensibly religious objections and assertions that vaccines spread the HIVvirus or were vehicles for sterilization programs masked deeper struggles related to political power, inadequate health services, and a controversial clinical trial of an investigational antibiotic. While the boycott was centered within Islamic social networks, most of the objections raised related to social issues, rather than theological issues. Eventually, the Nigerian government sent religious representatives to South Africa, Indonesia, and India to observe quality-control tests of poliovirus vaccines to be used in their areas and then sourced the vaccine from manufacturers they trusted.
    In contrast, multiple imams and other Islamic leaders issued clear statements and fatwas describing how immunization is consistent with Islamic principles. In the Nigerian case, engagement of the Organization of the Islamic Conference (including 17 African countries) and the 15th annual conference of the International Fiqh Council (a global forum of Islamic lawyers, scholars and philosophers to address the practice of Islam in contemporary life) provided assurances to Nigerian leaders.
    • p.2016
  • Earlier, in 1995, the Islamic Organization for Medical Sciences, a well-regarded set of 112 jurisprudents and medical experts conducted a seminar in Kuwait on “The judicially prohibited and impure substances in foodstuff and drugs”. Participants included themuftis (experts inIslamic law) of Egypt, Tunisia, Oman, and Lebanon, the secretary general of the Islamic Fiqh Academy in Jeddah, and many other accomplished Islamic scholars. Citing the accepted principle of transformation (fundamental change, as from wine to vinegar) within Islam, they concluded that “The Gelatin formed as a result of the transformation of the bones, skin, and tendons of a judicially impure animal is pure, and it is judicially permissible to eat it” (see also Section 3.2.4). The full document also addressed issues related to medication capsules, alcohol, pig fat, and porcine insulin.
    Omar Kasule, professor of Islamic medicine at the Institute of Medicine University of Brunei Darussalam noted that polio immunization is obligatory (wajib) when disease risk is high and the vaccine shown to have benefits far outweighing its risks. Muslims will be interested in issues of vaccine safety, Professor Kasule explained, because immunization to prevent disease should not lead to side effects of the same magnitude as the disease. He based this judgment on the purpose of the law to protect life, the principle of preventing harm (izalat aldharar), and the principle of the public interest (maslahat al-ummah). He noted that the Qur’an¯ uses the concept of wiqaya in multiple situations to refer to taking preventive action (e.g., against hell-fire, punishment, greed, bad acts, harm, heat) and concludes that prevention is one of the laws of Allah, ¯ with obvious application to medicine.
    • p.2016
  • Muslims may apply additional scrutiny to vaccines required for pilgrims to the annual Hajj in Mecca, when purity takes on extra significance. Another guiding principle comes from the prophetic statement of Muhammad: “God has not made things that are unlawful for you to consume to be your medicine”
    • pp.2016-2017
  • The Nation of Islam is a US-based movement that aims to improve the condition of African-Americans in the US. Its religious practices have some similarities and some differences, compared with traditional Islam. In 1997, the minister of health of the Nation of Islam advised believers to avoid all immunizations, based on concern about viral contamination with pathogens that cause “AIDS, Ebola, Hanta, Chronic Fatigue Syndrome, Gulf-War Syndrome, ‘mad cow’ disease, etc.”. No objective evidence to substantiate these claims has been offered. That statement was framed as “until further notice,” although it no longer appears on the Nation of Islam website. The basis was rooted in safety and distrust-of-government concerns, rather than theological grounds.
    • p.2017
  • Bacteria, viruses, cell substrates The Hindu, Buddhist, and Jain religions have long prioritized respecting all forms of life, in the form of ahimsa. The Jains in particular extend this respect even to the bacteria or viruses contained in a vaccine, as well as the culture-media cells used to grow viruses or produce recombinant proteins.
    • p.2017
  • Unlike bacteria, viruses do not replicate on their own. To make viral vaccines, large numbers of viruses must be grown in cell cultures specific to each virus. Some licensed viral vaccines (i.e., some formulations of hepatitis A, poliovirus, rabies, rubella, and varicellazoster viruses or combination vaccines containing such component viruses) are produced by growing viruses that infect humans in WI-38 or MRC-5 cell cultures. WI-38 and MRC-5 represent two commonly used lineages of human diploid cell cultures, batches of immature cells with twice as many chromosomes as sperm or egg cells. Embryonic diploid cells are valuable in vaccine manufacture, because each aliquot of these cells can propagate several dozen times before senescence.
    Each of these cell lines started with cells harvested from a deliberately aborted fetus. The cell lines are used to grow the viruses, then discarded and not included in vaccine formulations. These cell lines cannot form a human being.
    TheWI-38 line was developed attheWistar Institute in Philadelphia in 1961, with lung cells from a female fetus of 3 months gestation aborted in Sweden, whose parents felt they had too many children. Similarly, British scientists funded by the Medical Research Council developed the MRC-5 line in September 1966 with fetal lung fibroblasts “taken from a 14-weekold male fetus removed for psychiatric reasons from a 27-year-old woman. . .”. These cell lines, still in use today, gradually replaced primary cultures of monkey, duck, rabbit, chicken, dog, or mouse tissue, an approach vulnerable to contamination with viruses and bacteria.
    • p.2017
  • Vaccine manufacturers have few options for viral culture media, for reasons of microbiology and safety. It is not possible to simply replace one cell line with another, because various viruses grow abundantly only in some kinds of cell lines. WI-38 and MRC-5 lines are well described and understood, with experience accumulated via hundreds of millions of vaccinations, important for safety-assessment reasons. The fetal origins of WI-38 and MRC-5 cell lines pose an ethical or moral problem for people who disapprove of abortion. Critically, the two abortions were not conducted for the purpose of harvesting the cells that were transformed into these cell lines. This lack of intention is a key element in breaking the complicity link that could otherwise make use of the vaccines unacceptable. No additional abortions are needed to sustain vaccine manufacture. The cell lines are not the final product, and no human cells are present in the final vaccine formulations.
    • p.2017
  • In the late 1990s—early 2000s, teams of ethicists at the National Catholic Bioethics Center and then at the Vatican’s Pontifical Academy for Life and elsewhere considered the virology, epidemiology, and theology of the matter in detail. Their considerations included both cooperation with evil and the principle of double effect. In this case, the cooperation related to those involved with the specific abortions in the 1960s. The principle of double effect applied insofar as using implicated vaccines today could appear to endorse or acquiesce to the acceptability of additional abortions in our current time. These teams concluded that the association between implicated vaccines and abortion was noncomplicit, and that using these vaccines is not contrary to a principled opposition to abortion. These centers reasoned that, because the abortions that enabled the production of these vaccines are in the past and (critically) the abortions were not undertaken with the intent of producing the cell lines, being immunized does not involve any sharing in immoral intention or action of others. In short, they are morally separate actions. In 2008, this position was elevated to the status of official Roman Catholic teaching.
    The bioethicist teams agreed that use of a vaccine in the present does not involve sharing in the action of those who carried out the abortion in the past. Further,they foundthatparents have a moral obligation to provide for the life and health of their children by means of immunization. The situation with vaccines differs morally from ongoing harvest of fetal tissue for pharmaceutical manufacturing or research, which could be used to justify future abortions.
    Still, these ethicists concluded that alternate vaccines should be used if available. They also recommended that parents and clinicians should speak out against abortion by asking governments and vaccine manufacturers to stop using cell lines that have links to aborted fetuses.
    • p.2017
  • In 1964, the Wistar Institute developed the RA 27/3 strain of rubella virus. The rubella virus isolate “was recovered from the explanted [kidney] tissue of a fetus obtained at therapeutic abortion from a mother who had been infected with rubella virus”. The scientific literature of that era indicates that the abortion was not conducted with the motive of isolating the virus, but rather because the mother was infected with rubella virus and risked major birth defects. After the RA 27/3 strain was isolated, it has been propagated serially in human diploid cells. The RA 27/3 strain produced superior antibody responses and was better tolerated, compared with other rubella vaccine strains available in the 1960s. No further abortions are necessary to sustain the manufacture of additional batches of rubella RA 27/3-strain vaccine.
    Use of the RA 27/3 rubella virus strain was also considered by the National Catholic Bioethics Center and the Pontifical Academy for Life. Using the same logic, they reasoned that because the one abortion that yielded the viral isolate was not undertaken with the intent to retrieve the virus and because no additional abortions are needed to obtain more virus, being immunized is morally acceptable and also associated with parental duty. The same provisions for preferring alternatives and petitioning governments and manufacturers also apply.
    Some find it meaningful that rubella vaccination prevents many cases of fetal death and congenital rubella syndrome that would otherwise occur if women were infected with rubella virus during pregnancy. Immunized women exposed to the virus during pregnancy are no longer confronted with the question (what some religions might consider temptation) of whether to terminate their pregnancies on that basis.
    • pp.2017-2018
  • All vaccines require the use of excipients (inactive ingredients) in manufacturing. Some of these products, such as hydrolyzed gelatin or trypsin, may have a porcine (pork) origin. Hydrolyzed gelatin is a mixture of peptides and proteins produced by partial hydrolysis of collagen (connecting fibers and tissues) typically extracted from skin, bones, or other components, most often from pigs or cattle.
    Hydrolyzed refers here to the process of breaking down collagen molecules into chains of amino acids (polypeptides) by acidic or alkaline treatment, followed by purification. Gelatin hydrolysates are added to some vaccine formulations to help stabilize and preserve active ingredients during freeze-drying and storage; hydrolyzed gelatin may also act as a solvent.
    The enzyme trypsin may be used in producing some viral vaccines, to resuspend cells adhering to the cell-culture dish wall during the process of harvesting cells. Trypsin typically is removed from the product physically before further processing. Like hydrolyzed gelatin, trypsin is often derived from porcine or bovine sources.
    Some Jews, Muslims, and others have expressed concern about porcine-origin components, derived from faith-based concerns about consumption of pork in their diet, despite the injectable nature of most vaccines. Injectable medications are not subject to kosher rules. Permissibility of oral administration of medications with such ingredients, if necessary to preserve life, is described in earlier sections. Scholars of Judaism and Islam have issued various rulings or waivers that allow use of such vaccines, for several reasons:
    (1) the components of concern (e.g., hydrolyzed gelatin) have been sufficiently transformed from original pork origins,
    (2) the minute quantities per dose administered (e.g., hydrolyzed gelatin, trypsin) invoke exceptions based on dilution, or
    (3) the vaccine is intended for important medicinal purposes and not a matter of ingestion, to which dietary rules apply.
    Other important considerations include the necessity of the product to save life and the lack of alternatives. Different scholars may evaluate and weigh these criteria differently.
    • p.2018
  • For Muslims, Shar¯ı‘a¯ law includes the principle of transformation (istihaalah) in which unclean products can be made clean by extensive processing, transforming the original product into something new (e.g.,fromwine to vinegar). Under certain circumstances, this can make it permissible for observant Muslims to receive vaccines, even ifthe vaccines contain porcine excipients. This principle of transformation was invoked by the 1995 conference convened by the Islamic Organization for Medical Sciences. The scholars explicitly concluded that transformation of pork products into gelatin alters them sufficiently to make it permissible for observant Muslims to receive vaccines containing porcine gelatin and certain other medicines, including those formulated in gelatin capsules. Even so, alternative products without components of concern may be preferred, if available.
    In 2003, the European Council of Fatwa and Research issued a fatwafinding the permissibility of using oral poliovirus vaccine produced with porcine-origin trypsin. Their decision centered on lack of similarity between pork and purified trypsin, physical removal during processing, dilution of any residual, necessity, and lack of alternative.
    • p.2018
  • Many religions traditionally have been proponents of sexual propriety. This review identifiedseveral objections tohepatitis B immunization or to human papillomavirus (HPV) immunization, centered on the sexual route of exposure that can be associated with the corresponding pathogens. These objections to immunization were not theologically based per se, but rather arose indirectly as religious beliefs (usually of parents) affected views of acceptable sexual practices or timing. In the case of hepatitis B virus (HBV), sexual activity is only one of many risk factors for infection, including mother-to-child transmission. For HPV, several studies have shown that immunization does not increase or accelerate a woman’s likelihood of sexual behavior. The proportion of never-married teenaged females in the US who had been sexually active at least once fell from 51% in 1988 to 43% in 2006–10. With both HBV and HPV, a person could forego the vaccines, lead a life fully compliant with religious belief, and still be infected. Many religions have rites that allow for atonement or forgiveness of sins, but the many diseases caused by HBV and HPV (including multiple cancers) remain among the most difficult infectious diseases to attempt to cure.
    • p.2018
  • This review is intended to explain pivotal aspects of religious teaching that have been applied for and against the acceptability of vaccines and immune globulins. As various examples described above show, the scriptural, canonical passages cited here are not interpreted uniformly by each believer within a faith tradition. The multiple sects, denominations, and branches within each of the major religions demonstrates the multiple ways various passages have been applied.
    This review identified multiple religious doctrines or imperatives that call for preservation of life, caring for others, and duty to community (e.g., parent to child, neighbors to each other). Even in cases where vaccine components could be objectionable, this review found several themes favoring vaccine acceptance, including transformation of components of concern from their starting material, extensive dilution of such components, the medical purpose of immunization (in contrast to diet), and lack of alternatives (see Table 2).
    This review revealed few canonical bases for declining immunization, with Christian Scientists a notable exception. Along these lines, it would seem that the instances of personal objections that are properly theological in nature (defined here as systematic and rational exploration of the nature of God) are relatively few, and that the preponderance might more accurately be defined as philosophical (i.e., a more general consideration of existence and reason) or simply personal choice. For several religious groups, declination of immunization is more traditional or social than an essential religious precept. The bulk of the objections identified in the searches for this review reflected concerns about vaccine safety, not matters of theology, as did an analysis of exemptions for school-aged children. For Christian Scientists who believe “Man is incapable of sin, sickness, and death”, vaccines would be superfluous.
    • p.2019
  • Clinicians counseling people reluctant to be immunized may wish to probe for understanding of vaccine contents and provide factual information. From a Netherlands perspective, Ruijs et al. suggest discussing vaccine decision-making processes (e.g., criteria used, consequences), rather than medical information or an authoritarian stance. Collaboration between public-health leaders and (religious) community leaders historically has helped resolve objections and enabled immunization programs to continue. Religious communities are a powerful social force, as shown in this review and in other studies.
    The accumulation of susceptibles within a community creates vulnerability to infection. A community can afford to have a small number of conscientious objectors to immunization. But each unimmunized person adds to the vulnerability of the group.If geographic clusters within a city neighborhood, among preschoolers, or within a suburb, a rural town, an island, a parish, or some other focal area are immunized at only 60% or 80% levels, herd protection does not occur and outbreaks can develop. An increasing collection of vulnerable people is like an increasing collection of kindling wood. Introduce a spark and fire can spring forth. One contagious person among a cluster of vulnerable people can ignite an outbreak involving many, including those unable to respond to vaccination.
    One of the limitations of this review is that information about beliefs of less populous religions or denominations were not explicitly sought. On the other hand, the many searches and traces through reference lists frequently led to documents describing other religious traditions or denominations. None of those documents featured a canonical objection to immunization not already described above. But review of the medical literature identified multiple outbreaks of vaccine-preventable diseases among them.
    Outbreaks rooted in personal or philosophical beliefs are not referenced here, but are numerous. The outbreak reports cited in this review are likely not an exhaustive list of all religious-centered outbreaks, for several reasons: Some publications may not have been identified (especially those not written in English or relevantly coded in PubMed), some publications about outbreaks related to personal-belief exemptions may not have specified a religious basis for those beliefs, and some relevant outbreaks (or individual cases) may not have been published.
    • p.2019
  • One element of acceptability for some believers is whether vaccines of concern have any alternatives. Alternatives can be determined by comparing ingredients and culture media described in product prescribing information. Contrary to several web pages, measles vaccine is not a prophylactic alternative to measles-mumps-rubella (MMR) vaccine, insofar as selecting measles vaccine alone would be a decision to reject protection against mumps and rubella. Manufacturers attentive to global acceptability will endeavor to replace or avoid components of concern whenever possible.
    If we are to serve our patients’ needs in all their humanity, we should help them gain access to reasoned ethical and theological considerations of clinical issues.When dealing with vaccines, the implications of a personal infectiousdisease decision reach beyond the self, to affect neighbors . My decision to immunize or not immunize my family members changes the likelihood that you or your family will contract a contagious disease, and vice versa.
    • p.2019-2020

“Cultural Perspectives on Vaccination” (Last update 10 January 2018), “Cultural Perspectives on Vaccination”, (Last update 10 January 2018)

  • Individual versus public health priorities were first argued in the U.S. Supreme Court more than 100 years ago. In Jacobson versus Massachusetts, a Cambridge resident refused to be vaccinated for smallpox, because he believed the law violated his right to care for his own body how he knew best. The Court rejected Jacobson’s challenge. This seminal 1905 ruling has served as the foundation for state actions to limit individual liberties to protect the public’s health.[3]
    The tension exists because public health regulations aim to protect as many people as possible, but sometimes they privilege group needs over individual preferences. In the case of vaccination, mandates sacrifice individual autonomy to protect communities from disease. Unvaccinated individuals pose risks to children or people with medical contraindications who can’t be vaccinated, as well as vaccinated individuals (vaccines are not 100% effective).
  • Yet all public health interventions, including vaccination, include health risks. Individualism is also a strong tenet of U.S. citizens’ ideals and values. Thus, individuals want to exercise their right to protect themselves and/or their children if they do not accept existing medical evidence about the relative safety of vaccines, or if their ideological beliefs do not support vaccination.
    Good public health policies balance both individual rights and community needs. Therefore, public health officials must recognize and respect diverse social and cultural perspectives toward immunization policies, to help support their success and acceptance.
  • Certain religions and belief systems promote alternative perspectives toward vaccination. Religious objections to vaccines are generally based on (1) the ethical dilemmas associated with using human tissue cells to create vaccines, and (2) beliefs that the body is sacred, should not receive certain chemicals or blood or tissues from animals, and should be healed by God or natural means.
    For example, the Catholic Church recognizes the value of vaccines and the importance of protecting individual and community health. It asserts, however, that its members should seek alternatives to vaccines made using cell lines derived from aborted fetuses. Members of the Church of Christ, Scientist do not have a formal policy against vaccines, but generally rely on prayer for healing. They believe that medical interventions, which could include vaccines, are unnecessary. However, followers are also encouraged to do what is required of them by the authorities in order to safeguard their community's health.
  • Most U.S. states, with the exception of West Virginia and Mississippi, allow individuals to apply for religious exemptions to mandatory vaccines based on their religious beliefs and objections. Religious vaccine exemptions have risen in recent years. Although adults and children with these exemptions comprise a small part of the population, they often center controversy and media attention. Infections can spread quickly through small unvaccinated social and/or geographic church communities. For example, in Philadelphia in 1990, a major measles outbreak occurred among unvaccinated school children who were members of two fundamentalist churches that relied on prayer for healing, and opposed vaccines. In 1994, a measles outbreak occurred in a Christian Science community that objected to vaccination. The outbreak originated with a teenager who lived in Illinois, and attended a Christian Science boarding school in Missouri. Her illness contributed to significant outbreaks across both states. More recently, in 2005, a measles outbreak occurred among members of a religious community that opposed vaccination in Indiana, when an unvaccinated teenager returned ill from a trip overseas and infected others at a church gathering.
    Because of these outbreaks and the increasing number of religious vaccine exemptions, the CDC and other medical and public health officials warn parents that unvaccinated children are at a higher risk for acquiring vaccine preventable infections.
  • Suspicion and apprehension about vaccination are common, particularly among several specific disenfranchised communities in the United States and internationally. For these communities, suspicion is best understood in a social and historical context of inequality and mistrust. For example, several studies have found that the legacy of racism in medicine and the Tuskegee Syphilis Study, a clinical trial conducted with African Americans denied appropriate treatment opportunities, are key factors underlying African Americans’ distrust of medical and public health interventions, including vaccination.
    Internationally, in parts of Asia and Africa, mistrust of vaccines is often tied to “Western plot” theories, which suggest that vaccines are ploys to sterilize or infect non-Western communities.  Suspicion has existed for different infections and vaccines over the past 20 years. For example, in Cameroon in 1990, rumors and fears that public health officials were administering various childhood vaccines to sterilize women thwarted the country’s immunization efforts. Similarly, in Tanzania in the mid 1990s, a missionary raised concerns about tetanus immunizations, sparking sterilization rumors and halting the campaign. And in 2005, measles vaccine suspicions led to decreased vaccination rates and increased infections in Nigeria. One of the most striking cases of vaccine suspicion in Africa is about the polio vaccine. In 1999, British journalist Edward Hooper wrote The River: A Journey to the Source of HIV/AIDS. He speculated that the virus that causes AIDS transitioned from monkeys to humans via a polio vaccine. He argued the polio vaccine was made from the cells of chimpanzees infected with the primate form of HIV (Simian immunodeficiency virus, or SIV), which adapted in humans and caused disease; and that there were coincidences in the sites where the polio vaccine was first administered and where the first cases of HIV originated. Although scientists and medical scholars have provided plentiful evidence to discount Hooper’s ideas, media attention has sparked conspiracy theories and concerns globally.
    Religious and political objections by Muslim fundamentalists have driven suspicions about the polio vaccine in Pakistan, Afghanistan, and Nigeria. For example, the local Taliban in Southern Afghanistan have called polio vaccination an American ploy to sterilize Muslim populations and an attempt to avert Allah’s will. Resistance to vaccination has even led to violent beatings and kidnappings. Similar objections halted polio vaccination campaigns in Nigeria. In 2003, religious leaders in three different Nigerian states claimed the vaccines were contaminated with the virus that causes AIDS, sterilization, and cancer-causing agents, despite tests confirming the vaccine’s safety. The standoff was eventually resolved through dialogue between religious and political leaders, WHO, and UNICEF. In Pakistan, Taliban militants have attacked polio vaccination workers and their security forces. More than 70 polio workers have been killed since the attacks began in 2012.
    Divergent cultural perspectives and opinions toward vaccination, including libertarian and religious objections, as well as vaccine suspicions, signal the need for continued communication and collaboration between medical and public health officials and the public regarding acceptable and effective immunization policies.

“Different Types of Vaccines” (Last updated 18 April 2022), “Different Types of Vaccines”, (Last updated 18 April 2022)

  • The first human vaccines against viruses were based on using weaker or attenuated viruses to generate immunity, while not giving the recipient of the vaccine the full-blown illness or, preferably, any symptoms at all. For example, the smallpox vaccine used cowpox, a poxvirus similar enough to smallpox to protect against it, but usually didn’t cause serious illness. Rabies was the first virus attenuated in a lab to create a vaccine for humans.
  • Attenuated vaccines can be made in several ways. Some of the most common methods involve passing the disease-causing virus through a series of cell cultures or animal embryos (typically chick embryos). Using chick embryos as an example, the virus is grown in different embryos in a series. With each passage, the virus becomes better at replicating in chick cells, but loses its ability to replicate in human cells. A virus targeted for use in a vaccine can be grown through—“passaged” through—upwards of 200 different embryos or cell cultures. Eventually, the attenuated virus will not replicate well (or at all) in human cells, and can be used in a vaccine. All the methods that involve passing a virus through a non-human host produce a version of the virus that can still be recognized by the human immune system, but cannot replicate well in a human host.
  • One concern that must be considered is the potential for the vaccine virus to revert to a form capable of causing disease. Mutations that can occur when the vaccine virus replicates in the body may lead to a more virulent strain. This is unlikely, as the vaccine virus’s ability to replicate is limited. However, possible mutations are considered when developing an attenuated vaccine. It is worth noting that mutations are somewhat common with the oral polio vaccine (OPV), a live vaccine that is ingested instead of injected. The vaccine virus can mutate into a virulent form and lead to rare cases of paralytic polio. For this reason, OPV is no longer used in the United States, and has been replaced on the Recommended Childhood Immunization Schedule by the inactivated polio vaccine (IPV).
    Protection from a live, attenuated vaccine typically outlasts the protection provided by a killed or inactivated vaccine.
  • One alternative to attenuated vaccines is a killed or inactivated vaccine. Vaccines of this type are created by inactivating a pathogen, typically using heat or chemicals such as formaldehyde or formalin. This destroys the pathogen’s ability to replicate, but keeps it “intact” so that the immune system can still recognize it. (“Inactivated” is generally used rather than “killed” to refer to viral vaccines of this type, as viruses are generally not considered alive.)
    Because killed or inactivated pathogens can’t replicate at all, they can’t revert to a more virulent form capable of causing disease (as discussed above with live, attenuated vaccines). However, they tend to provide shorter protection than live vaccines, and are more likely to require boosters to create long-term immunity. Killed or inactivated vaccines on the U.S. Recommended Childhood Immunization Schedule include the inactivated polio vaccine and the seasonal influenza vaccine (injectable).
  • Subunit vaccines use only part of a target pathogen to provoke a response from the immune system. This can be done by isolating a specific protein from a pathogen and presenting it as an antigen on its own. The acellular pertussis vaccine and influenza vaccine (in shot form) are examples of subunit vaccines.
  • Another type of subunit vaccine can be created via genetic engineering. A gene coding for a vaccine protein is inserted into another virus, or into producer cells in culture. When the carrier virus reproduces, or when the producer cell metabolizes, the vaccine protein is also created. The end result of this approach is a recombinant vaccine: the immune system will recognize the expressed protein and provide future protection against the target virus. The Hepatitis B vaccine currently used in the United States is a recombinant vaccine.
    Another vaccine made using genetic engineering is the human papillomavirus (HPV) vaccine. Two types of HPV vaccine are available—one provides protection against two strains of HPV, the other four—but both are made in the same way: for each strain, a single viral protein is isolated. When these proteins are expressed, virus-like particles (VLPs) are created. These VLPs contain no genetic material from the viruses and can’t cause illness, but prompt an immune response that provides future protection against HPV.
  • Conjugate vaccines are somewhat similar to recombinant vaccines: they’re made using two different components. Conjugate vaccines, however, are made using pieces from the coats of bacteria. These coats are chemically linked to a carrier protein, and the combination is used as a vaccine. Conjugate vaccines are used to create a more powerful, combined immune response: typically the “piece” of bacteria presented would not generate a strong immune response on its own, while the carrier protein would. The piece of bacteria can’t cause illness, but combined with a carrier protein, it can generate immunity against future infection. The vaccines currently used for children against pneumococcal bacterial infections are made using this technique.

“Early Laboratory Methods for Developing Vaccines” (Last updated 18 April 2022), “Early Laboratory Methods for Developing Vaccines”, (Last updated 18 April 2022)

  • To develop vaccines that could be mass-produced, researchers first had to grow the viruses or bacteria with which to develop those vaccines – in large quantities and with great consistency. Compared with bacteria, which can be grown in a laboratory environment when placed in a suitable growth medium, viruses cannot reproduce on their own and require living cells to infect. After a virus infects a cell, it uses the cell’s own components to produce more copies of itself. 
    So, while material for early bacterial vaccines could be grown in a lab without laboratory animals, researchers trying to develop material for viral vaccines faced an additional challenge. With techniques for growing viruses outside of live hosts not yet available, they were limited to obtaining materials from infected animal hosts.
    During the early efforts to develop a vaccine against polio, researchers discovered that the virus could cause disease not only in humans, but also in monkeys. This led to early field trials in the 1930s of vaccine candidates developed using material taken from polio-infected monkeys, such as monkey spinal cords. These candidates proved dangerous, sometimes causing paralysis in the limb where the vaccine was administered. Vaccines derived using nervous system tissue have a higher side effect profile than those developed using other methods (the myelin in the vaccine material can stimulate an adverse neurological reaction). The trials ceased, and researchers moved on to find another way to grow the virus for vaccine development.
  • Hopes of growing poliovirus in the lab without the use of live animals drove many researchers in the 1930s and 1940s. Cell cultures involve growing cells in a culture dish, often with a supportive growth medium like collagen. They offer a level of control unavailable using live animals, and can also support large-scale virus production. (For more about cell cultures and cell lines, as well as cell lines made using human cells, see our article “Human Cell Strains in Vaccine Development.”) Early efforts to grow poliovirus in culture, however, repeatedly ended in failure.
    In 1936, Albert Sabin and Peter Olitsky at the Rockefeller Institute successfully grew poliovirus in a culture of brain tissue from a human embryo. The virus grew quickly, which was promising, but Sabin and Olitsky were concerned about using this as starting material for a vaccine, fearing nervous system damage for vaccine recipients. They tried to grow poliovirus in cultures using tissue taken from other sources, but were unsuccessful.
  • Thirteen years after Sabin and Olitsky’s success with growing poliovirus in brain tissue, researchers at the lab of John Enders at the Children’s Hospital in Boston successfully grew the virus in a culture of skin and muscle tissue from a human embryo—in a fortunate happenstance. At the time, the researchers were focused on trying to isolate and grow varicella, the chickenpox virus. They had already succeeded in growing mumps and influenza viruses, and had moved on to varicella, which they knew grew in human cells. After preparing flasks with human embryonic tissue, they inoculated four flasks with throat washings from chickenpox patients. Another four flasks were inoculated with a strain of poliovirus as a control group. The chickenpox virus did not grow in this case, but to the researchers’ great surprise, poliovirus did.
    They went on to grow two other strains of poliovirus, and in many types of human embryonic tissue, without using nervous system tissue. They were able to grow the virus rapidly and to very high concentrations using the “roller tube” apparatus created by researcher George Otto Gey in the 1930s. (Gey also established perhaps the most famous human cell line, the HeLa, or Henrietta Lacks line.) While many tissue cultures at the time were done in flasks, Gey realized that the environment in the flask did not adequately simulate the environment inside a living body, where tissues are exposed to periods of nutrients being supplied, as well as waste removal. Instead of a flask, he placed tissue on the sides of test tubes, and then placed the tubes horizontally into holes in a wooden cylinder. The cylinder slowly turned like a wheel, rotating the tubes so that the tissue would alternate, coming into contact with air and a nutrient fluid added to the tube.
    The researchers in Enders’s lab used the same technique, growing poliovirus much more rapidly than in static flasks. For demonstrating that poliovirus could be reliably grown without using nervous tissue, Enders and his colleagues Thomas Weller and Frederick Robbins were awarded the Nobel Prize in Physiology or Medicine in 1954.
    Their discovery proved to be the breakthrough needed to develop a polio vaccine. In 1951, Jonas Salk and his colleagues at the University of Pittsburgh found that poliovirus could also be propagated on a large scale in monkey kidney cells.
    Over time, most vaccine development efforts shifted to cell strains—cultures made up of only a single type of cell. These strains can be derived from tissue cultures, which contain multiple types of cells. While viruses can be grown in tissue cultures, cell strains allow continuous observation and control that may not be possible in cultures containing multiple types of cells. This same transition was made in the development of polio vaccines. A monkey kidney cell strain is used to grow poliovirus for the inactivated polio vaccine made today.
  • Today, many different animal cell strains are available for use in scientific research and development. Several vaccines currently available in the United States were developed using the Vero cell line, started from African green monkey kidney cells: 
    *Rotavirus vaccines [Rotarix/GlaxoSmithKline, RotaTeq/Merck]
    *Polio [IPOL/Sanofi Pasteur]
    * Smallpox [ACAM2000/Sanofi Pasteur – Used only for selected military personnel]
    *Japanese encephalitis [Ixiaro/Intercell – Used only for those traveling to areas with known outbreaks of disease]
    Future U.S. vaccines may use other animal cell strains, including the Madin Darby Canine Kidney (MDCK) line, started in 1958 with kidney cells from a cocker spaniel. (Some European vaccines are already made using MDCK.)

“Ethical Issues and Vaccines” (Last update 18 April 2022), “Ethical Issues and Vaccines”, (Last update 18 April 2022)

  • Vaccines are responsible for many global public health successes, such as the eradication of smallpox and significant reductions in other serious infections like polio and measles. Even so, vaccinations have also long been the subject of various ethical controversies. The key ethical debates related to vaccine regulation, development, and use generally revolve around (1) mandates, (2) research and testing, (3) informed consent, and (4) access disparities.
  • In the United States, state policies mandate certain immunizations, including school entry requirements, which cover significant numbers of children.The first school vaccination requirements were enacted in the 1850s to prevent smallpox. Federal and state efforts to eradicate measles in the 1960s and 1970s motivated many modern mandates policies. By the 1990s, all 50 states required students to receive certain immunizations, and most states required coverage for older schoolchildren and those in daycare centers and Head Start programs.Vaccines are licensed and added to the immunization schedule after research, testing, and monitoring, which is coordinated and reviewed by The National Vaccine Program and other key vaccine committees, like the Advisory Committee on Immunization Practices (ACIP). States then devise mandates according to this body of knowledge.
  • Sometimes vaccine mandate controversies include multiple and interrelated ethical dilemmas. This is the case for the vaccine for the human papillomavirus (HPV), a sexually transmitted disease (STD). The FDA approved the first HPV vaccine in 2006. After the ACIP recommended three doses of the vaccine for girls aged 11-12, various state legislatures attempted to mandate vaccination. Ethical objections to this mandate range from religious concerns that a vaccine to protect against an STD contradicts abstinence-based messages; fears that the vaccine could potentially force a child to undergo an intervention misaligned with her family’s beliefs; and human rights questions about the fairness of providing a vaccine to one sex only (though now in the United States the vaccine is recommended for all adolescents).
  • All 50 states allow vaccination exemptions for medical contraindications; to address individuals’ beliefs and their varied concerns about vaccination, 48 states allow religious exemptions; and 20 states allow exemptions for philosophical reasons. Many scientific and medical research studies have found that individuals who exercise religious and/or philosophical exemptions are at greater risk of contracting infections, which put themselves and their communities at risk. Thus, medical and public health advocates often struggle to balance the ethics of protecting individual beliefs and the community’s health.
  • To be licensed, vaccines undergo many years of research, and must pass rigorous safety and efficacy standards. The vaccine development and research process includes diverse experts of many scientific and social disciplines, including public health, epidemiology, immunology, and statistics, and from pharmaceutical companies. These stakeholders may have conflicting priorities and motives, which contributes to various ethical discussions.
    Sometimes researchers disagree about who to include in vaccine trials. To properly test a vaccine’s effectiveness, a clinical trial including a control group that does not get the test vaccine is usually necessary. However, failing to provide any adequate preventive option can be a difficult decision when the vaccine can potentially prevent a serious, untreatable, or fatal infection. For instance, TB vaccine researchers struggled to devise ethical control group procedures. Existing TB vaccines, called Bacillus Calmette-Guérin (BCG) vaccines, are not always effective to prevent TB, and can cause infections in people with compromised immune systems, such as people living with HIV/AIDS. When they test the effectiveness of new strategies, researchers debate whether it is safe and ethical to give control participants these vaccines.
  • Additionally, it is important to understand a vaccine’s safety and efficacy in various populations, but testing a vaccine in vulnerable populations, such as children, also raises ethical concerns. Researchers must balance the need to protect children’s safety with the need to adequately understand how a vaccine will perform, and protect children when administered.
    Similarly, it is important to understand how vaccines affect people in developing countries. Yet, conducting vaccine research in developing countries includes ethical concerns, such as how to provide necessary screening or treatment if diseases are detected; how to meaningfully involve local communities in the research design process; how to ensure that the trial and vaccine can be supervised by local ethical review panels; and how to ensure that participants understand consent. For example, participants in a malaria vaccine trial in Mali reported difficulty understanding several concepts, including withdrawal from the study, side effects from the vaccine, and the difference between a research study and therapy, suggesting that better communication strategies are required to ensure proper consent across cultures.
  • Ethical debates also surround vaccine implementation and delivery, such as those concerning informed consent. Although federal guidelines do not require written consent before vaccination (as they do for certain other procedures, such as surgeries), the National Childhood Vaccine Injury Act of 1986 requires healthcare providers to give vaccine recipients, or their parents or legal representatives, a Vaccine Information Statement (VIS). The VIS provides basic information about vaccine risks and benefits, and is designed to provide the information a patient or parent needs to make an informed decision.
    Some states have specific informed consent laws. Certain lawmakers and other patient rights advocates believe that requiring specific consent is ethical and appropriate, so that parents are better informed about vaccines, and have adequate time to ask questions if needed. Opponents fear that a regulated written consent procedure may add unnecessary fear or concern to the vaccination process.
  • Several vaccine shortages have made headlines over the last 10 years. Between November 2000 and May 2003, the United States saw shortages of 8 of the 11 vaccines for childhood diseases. And in 2004, the flu vaccine shortage grabbed national media attention. Shortages result from too few vaccine producers and suppliers. Various factors limit vaccine research and development, including liability, expense, time, and decreased demand. For example, demand for flu vaccines varies annually, and producers must dispose of extra vaccines each year. From an ethical perspective, increasing the number of vaccine producers would positively influence health. When vaccines are in short supply, medical providers must decide who should be protected, and who must be left vulnerable to disease
  • In the United States, low-income children and children without health insurance can face challenges in receiving vaccinations. The Section 317 program, a federal program to vaccinate underserved children, attempts to help support coverage, but cannot serve all children in need. Access disparities also affect adults. Even after controlling for economic status, researchers have found that racial ethnic minority adults are less likely than whites to receive preventive care, including vaccination.
    Global health disparities are even more extreme and highlight additional ethical dilemmas. Developing countries face threats from disabling and deadly infections, called “poverty diseases,” such as hookworm and leprosy, which are unknown to most Americans. Although vaccines can help prevent these diseases, vaccine development lags behind community health needs. To further complicate matters, the places affected by poverty diseases often lack the infrastructure to support wide-scale vaccination, and face many competing health and social priorities, such as poverty, violence, and poor roads. Public health and medical officials must make difficult decisions about which health needs to address, and how to incorporate vaccination into often-scarce services.

"Human Cell Strains in Vaccine Development" (Retrieved January 5, 2021), "Human Cell Strains in Vaccine Development". (Retrieved January 5, 2021).

  • Animals have been used in the industrialized production of human vaccines since vaccine farms were established to harvest cowpox virus from calves in the late 1800s. From that point, and through the first half of the 20th Century, most vaccines would continue to be developed with the use of animals, either by growing pathogens in live animals or by using animal cells.
    Although many vaccines and anti-toxin products were successfully developed this way, using animals in vaccine development – particularly live animals – is not ideal. Research animals are costly and require extensive monitoring, both to maintain their health and to ensure the continued viability of the research. They may be carrying other bacteria or viruses that could contaminate the eventual vaccine, as with polio vaccines from the mid 20th century that were made with monkey cells and eventually found to contain a monkey virus called SV40, or Simian Virus 40. (Fortunately, the virus was not found to be harmful to humans.) Moreover, some pathogens, such as the chickenpox virus, simply do not grow well in animal cells.
    Even when vaccine development is done using animal products and not live animals – such as growing influenza vaccine viruses in chicken eggs – development can be hindered or even halted if the availability of the animal products drops. If an illness were to strike the egg-producing chickens, for example, they might produce too few eggs to be used in the development of seasonal flu vaccine, leading to a serious vaccine shortage. (It’s a common misconception that influenza vaccines could be produced more quickly if grown in cell cultures compared to using embryonated chicken eggs. In fact, growing the vaccine viruses in cell cultures would take about the same amount of time. However, cell cultures do not have the same potential availability issues as chicken eggs.)
  • Researchers can grow human pathogens like viruses in cell strains to attenuate them – that is, to weaken them. One way viruses are adapted for use in vaccines is to alter them so that they are no longer able to grow well in the human body. This may be done, for example, by repeatedly growing the virus in a human cell strain kept at a lower temperature than normal body temperature. In order to keep replicating, the virus adapts to become better at growing at the lower temperature, thus losing its original ability to grow well and cause disease at normal body temperatures. Later, when it’s used in a vaccine and injected into a living human body at normal temperature, it still provokes an immune response but can’t replicate enough to cause illness.
  • The first licensed vaccine made with the use of a human cell strain was the adenovirus vaccine used by the military in the late 1960s. Later, other vaccines were developed in human cell strains, most notably the rubella vaccine developed by Stanley Plotkin, MD, at the Wistar Institute in Philadelphia.
  • Although it has now been used in the United States for more than 30 years, Plotkin’s rubella vaccine was initially ignored by the U.S. Food and Drug Administration in favor of rubella vaccines developed using duck embryo cells and dog kidney cells. In the late 1960s, there was concern in the country that a vaccine developed using human cells could be contaminated with other pathogens, though this concern was not supported by documented evidence. This is interesting in light of the discovery earlier in the decade that polio vaccines developed using primary monkey kidney cells were contaminated with simian viruses: this was one of the reasons researchers began using the normal human cell strain WI-38 in the first place. According to Hayflick, however, the main reason for using WI-38 was the fact that it could be stored in liquid nitrogen, reconstituted, and tested thoroughly before use for contaminating viruses. (None has ever been found in WI-38.) Primary monkey kidney cells could not be frozen and then reconstituted for testing as this would violate the concept of primary cells--originally the only class of cells allowed by the FDA to produce human virus vaccines.

“The Scientific Method in Vaccine History” (Last updated 18 April 2022)

Historyofvaccines, [ “The Scientific Method in Vaccine History”', (Last updated 18 April 2022)

  • During the 1930s, Pearl Kendrick at the Michigan Department of Health developed a whooping cough (pertussis) vaccine that she hoped would be more effective than previous vaccines. An important part of showing the effectiveness of the vaccine involved a control group of children who did not receive the vaccine. This was something of an innovation at the time, but Kendrick knew that having a control group would add weight to her findings if the vaccine proved effective. The rate of pertussis disease in the control group would allow Kendrick to easily demonstrate whether her vaccine could reduce the rate of disease in the experimental group. Kendrick assigned children to her pertussis experimental group if they came to a clinic seeking pertussis vaccination. For the control group, she found children at random from a list kept by a city health department of unimmunized children.
    One fault that we would see today in Kendrick’s experiment design was the lack of randomization in the assignment of children to either the experimental group or the control group. Randomization is a method of using chance alone to assign subjects to a control or experimental group. Researchers use randomization because it helps ensure that differences between the two groups will not influence the outcome of the experiment. If Kendrick had randomized assignments, she would have minimized differences between the vaccinated group and the group she merely observed.
    In spite of this shortcoming, Kendrick’s trial helped establish norms and expectations for future vaccine trials, and it clearly showed the efficacy of her vaccine.
  • The 1954 field trial of Jonas Salk’s inactivated poliovirus vaccine (IPV) was another important milestone in the use of the scientific method to test a vaccine. This trial enrolled many subjects—1.3 million children in all—in what is the largest medical field trial ever conducted.
    The Salk trial was a carefully designed double-blind randomized experiment. This meant, first, that children were randomly assigned to either the control or the experimental group. “Double-blind” meant that no one—not the child, the parent, the person who gave the injection, nor the person who assessed the child's health—knew whether an individual child received the polio vaccine or a placebo injection. (A placebo is an inactive substance. In this case, the placebo was a saltwater solution.) The information about whether the child received the vaccine or the placebo was encoded in numbers on vials from which the injected material was taken, and it was linked to the child’s record. Only after the observation period was over and the result recorded—did the child develop polio during the observation period or not?—was the child’s experimental or control status revealed?
    Authorities did not achieve the double-blind, randomized standard across the entire polio vaccine trial. In some communities, officials objected to a placebo injection, so the children in the control group were merely observed for signs of polio. These groups were known as observed controls. Some designers of the study worried that differences between observed control and experimental groups might influence the outcome. For instance, the observed control group included children whose parents would not consent to receiving the vaccine. Were there important differences, such as income, housing, or parental age, between children whose parents would not consent and those who would? And might those differences affect whether children had already been exposed to and become immune to polio?
    The Salk vaccine trial successfully showed that the vaccine helped prevent paralytic polio, and licensure of the vaccine quickly followed. The disease that once paralyzed thousands of children has now been eliminated in the Western Hemisphere.
  • The history of the scientific method in vaccine research has led to today’s carefully regulated vaccine development process. Over the years, the standards for vaccine studies have grown progressively more stringent, to make the control groups and the vaccine groups as similar as possible. The principles of control, blinding, and randomization play key roles in the way vaccines are tested.

“Vaccine Development, Testing, and Regulation” (Last updated 18 April 2022), “Vaccine Development, Testing, and Regulation” (Last updated 18 April 2022)

  • Vaccine development is a long, complex process, often lasting 10-15 years, and involves a combination of public and private involvement.
    The current system for developing, testing, and regulating vaccines developed during the 20th century, as the groups involved standardized their procedures and regulations.
  • At the end of the 19th century, several vaccines for humans were developed. They were smallpox, rabies, plague, cholera, and typhoid vaccines. However, no regulation of vaccine production existed.
    On July 1, 1902, the U.S. Congress passed "An act to regulate the sale of viruses, serums, toxins, and analogous products," later referred to as the Biologics Control Act (even though "biologics" appears nowhere in the law). This was the first modern federal legislation to control the quality of drugs. This act emerged in part as a response to 1901 contamination events in St. Louis and Camden, which involved smallpox vaccine and diphtheria antitoxin.
    The Act created the Hygienic Laboratory of the U.S. Public Health Service to oversee the manufacture of biological drugs. The Hygienic Laboratory eventually became the National Institutes of Health. The Act established the government’s right to control the establishments where vaccines were made.
    The United States Public Service Act of 1944 mandated that the federal government issue licenses for biological products, including vaccines. After a poliovirus vaccine accident in 1954 (known as the Cutter incident), the Division of Biologics Standards was formed to oversee vaccine safety and regulation. Later, the DBS was renamed the Bureau of Biologics, and became part of the Food and Drug Administration. It is now known as the Center for Biologics Evaluation and Research.
  • Exploratory Stage
    This stage involves basic laboratory research and often lasts 2-4 years. Federally funded academic and governmental scientists identify natural or synthetic antigens that could help prevent or treat a disease. These antigens could include virus-like particles, weakened viruses or bacteria, weakened bacterial toxins, or other substances derived from pathogens.
  • Pre-Clinical Stage
    Pre-clinical studies use tissue-culture or cell-culture systems and animal testing to assess the safety of the candidate vaccine and its immunogenicity, or ability to provoke an immune response. Animal subjects may include mice and monkeys. These studies give researchers an idea of the cellular responses they might expect in humans. They may also suggest a safe starting dose for the next phase of research, as well as a safe method of administering the vaccine.
    Researchers may adapt the candidate vaccine during the pre-clinical state to try to make it more effective. They may also do challenge studies with the animals, meaning they vaccinate the animals and then try to infect them with the target pathogen.
    Many candidate vaccines never progress beyond this stage, because they fail to produce the desired immune response. The pre-clinical stages often last 1-2 years and usually involve researchers in private industry.
  • IND Application
    A sponsor, usually a private company, submits an application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration. The sponsor describes the manufacturing and testing processes, summarizes the laboratory reports, and describes the proposed study. An institutional review board, representing an institution where the clinical trial will be conducted, must approve the clinical protocol. The FDA has 30 days to approve the application.
    Once the IND application has been approved, the vaccine is subject to three phases of testing.
  • Phase I Vaccine Trials
    This first attempt to assess the candidate vaccine in humans involves a small group of adults, usually between 20-80 subjects. If the vaccine is intended for children, researchers will first test adults, and then gradually step down the age of the test subjects until they reach their target. Phase I trials may be non-blinded (also known as open-label in that the researchers and perhaps subjects know whether a vaccine or placebo is used).
    The goals of Phase 1 testing are to assess the safety of the candidate vaccine and determine the type and extent of immune response that the vaccine provokes. In a small minority of Phase 1 vaccine trials, researchers may use the challenge model, attempting to infect participants with the pathogen after the experimental group has been vaccinated. The participants in these studies are carefully monitored, and conditions are carefully controlled. In some cases, an attenuated, or modified, version of the pathogen is used for the challenge.
  • Phase II Vaccine Trials
    A larger group of several hundred individuals participates in Phase II testing. Some individuals may belong to groups at risk of acquiring the disease. These trials are randomized and well controlled, and include a placebo group.
    The goals of Phase II testing are to study the candidate vaccine’s safety, immunogenicity, proposed doses, schedule of immunizations, and method of delivery.
  • Phase III Vaccine Trials
    Successful Phase II candidate vaccines move on to larger trials, involving thousands to tens of thousands of people. These Phase III tests are randomized and double blind, and involve the experimental vaccine being tested against a placebo (the placebo may be a saline solution, a vaccine for another disease, or some other substance).
    One Phase III goal is to assess vaccine safety in a large group of people. Certain rare side effects might not surface in the smaller groups of subjects tested in earlier phases. For example, suppose that an adverse event related to a candidate vaccine could occur in 1 of every 10,000 people. To detect a significant difference for a low-frequency event, the trial would have to include 60,000 subjects, half of them in the control, or no vaccine, group (Plotkin SA et al. Vaccines, 5th ed. Philadelphia: Saunders, 2008). Vaccine efficacy is also tested. These factors might include 1) Does the candidate vaccine prevent disease? 2) Does it prevent infection with the pathogen? 3) Does it lead to the production of antibodies or other types of immune responses related to the pathogen?
  • After a successful Phase III trial, the vaccine developer will submit a Biologics License Application to the FDA. The FDA will then inspect the factory where the vaccine will be made and approve the labeling of the vaccine.
    After licensure, the FDA will continue to monitor the production of the vaccine, including inspecting facilities and reviewing the manufacturer’s tests of lots of vaccines for potency, safety and purity. The FDA has the right to conduct its own testing of manufacturers’ vaccines.
  • Phase IV trial are optional studies that drug companies may conduct after a vaccine is released. The manufacturer may continue to test the vaccine for safety, efficacy, and other potential uses.
  • The CDC and FDA established The Vaccine Adverse Event Reporting System in 1990. According to the CDC, VAERS' goal is “to detect possible signals of adverse events associated with vaccines.” (A signal in this case is evidence of a possible adverse event that emerges in the data collected.) About 30,000 events are reported each year to VAERS. Between 10% and 15% of these reports describe serious medical events that lead to hospitalization, life-threatening illness, disability, or death.
    VAERS is a voluntary reporting system. Anyone, such as a parent, a health care provider, or friend of the patient, who suspects an association between a vaccination and an adverse event, may report that event and information about it to VAERS. The CDC then investigates the event and tries to find out whether the vaccination actually caused the adverse event.
  • Vaccines are developed, tested, and regulated in a similar manner to other drugs. In general, vaccines are even more thoroughly tested than non-vaccine drugs, because the number of human subjects in vaccine clinical trials is usually greater.

“Vaccines for Pandemic Threats”, “Vaccines for Pandemic Threats”

  • Vaccination will likely be part of a multi-faceted public health response to the future emergence of a pandemic illness. In addition to other measures designed to respond to and control a pandemic, such as surveillance, communication plans, quarantine, and disease treatment, deployment of effective vaccines has the potential to protect lives and limit disease spread. Not all disease threats, however, have a corresponding vaccine, and for those that do, there are significant challenges to their successful use in a pandemic.
  • A challenge in responding to pandemic diseases is that vaccines may not exist for them or that, especially in the case of influenza viruses, existing vaccines may not be effective against them. Though production methods and infrastructure for influenza vaccines are well established, each new influenza strain requires a new vaccine. Thus, any new pandemic influenza vaccine will take about 4-6 months to produce in large quantity. For other newly emerging threats without licensed vaccines, such as SARS, Marburg virus, Nipah virus, and the like, the time required to develop and produce a safe, effective vaccine is unknown and would depend on the nature of the threat and the state of current vaccine research for that threat. In almost all cases, several months would be needed to respond with the first doses of vaccines. Until a safe, effective vaccine were ready, other public health and medical measures, such as social distancing, quarantine, and use of anti-viral medications, would need to be employed to try to limit disease spread.
  • In all pandemic situations in which a vaccine is available or potentially available, a large supply of vaccine would be necessary and would be needed quickly. Currently, the U.S. Strategic National Stockpile includes several types of influenza vaccines, including an H5N1 vaccine. The stockpile also holds millions of doses of other vaccines, antibodies, antiviral medications and other medical supplies. Should any of these stockpiled vaccines directly relate to an emerging pandemic, they would be deployed. But chances are that an emerging pandemic illness will require a new vaccine.
  • In situations when a new vaccine is needed quickly, the FDA has developed alternative pathways to licensure. One is an accelerated pathway to approval that might apply in the case of a life-threatening disease when a new process will produce a vaccine with meaningful therapeutic benefit over existing options. In other, more drastic threats, the so-called animal rule might be used—if research toward a vaccine or treatment would necessitate exposing humans to a toxic threat, then animal studies may be sufficient for approval. To date, these two rapid pathways have not been invoked for vaccines.

“Vaccine Injury Compensation Programs” (19 April 2022), “Vaccine Injury Compensation Programs”, (19 April 2022)

  • No medical intervention is risk free. Vaccines, though designed to protect from disease, can cause side effects that range from mild to serious. The most common side effects of vaccination are soreness, swelling, or redness at the injection site. Some vaccines are associated with fever, rash, and achiness. Serious side effects from vaccination are rare, but may include life-threatening allergic reaction, seizure, and even death.
    When vaccines first began to be widely used, people who experienced serious side effects from vaccination had little recourse to compensation from manufacturers, physicians, or the government. This was particularly a problem when vaccine production techniques were in their infancy, and contamination of vaccines occasionally occurred during or after manufacture. Since the passage in 1902 of the U.S. Biologics Control Act, which initiated the regulation of vaccines, such problems with negligence in manufacture have declined greatly.
    As product liability law evolved during the 20th century, it eventually provided an avenue for compensation for individuals harmed by vaccines: they could sue a manufacturer for harm caused by an improperly made vaccine, or they could sue a physician for administering a vaccine when it was contraindicated. In the United States, the civil court system applies the principles of tort law to these suits.
  • Individuals harmed by properly manufactured vaccines had few options for compensation before an important court case in the 1950s addressed the issue. In 1955, about 200 people were paralyzed and ten died after contracting polio from the Salk polio vaccine, some of which contained viruses that had not been inactivated, despite manufacturers’ adherence to federal government standards. The event was known as the Cutter Incident, after the manufacturer of one of the implicated vaccines. Many injured people and their families filed lawsuits against vaccine manufacturers, and most cases were settled out of court with monetary awards by the manufacturers. One case, Gottsdanker v. Cutter Laboratories, was heard on appeal by the California Supreme Court, and the justices upheld a jury ruling that although Cutter Laboratories was not negligent in its design or manufacture of the vaccine, the company was financially responsible for the harm the vaccine caused. It was a significant ruling, and many similar awards followed in other cases. No standards existed, however, for determining when a vaccine caused a clinical event or was simply associated temporally with it—that is, whether the event happened after vaccination without a causal relationship. Juries decided these matters case by case, sometimes with little medical or scientific support for claims of vaccine injury causation.
  • Through the 1970s and 1980s, the number of lawsuits brought against vaccine manufacturers increased dramatically. Manufacturers made large payouts to individuals and families claiming vaccine injury, particularly from the combined diphtheria-pertussis-tetanus (DPT) immunization. In this environment of increasing litigation, mounting legal fees, and large jury rewards, many pharmaceutical companies left the vaccine business. By the end of 1984, only one U.S. company still manufactured the DPT vaccine, and other vaccines were also losing manufacturers.
  • In October 1986, the U.S. Congress responded to the precarious situation in the vaccine market by passing the National Childhood Vaccine Injury Act (NCVIA). The act included many regulations related to informed consent and adverse event reporting. For example, the act required that providers administering certain vaccines provide a Vaccine Information Statement (VIS) to the vaccine recipient or legal guardian. The VIS lists the risks and benefits of a particular vaccine. The NCVIA also established a system for reporting suspected vaccine-related adverse events. This system, the Vaccine Adverse Event Reporting System (VAERS), is described here. Additionally, the act contained provisions for a program that would fairly and efficiently compensate individuals harmed by certain vaccines properly manufactured. Such a system, it was hoped, would stabilize the legal environment for manufacturers, allowing them to limit their liability, better anticipate their legal costs, and reduce potential barriers to research into new vaccines.
  • Under the NVICP, those claiming a vaccine injury from a covered vaccine cannot sue a vaccine manufacturer without first filing a claim with the U.S. Court of Federal Claims. Certain medical events are presumed to be side effects of vaccination, as long as no other cause is found. The claim filer is reimbursed according to a formula, provided that all medical records meet NCVIA standards, and that the U.S. Department of Justice reviews all legal standards. If a claim is denied, or if the claim is approved and the claimant rejects the compensation, only then may the claimant file a civil lawsuit.
  • Examples of compensable injuries are intussusception within 30 days of receipt of oral, rhesus-based rotavirus vaccine, brachial neuritis within 0-28 days of receipt of tetanus toxoid containing vaccines, anaphylaxis within 0-4 hours of receipt of various vaccines, etc. The VIT is subject to review by DHHS, and vaccine injuries may be added to and removed from the tables depending on the best available evidence. Seizure disorder after DPT vaccination, which was the cause of many successful lawsuits against vaccine manufacturers before the NVICP, was removed from the list of compensable events in 1995 because of lack of evidence supporting a link.
  • Compensation payments from NVICP have averaged $782,136 per successful claim through 2011, with an additional $113 million dispersed to pay attorney fees and legal costs (the act awards attorney fees and costs for unsuccessful claims provided that the litigants bring their claims in good faith and upon a reasonable basis, as well as for successful claims). Compensation for a death resulting from vaccination is capped at $250,000. As of December 1, 2011, the program had awarded $2.35 billion in 2,810 separate claims, including compensation for 390 deaths.
  • Beginning around 2001, hundreds and then thousands of families began to petition NVICP, claiming their children’s autism resulted from vaccination. (See the article The History of Anti-vaccination Movements, and specifically the section “The Measles, Mumps, Rubella (MMR) Vaccine Controversy” for a discussion of the origin of these claims.) To deal with the volume of these petitions, and to address the assertion that a causal relationship existed between vaccination and autism, the NVICP established a special program in 2002 called the Omnibus Autism Proceeding, housed within the U.S. Court of Federal Claims Office of Special Masters.
    The OAP consolidated many autism claims into three test cases that focused on different theories of causation. The first test case addressed whether measles-mumps-rubella (MMR) vaccine alone, or along with thimerosal-containing vaccines (TCVs), is a causal factor in autism. (Thimerosal is an ethylmercury compound that was a common preservative in some killed vaccines.) The second test case examined TCVs alone. The third test case was to look solely at MMR vaccines, but the case was withdrawn after parties announced they would rely on the findings of the first test case.
    A special master issued the first opinion in the OAP on theory one in 2009. The ruling found, in three test cases consolidated into theory one, that the MMR vaccine given alone or with TCVs is not a causal factor in autism. Theory two was decided in 2010, with a finding of no causal relationship between TCVs and autism. Appeals by petitioners in the two test cases have been unsuccessful, and autism has not been added to the VIT for any vaccine.
  • Many developed nations have instituted similar programs to the NVICP in the United States. Their means of funding vary, as do other details of the programs, such as vaccines and covered adverse events, and how the programs handle petitioners’ legal fees. In some cases (Germany and Switzerland), the state, rather than the national government, administers the program. And in countries with national health plans, vaccine injury compensation is a secondary source of support, as basic health care is provided at no or very little cost. In general, developing nations have not established compensation systems for vaccine injuries. Attention is however paid to the need to monitor adverse events after immunization, as GAVI, PATH, the World Health Organization, and other NGOs continue their efforts to fund and deliver vaccines to the developing world. Such efforts may eventually lead to compensation systems.
  • The vaccine market has stabilized since the NCVIA and the establishment of the NVCIP. In the United States, six manufacturers supply most of the standard childhood and adult vaccines, and a handful of smaller companies and organizations supply other, less commonly used vaccines. Occasional vaccine shortages occur (such as with the influenza vaccine in 2003 through 2005), but these shortages may be due to factors without strong connection to liability issues, such as the effect of corporate mergers, the level of government reimbursement for vaccines in the federally funded Vaccine for Children program, and regulatory issues.

“Vaccine Timeline”, “Vaccine Timeline”

  • The history of vaccines did not begin with Jenner's smallpox vaccine. It will not end with the recent vaccines against the novel coronavirus, which caused the COVID-19 pandemic. The history of vaccines begins before the first vaccine, with an immunizing procedure called "inoculation" by some and "variolation" by others. According to researchers, inoculation with materials from smallpox lesions to trigger immunity against smallpox dates back to antiquity in China. And the first written account of the procedure was written in 1549.
  • Versions of an earlier time of practicing inoculation were more oral histories than written records. According to Arthur Boyleston, "In this version [of inoculation in China before it was written] (inoculation) was invented by a Taoist or Buddhist monk, or possibly a nun, about 1000 AD and practiced by Taoists as a mixture of medicine, technique, magic, and spells which were transmitted orally and which were covered by a taboo so that they were never written down. Needham can give no firmer evidence for this version than the fact that it was a widely accepted tradition. An editorial commentator wonders whether it is realistic to believe that something with the importance of inoculation would have remained completely secret for over 500 years."
  • Secret or not, the practice of inoculation traveled west toward the Ottoman Empire in the 1500s, reaching Constantinople (modern day Istanbul, Turkey) in the mid-1600s. From there, inoculation traveled to Europe and Northern Africa. From Northern Africa, the practice traveled to the Massachusetts Colony through an enslaved man named Onesimus. He told Reverend Cotton Mather -- of Salem Witchcraft Trials fame -- about being inoculated by enslavers to resist smallpox and get better pay for his enslavement. Cotton Mather, together with a local doctor in Boston, adopted and promoted inoculation as a deadly smallpox epidemic arrived in Boston in 1721.
    Around the same time, Lady Mary Wortley Montague, a British socialite living in Constantinople with her diplomat husband, had her son inoculated by a local physician. She then asked her daughter -- back home in Scotland -- to be inoculated. By 1723, the evidence was clear that inoculation in a controlled setting and under the supervision of a physician was preferable to catching smallpox "the natural way." 
    After his son died from smallpox in 1736, Benjamin Franklin became a champion of inoculation. He wrote several introductions to written works of the time about the procedure. In one such document written in 1759, Benjamin Franklin even included some numbers on the death rates of those who were inoculated (also known as "variolated"). The numbers gave even more proof that the risk of death was lower in those who were inoculated, cementing the practice in Europe and North America. Such was the adoption of variolation that General George Washington ordered the American troops to be inoculated as part of their intake into the Continental Army during the American Revolutionary War.
  • By the late 1700s, Edward Jenner observed that milkmaids and others previously infected with cowpox were immune to smallpox. Cowpox caused lesions similar to smallpox, but the lesions were localized, and the disease was much milder and not considered deadly. Building on the world and observations of other physicians at the time, Jenner devised a series of experiments in which a person who had not previously acquired smallpox nor cowpox would be inoculated first with cowpox and later with smallpox. The gambit paid off. The subjects of these experiments showed a mild reaction to cowpox, and no reaction nor disease to smallpox inoculation. The first vaccine was born.
    For almost eighty years, cowpox vaccination against smallpox remained the only vaccine in use around the world. Science and technology were not yet there to create vaccines against other disease-causing organisms, though many tried. One such person was Louis Pasteur, a French biochemist who enjoyed experimenting with microorganisms and kept detailed records of all his laboratory procedures. In Pasteur's time, rabies was of great concern in European cities. Rabid animals from the forest would bite and infect street dogs or cattle. People who would then be bitten by the dogs or exposed through their cattle would succumb to rabies.
  • Pasteur theorized that something in the saliva of the rabid animals was causing rabies. Though he could not see the rabies virus, Pasteur proved the disease was communicable, and he got to work on a vaccine. The work involved exposing animals to small doses of rabies, much like the variolation had been done in the past. This did not work, however. The rabies virus was too infectious, too virulent. As a result, Pasteur approached the problem differently: weaken the infectious agent somehow before giving it to a person.
    One version of smallpox variolation involved drying the material extracted from smallpox lesions before giving it to someone. It was believed the drying caused the material to be less virulent, so Pasteur tried this with the brains and spinal cords of infected rabbits. By this time, it was understood that the virus attacked the central nervous system of infected animals. Even if the virus could not be seen, the damage was visible. Pasteur took the dried brain and spinal cord from one rabbit, and gave it to another. He would wait for that rabbit to develop rabies, euthanize it, and repeat the process with a third, then a fourth, etc. Late down the chain, rabbits exposed to the dried brain and spinal cord were not getting sick. Furthermore, they were resisting any attempts at infection through fresh specimens of saliva from rabid animals.
    Before going public with his findings, Louis Pasteur -- like Edward Jenner -- took a gamble and exposed human subjects to the dried material in reverse. He started with dried brain and spinal cord from the last rabbit to be inoculated, and worked toward the material from the first rabbit, delivering stronger and stronger doses of the rabies virus. The most well-known human subject was Joseph Meister, a young man bitten by a rabid animal. To save Joseph's life, physicians allowed Pasteur to practice his procedure on Joseph. After all, without a cure, Joseph would likely suffer a painful death from rabies. Attempting something was better than nothing.
    After the expected incubation period of rabies of about 21 days, Joseph did not develop any signs or symptoms of the disease. Pasteur's vaccine was a success. The next leap in vaccination technology had occurred. Scientists used an analogue to the infectious agent -- cowpox for smallpox -- to use the infectious agent in a less virulent ("attenuated") way. Other vaccines developed at, or in collaboration with, the Pasteur Institute in Paris, France, were based on the same principle of weakening the pathogen before giving it as an inoculation.
  • In the 1940s, scientists worked on vaccines against influenza, polio, measles, and other viruses deemed critical national security importance. That decade brought vaccines against influenza, which was then understood to be not just one virus, but several types of influenza virus for which different vaccines would be needed. Similarly, polio was understood to be three types of virus in the same group, so a vaccine against one type did not protect against the others.
  • Armed with the knowledge of different virus types of the same virus group, scientists worked on vaccines against all types to prevent all disease. By 1954, after decades of well-funded research, Jonas Salk and his team developed the first killed virus vaccine. It was a vaccine against polio, and it went against the dogmas established at the time: the vaccine had to contain live/attenuated virus, and that a dead virus could not cause an immune response.
  • More advances in scientific understanding of microorganisms and immunity brought leaps in vaccine technology. When it was understood that the pathogen could be killed and still elicit an immune response, the question was asked whether the whole pathogen was needed or just a protein on its surface. The answer was that some pathogens' surface proteins were enough to trigger an immune response against future infection. The era of subunit vaccines was born.
    Later, scientists discovered that the genetic material of pathogens could be used in the laboratory to create the proteins. This did away with the need to grow pathogens in hazardous settings, reducing the risk of accidental exposures for laboratorians working on vaccines. The proteins created could then be "glued" onto another material and delivered to the body via a vaccine, triggering an immune response. The era of recombinant vaccines was born.

“Stanford students study the stories behind medical breakthroughs” (June 25, 2020)

S. Lochlann Jain as qtd. in “Stanford students study the stories behind medical breakthroughs”, by Melissa De Witte, (June 25, 2020)

  • “This history of vaccines is an incredibly interesting history of social relationships, colonial relationships, global relationships, and relationships between animals and humans,” said Jain, a professor of anthropology in the School of Humanities and Sciences.
    For example, when British physician Edward Jenner developed the smallpox vaccine in the late 18th century, he used his gardener’s 8-year-old child as one of his test subjects – an action that demonstrates both the loose ethical standards and social hierarchies of Georgian England. Jain also pointed out that Jenner’s idea for inoculation came from countryside folklore that dairymaids’ exposure to cowpox made them immune to smallpox.
    “Although Jenner is known as the father of vaccinations, the idea didn’t come from nowhere. He built on social knowledge of the time,” said Jain.
  • While Jenner discovered a preventive measure against smallpox, it took over 150 years for his method to be administered in a way that was safe to vaccine recipients. For example, early experiments exposed test subjects to the virus to make sure the vaccine worked, which sometimes led to infection and even death from the very illness one was being inoculated against. In other instances, early doses of the vaccine were sometimes contaminated with other harmful agents, such as the bacterium that causes syphilis.
    “This history raises a host of questions about how we think about what is effective,” said Elliott M. Reichardt, a PhD student in anthropology, who took the class. “It challenges this history that we have of Edward Jenner and that the development of the smallpox vaccine was just perfect. No – it was quite dangerous for a lot of people.”
    Reichardt said he was also surprised to learn about other dangers scientists encountered as they developed vaccines for other diseases, including the polio vaccine. For example, throughout the 1940s and 1950s, researchers in the U.S. relied on monkey cell lines in vaccine production. However, due to inadequate sterilization procedures, millions of Americans were inadvertently infected with an animal virus, simian virus 40.
    “What these examples reveal is the iterative nature of engineering and medical research,” said Reichardt. “It also illustrates how this complex past is at times neglected in explaining the origins of contemporary vaccinology.”
  • [D]uring development of the polio vaccine in the 1950s, scientists and government officials put aside Cold War politics of the era in a global effort to eradicate the disease. Students studied the case of communist Hungary, which even during the midst of civilian uprisings lifted the Iron Curtain to allow scientific collaborations with the West, enabling the import of both the polio vaccine and iron lungs, tank respirators used to support breathing in polio patients.
    “If there is the right disease, avenues for collaboration can open up politically that otherwise might seem impossible,” said Reichardt.
  • As the class learned about the global challenges of combating smallpox and other diseases like yellow fever, polio, HIV/AIDS, Ebola and Zika, they had to reckon with a pandemic of their own: the novel coronavirus.
    With their own world upended by uncertainty of a new virus, stories from previous outbreaks felt all too familiar – particularly how people grappled with an illness they knew little about. For example, during the polio outbreak in the 1950s, all that people knew about the disease was that children were particularly vulnerable. Out of fear, some parents forbade their children from going outdoors.
    “We could understand it from a very personal, urgent kind of way,” said Jain, who is currently studying how HIV/AIDS first emerged in New York and San Francisco when little was known about the disease – other than that it was fatal.
    “Having to personally weigh our own risks amid uncertainty gave us a new insight into how people may have made decisions about sociality before they understood what they were dealing with, in the polio epidemic or in the HIV epidemic,” Jain said. “The pandemic has been particularly difficult for people in non-normative families, such as young people and queer people. This has provided insight into the early days of HIV.”
    As Reichardt adjusted to sheltering-in-place, he said he was consoled by the knowledge that this was by no means the first occasion in history when people had to confine themselves to prevent contagion.
    “Humans have been isolating themselves for extended periods of time for very long periods of time,” said Reichardt, observing that Italians in the 14th century quarantined themselves as a way to thwart the bubonic plague. “It was reassuring to know society is not going to collapse and we will be fine. Humans are resilient and we’re going to get through this.”

“Religious Objections to the Measles Vaccine? Get the Shots, Faith Leaders Say” (April 26, 2019)

“Religious Objections to the Measles Vaccine? Get the Shots, Faith Leaders Say”, by Donald G. McNeil Jr., The New York Times, (April 26, 2019)

“Vaccines, Abortion, and Moral Coherence” (2022)

Daniel P. Maher “Vaccines, Abortion, and Moral Coherence”, The National Catholic Bioethics Quarterly, Spring 2002

  • The health benefits associated with relatively recent advances in vaccine therapy are well documented. To mention just a few: in 1921 there were nearly 207,000 reported cases of diphtheria in the United States. In 1991, there were two. In the same year, apart from a small number (five to ten) of vaccine-associated cases, there were no reported cases of poliomyelitis, as compared with more than twenty one thousand in 1952; “The CDC projects that the world will be polio-free by 2003.”3 Smallpox is said to be “eradicated globally” since late 1977, success that has rendered the vaccine itself normally unnecessary and even inadvisable since the risks associated with this vaccine are greater than the risk of contracting smallpox. Even in the case of diseases that remain somewhat common, such as mumps—there were approximately 4,000 reported cases in the United States in 1991—it must be noted that this figure represents only about 2.6% of the 152,000 cases reported in 1968. Occasional outbreaks of vaccine-preventable diseases, such as pertussis in Japan (1974–1979) and measles in the United States (1989–1991), have been traced to failure to use available vaccines.
    Now, it is certainly difficult to isolate a single cause to explain why diseases have not occurred, and there is evidence that the health of populations owes much also to improvements in diet, sanitation, and other public health measures. Nevertheless, such dramatic improvements in the health of the populations of the United States and of the world are attributed largely, though not exclusively, to policies of widespread immunization by vaccine.9Even assuming, then, that vaccines account for only a part of the improved health of the population in this country especially,10 and in the world generally, the bulk of evidence indicates that vaccines are highly effective in protecting individuals from a variety of infectious agents (e.g., anthrax, diphtheria, tetanus, tuberculosis, and typhoid).
    • pp.51-53
  • “In Japan in 1974 and 1975 two children died within 24 hours of receiving pertussis vaccine. As a result, pertussis vaccine use dropped to very low levels. The number of pertussis cases in Japan climbed from less than 1,000 cases in 1974 to more than 13,000 cases in 1979. In that year there were 41 deaths from pertussis,” (Tizard, Immunology, 361). See also: E. J. Gangarosa, “Impact of Anti-Vaccine Movements on Pertussis Control: The Untold Story,” The Lancet 351 (January 31, 1998): 356–61. 7 “The U.S. measles epidemics of 1989–91, with over 55,000 cases and 136 deaths, have shown that many of the nation’s children are at risk of preventable diseases because they are not vaccinated on the proper schedule during the critical first two years of life,” (NVPO, ix). “Almost one-half of the cases occurred in unvaccinated preschool children, mostly minorities …. Emergency vaccination efforts contained the epidemics, but only after they had caused considerable avoidable suffering”. See also National Vaccine Advisory Committee, “The Measles Epidemic: The Problems, Barriers, and Recommendations,” Journal of the American Medical Association 266 (1991): 1547–52.
    • Footnote 3, p.52
  • The success of vaccines remains impressive despite the fact that all vaccines themselves present health risks of one kind or another. The health risks associated with vaccinations have been the basis of rare but sometimes vigorous opposition to vaccinations at least from the beginning of this century (in Jacobson v. Massachusetts, concerning mandatory smallpox vaccinations) and have reappeared more recently, leading, for example to the National Childhood Vaccine Injury Act of 1986, designed to compensate individuals for reactions to federally approved and, in some cases, legally mandated vaccines.
    The opposition between the public health benefits of vaccination and the private health risks incurred by a given individual is complicated enough, but is, I submit, still too narrow for adequately addressing the question of the goodness of vaccines. It is too narrow because unless an opponent of vaccination raises objections based upon religious or personal liberty, systematic or principled opposition to vaccinations tends to focus principally on the health risks associated with vaccines, just as proponents tend to focus on the health benefits of vaccination. Having acknowledged that this is the traditional field of dispute, I would like to consider another kind of opposition to vaccination, an opposition based not upon health concerns but on moral concerns.
    • p.53
  • For example, vaccination against whooping cough (Bordetella pertussis) presents a risk of one death per million, whereas nonvaccination risks one death per 200 to 1,000 persons. The vaccine risks severe brain damage in one person per 310,000 as opposed to one per 2,000 to 8,000 persons who are not vaccinated. The vaccine also presents significantly lowered risk of encephalitis and seizures. See Tizard, Immunology, 361. See also Farrington, Nash, and Miller, “Case Series Analysis of Adverse Reactions to Vaccines,” American Journal of Epidemiology 143.11 (1996): 1165–73.
    • Footnote 11, p.53
  • Since measles vaccine was introduced into the United States it has been estimated that it prevented 52 million cases of measles, 5,200 deaths, and 15,400 cases of mental retardation and produced a net savings of $5.1 billion to society. The overall savings in costs to society as a result of measles, mumps, and rubella vaccination in 1983 were calculated to be $1.3 billion with a benefit-cost ratio of 14:1. There is no doubt that routine childhood vaccination confers huge benefits on society as a whole and has been largely responsible for the control of viral diseases in our society. Few other scientific disciplines can claim to have had such an impact.
    • p.54
  • The success of vaccinations in conferring health benefits upon society appears to confirm the goodness of the scientific discipline that produced vaccinations. Leaving aside the question of whether there are other or higher goals or achievements of at least some scientific disciplines, the author of this immunology text appears to answer what is essentially a moral or political question—the goodness of vaccinations—in terms of health and financial benefits and risks or costs. Oversimplification occurs to the extent that potentially unacceptable moral costs are ignored. The only costs he takes into account are the few incidents of adverse reactions to vaccines that occur when routine vaccination policies are carried out on sufficiently large populations. This sort of cost–benefit analysis is not bad, but merely incomplete. The author assumes, as he should, that health is good, but he also appears to make the common assumption that there is no other significant or perhaps higher good that deserves attention. Because it is possible that something more important than health might be jeopardized by some vaccines, it is insufficient to sanction the production and use of vaccines solely on the basis of their health benefits measured against their health risks and financial costs. To charge the author of the text in question with an incomplete treatment is not yet to accuse him of moral failure, but only of not raising the question of whether the production and use of all vaccines is itself free of moral difficulty.
    • p.54
  • This raises a difficult medical question that goes beyond the scope of this paper. In any given population, there are a certain number of people who remain unimmunized against various diseases. Assuming that these people are a sufficiently small portion of the population (such that an outbreak would not lead to each case infecting on average more than one other person), the population is said to benefit from herd immunity (Theodore C. Eickhoff, “Airborne Disease: Including Chemical and Biological Warfare,” American Journal of Epidemiology 144.8 Supp. (1996): S39–S46). Herd immunity could easily support some few isolated individuals and their families who objected to certain vaccines on moral grounds. Whether large numbers of people concentrated in one area, such as a parish, would present the risk of an epidemic would require additional medical research. Conyn-van Spaendonck writes: “The risk of poliomyelitis was restricted to religious subpopulations rejecting vaccination. Unvaccinated persons in the general population appeared to be protected by herd immunity and the persons above 40 years of age, by natural immunity” (“Circulation of Poliovirus,” 934). David Mowery and Violaine Mitchell assess the herd immunity in the United States as “relatively fragile” based upon the childhood measles epidemic of 1989 to 1991 (“Improving the Reliability of the U.S. Vaccine Supply,” 975). See also M. Carolina Danovaro-Holliday et al., “A Large Rubella Outbreak with Spread from the Workplace to the Community,” Journal of the American Medical Association 284.21 (6 December 2000): 2733–39.
    • Footnote 45, p.66

Deadly Choices: How the Anti-Vaccine Movement Threatens Us All (April 3, 2012)

Offit, Paul A. (April 3, 2012). “Deadly Choices: How the Anti-Vaccine Movement Threatens Us All”.

  • There's a war going on out there- a quiet, deadly war.
    On one side are parents. Every week they're bombarded with stories about the dangers of vaccines. They hear that babies get too many vaccines, overwhelming their immune systems-then they watch them get as many as thirty-five shots in a span of only a few years and sometimes five at one time. They hear that vaccines cause chronic diseases. And they hear this from people they trust: celebrities like Oprah Winfrey, Larry King, Bill Maher, Don Imus, Jenny McCarthy, and Jim Carrey; elected representatives like Carolyn Maloney, Chris Smith, Dave Weldon, and Dan Burton; television correspondents like Sharyl Attkisson of CBS Evening News; and popular doctors like Mehmet Oz and Robert Sears. Nit mostly they hear it from parents like themselves-parents who claim their children were fine one minute, got a vaccine, then weren't fine anymore. Understandably, some parents are backing away from vaccines; one in ten are choosing not to give one or more vaccines. Some aren't giving any vaccines at all; since 1991 the percentage of unvaccinated children has more than doubled.
    On the other side are doctors. Weary of parents who insist on individualized schedules, scared to send children out of their offices unvaccinated, and concerned that their waiting rooms, packed with unvaccinated children, are becoming a dangerous place, they're taking a stand. As many as four in ten pediatricians now refuse to see families who don't vaccinate, causing some parents to seek the comfort of doctors or chiropractors more willing to do what they ask.
    Caught in the middle are children. Left vulnerable, they're suffering the diseases of their grandparents. Recent outbreaks of measles, mumps, whooping cough, and bacterial meningitis have caused hundreds to suffer and some to die-die because their parents feared vaccines more than the diseases they prevent.
    Amid the confusion, another group has emerged: parents angry that unvaccinated children have put their children at risk. Some of these parents have children who can't be vaccinated. Weakened by chemotherapy for their cancers, or immunosuppressive therapy for their transplants, or steroid therapy for their asthma, these children are particularly vulnerable. They depend on those around them to be vaccinated; if not, they're the ones most likely to suffer during outbreaks.
    • pp.ix-x
  • Most parents today have probably never heard of Hib. But older doctors certainly remember it; so do grandparents. Before the vaccine, Hib caused meningitis, bloodstream infections, and pneumonia in twenty thousand children every year, killing a thousand and leaving many with permanent brain damage. Today's outbreaks are a fraction of what they were in the past. But, as more parents choose not to vaccinate, more outbreaks of preventable infections are popping up across the country. And more children are needlessly harmed. The phenomenon doesn't seem to be going away.
    • p.xii
  • The Indiana and nation wide outbreaks shared one important feature: in both cases, the first infection occurred outside the United States. This isn't unusual. Every year about sixty people traveling from countries where immunization rates are lower, such as Switzerland, Austria, Ireland, Israel, the Netherlands, Japan, and the United Kingdom, enter the United States with measles. Indeed, all of these countries continue to suffer measles outbreaks. But the situation in 2008 was different; this time measles spread form one unvaccinated American child to another to another. The problem wasn't that national immunization rates were low; they were actually quite high. The problem was that certain communities had so many unvaccinated children that infections could spread unchecked.
    • p.xv-xvi
  • In the early 1900s, children routinely suffered and died from diseases now easily prevented by vaccines. Americans could expect that every year diptheria would kill twelve thousand people, mostly young children; rubella (German measles) would cause as many as twenty thousand babies to be born blind, deaf, or mentally disabled; polio would permanently paralyze fifteen thousand children and kill a thousand; and mumps would be a common cause of deafness. Because of vaccines, all these diseases have been completely or virtually eliminated. But now, because more and more parents are choosing not to vaccinate their children, some of these diseases are coming back.
    How did we get here? How did we come to believe that vaccines, rather than saving our lives, are something to fear? The answer to that question is rooted in one of the most powerful citizen activist groups in American history; founded in 1982, it is a group that, despite recent epidemics and deaths, has continued to gain followers in both the United States and the world.
    • p.xviii
  • On May 7, 1982, Senator Paula Hawkins, a Republican from Florida, called a hearing before the Committee on Labor and Human Resources of the U.S. Senate. Only eighteen days had elapsed since the airing of “Vaccine Roulette”. The speed of the Hawkins hearing was the result of a series of chance events. Lea Thompson had first become interested in pertussis vaccine after she'd been contacted b the parents of Tony and Leo Resciniti, the teenagers from New York who hd apparently suffered permanent brain damage. The Rescinities, as it turned out, were cousins of Dan Mica, a Republican Congressman from Florida. On April 28, 1982, nine days before the Hawkins hearing, Kathi Williams, Jeff Schwartz, Barbara Loe Fisher, and several other parents met to discuss strategy at Dan Mica's office in Washington, D.C. Mica's brother, John, was on Paula Hawkins's staff.
    Hawkins opened her hearing with a statement. “The immunization program s now threatened on another front,” she warned: “the fear of adverse health events resulting from immunization. To combat this fear and to achieve and maintain high immunization rates, full public communication and health education is essential. The general public has a right to be given information about vaccines-even in areas of scientific or medical uncertainty.” Hawkin then made an ominous and all-too-accurate prediction of future events. “It would be tragic if efforts to eliminate or control communicable disease were to become hampered because ethe public's confidence was so eroded as to cause frightened segments of the population to oppose and reject vaccines. Neither can be afford revival of serious childhood epidemics because a complacent and apathetic public, with a diminishing memory, forgets the iron lung.”
    One of the first parents to testify was Kathi Williams. On behalf of Dissatisfied Parents Together, she made a list of demands. “Number one: Although several studies have been done, why has the government had a limited research program dealing with adverse effects of vaccines? Number two: Why hasn't a safer vaccine been developed? Number three: Why haven't high-risk children been identified? Number four: Why haven't physicians been required to report adverse reactions to a central record keeping agency? Number five: Why haven't physicians and parents been better informed about the possible reactions to the pertussis vaccine? Number six: Should the states mandate that the present pertussis vaccine be given to all children who attend school? Number seven: Should there be a compensation program for children who have been retarded or seriously disabled by the pertussis vaccine?”
    Remarkably, within a few years, almost all of Kathi Williams's demands would be met.
    • pp.8-10
  • On Friday, October 26, 1973, John Wilson, a pediatric neurologist, stood in front of a group of professors, consultants, and specialists at the Royal Society of Medicine in London. Wilson placed a typed manuscript on the lectern and looked up. What he was about to say arguably would lead to more suffering, more hospitilizations, more permanent disabilities, and more deaths than any other pronouncement in the history of vaccines.
    “Between January 1961 and December 1972,” Wilson began, “approximately fifty children have been seen at the Hospital for Sick Children in London because of neurological illness thought to be due to the DTP inoculation.” For years Wilson had accumulated these children's stories. For years he had struggled with the damage caused by pertussis vaccine. Now it was time to tell the world about it. Wilson reported one child who had transient blindness and mental deterioration. Another had vomited for four days, become blind, and died six months later during an uncontrolled seizure. Yet another ahd been completely paralyzed on one side of her body. The final accounting was grim: of fifty children studied, twenty-two had become mentally disabled or epileptic or both. To John Wilson, the cause of all of this suffering and death was clear. “We do not think . . . that the majority of cases here represent a chance association,” he said. Wilson was convinced by “the clustering of illness in the seven days after innoculation and particularly in the first 24 hours” that the damage had been caused by pertussis vaccine.
    • Chapter 2 This England, pp.13-14
  • Although he was the most influential, John Wilson wasn't the first to propose that pertussis vaccine permanently harmed or killed children.
    In 1933 Thorvald Madsen from the State Serum Institute in Denmark reported two children who had died after receiving pertussis vaccine.
    In 1946 Jacob Weren and Irene Garrow from St. John's Long Island City Hospital in New York reported twin brothers two “cried considerably,” “vomited,” fell asleep,” and “when next noticed by their parents, appeared 'lifeless.'” One child was dead on arrival t the hospital; the other died a few hours later.
    In 1948 Randolph Byers and Frederic Moll, from Boston Children's Hospital and Harvard Medical School, reported fifteen children with seizures, coma, or paralysis within a day or receiving pertussis vaccine. Most became severely retarded; two died.
    In 1960 Justus Strom from the Hospital for Infectious Diseases in Stockhold, Sweden, reported thirty-six children harmed by pertussis vaccine. “In twenty-four of these, the initial symptom was convulsions, in six cases coma, and in four, acute collapse.” Seven years later, Strom examined the records of more than five hundred thousand children, this time finding one hundred and seventy with seizures or “destructive brain dysfunction” or shock.
    • p.14
  • In 1973, when John Wilson finished his presentation to the Royal Society of Medicine a murmur spread through the crowd. The society was one of the most prestigious institutions in London, and Wilson worked at the Hospital or Sick Children at Great Ormond Street, a world-renowned medical center. Further, Wilson, a doctor of philosophy and medicine, was a member of the prestigious Royal College of Physicians. When John Wilson said that pertussis vaccine caused brain damage, the charge was taken seriously.
    • p.14

“mRNA vaccines — a new era in vaccinology” (12 January 2018)

Norbert Pardi, Michael J. Hogan, Frederick W. Porter & Drew Weissman; “mRNA vaccines — a new era in vaccinology”, Nature Reviews Drug Discovery, (12 January 2018), volume 17, pp. 261–279

  • mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.
  • Nucleic acid therapeutics have emerged as promising alternatives to conventional vaccine approaches. The first report of the successful use of in vitro transcribed (IVT) mRNA in animals was published in 1990, when reporter gene mRNAs were injected into mice and protein production was detected5. A subsequent study in 1992 demonstrated that administration of vasopressin-encoding mRNA in the hypothalamus could elicit a physiological response in rats. However, these early promising results did not lead to substantial investment in developing mRNA therapeutics, largely owing to concerns associated with mRNA instability, high innate immunogenicity and inefficient in vivo delivery. Instead, the field pursued DNA-based and protein-based therapeutic approaches.
    Over the past decade, major technological innovation and research investment have enabled mRNA to become a promising therapeutic tool in the fields of vaccine development and protein replacement therapy. The use of mRNA has several beneficial features over subunit, killed and live attenuated virus, as well as DNA-based vaccines. First, safety: as mRNA is a non-infectious, non-integrating platform, there is no potential risk of infection or insertional mutagenesis. Additionally, mRNA is degraded by normal cellular processes, and its in vivo half-life can be regulated through the use of various modifications and delivery methods. The inherent immunogenicity of the mRNA can be down-modulated to further increase the safety profile. Second, efficacy: various modifications make mRNA more stable and highly translatable. Efficient in vivo delivery can be achieved by formulating mRNA into carrier molecules, allowing rapid uptake and expression in the cytoplasm (reviewed in Refs 10,11). mRNA is the minimal genetic vector; therefore, anti-vector immunity is avoided, and mRNA vaccines can be administered repeatedly. Third, production: mRNA vaccines have the potential for rapid, inexpensive and scalable manufacturing, mainly owing to the high yields of in vitro transcription reactions.
  • mRNA is the intermediate step between the translation of protein-encoding DNA and the production of proteins by ribosomes in the cytoplasm. Two major types of RNA are currently studied as vaccines: non-replicating mRNA and virally derived, self-amplifying RNA. Conventional mRNA-based vaccines encode the antigen of interest and contain 5′ and 3′ untranslated regions (UTRs), whereas self-amplifying RNAs encode not only the antigen but also the viral replication machinery that enables intracellular RNA amplification and abundant protein expression.
    The construction of optimally translated IVT mRNA suitable for therapeutic use has been reviewed previously. Briefly, IVT mRNA is produced from a linear DNA template using a T7, a T3 or an Sp6 phage RNA polymerase16. The resulting product should optimally contain an open reading frame that encodes the protein of interest, flanking UTRs, a 5′ cap and a poly(A) tail. The mRNA is thus engineered to resemble fully processed mature mRNA molecules as they occur naturally in the cytoplasm of eukaryotic cells.
    Complexing of mRNA for in vivo delivery has also been recently detailed. Naked mRNA is quickly degraded by extracellular RNases and is not internalized efficiently. Thus, a great variety of in vitro and in vivo transfection reagents have been developed that facilitate cellular uptake of mRNA and protect it from degradation. Once the mRNA transits to the cytosol, the cellular translation machinery produces protein that undergoes post-translational modifications, resulting in a properly folded, fully functional protein. This feature of mRNA pharmacology is particularly advantageous for vaccines and protein replacement therapies that require cytosolic or transmembrane proteins to be delivered to the correct cellular compartments for proper presentation or function. IVT mRNA is finally degraded by normal physiological processes, thus reducing the risk of metabolite toxicity.
  • Various mRNA vaccine platforms have been developed in recent years and validated in studies of immunogenicity and efficacy. Engineering of the RNA sequence has rendered synthetic mRNA more translatable than ever before. Highly efficient and non-toxic RNA carriers have been developed that in some cases allow prolonged antigen expression in vivo. Some vaccine formulations contain novel adjuvants, while others elicit potent responses in the absence of known adjuvants. The following section summarizes the key advances in these areas of mRNA engineering and their impact on vaccine efficacy.
  • Physical delivery methods in vivo. To increase the efficiency of mRNA uptake in vivo, physical methods have occasionally been used to penetrate the cell membrane. An early report showed that mRNA complexed with gold particles could be expressed in tissues using a gene gun, a microprojectile method. The gene gun was shown to be an efficient RNA delivery and vaccination method in mouse models, but no efficacy data in large animals or humans are available. In vivo electroporation has also been used to increase uptake of therapeutic RNA; however, in one study, electroporation increased the immunogenicity of only a self-amplifying RNA and not a non-replicating mRNA-based vaccine. Physical methods can be limited by increased cell death and restricted access to target cells or tissues. Recently, the field has instead favoured the use of lipid or polymer-based nanoparticles as potent and versatile delivery vehicles.
  • Cationic lipid and polymer-based delivery. Highly efficient mRNA transfection reagents based on cationic lipids or polymers, such as TransIT-mRNA (Mirus Bio LLC) or Lipofectamine (Invitrogen), are commercially available and work well in many primary cells and cancer cell lines, but they often show limited in vivo efficacy or a high level of toxicity (N.P. and D.W., unpublished observations). Great progress has been made in developing similarly designed complexing reagents for safe and effective in vivo use, and these are discussed in detail in several recent reviews. Cationic lipids and polymers, including dendrimers, have become widely used tools for mRNA administration in the past few years. The mRNA field has clearly benefited from the substantial investment in in vivo small interfering RNA (siRNA) administration, where these delivery vehicles have been used for over a decade. Lipid nanoparticles (LNPs) have become one of the most appealing and commonly used mRNA delivery tools. LNPs often consist of four components: an ionizable cationic lipid, which promotes self-assembly into virus-sized (~100 nm) particles and allows endosomal release of mRNA to the cytoplasm; lipid-linked polyethylene glycol (PEG), which increases the half-life of formulations; cholesterol, a stabilizing agent; and naturally occurring phospholipids, which support lipid bilayer structure. Numerous studies have demonstrated efficient in vivo siRNA delivery by LNPs (reviewed in Ref. 81), but it has only recently been shown that LNPs are potent tools for in vivo delivery of self-amplifying RNA19 and conventional, non-replicating mRNA21. Systemically delivered mRNA–LNP complexes mainly target the liver owing to binding of apolipoprotein E and subsequent receptor-mediated uptake by hepatocytes, and intradermal, intramuscular and subcutaneous administration have been shown to produce prolonged protein expression at the site of the injection. The mechanisms of mRNA escape into the cytoplasm are incompletely understood, not only for artificial liposomes but also for naturally occurring exosomes. Further research into this area will likely be of great benefit to the field of therapeutic RNA delivery.
  • Development of prophylactic or therapeutic vaccines against infectious pathogens is the most efficient means to contain and prevent epidemics. However, conventional vaccine approaches have largely failed to produce effective vaccines against challenging viruses that cause chronic or repeated infections, such as HIV-1, herpes simplex virus and respiratory syncytial virus (RSV). Additionally, the slow pace of commercial vaccine development and approval is inadequate to respond to the rapid emergence of acute viral diseases, as illustrated by the 2014–2016 outbreaks of the Ebola and Zika viruses. Therefore, the development of more potent and versatile vaccine platforms is crucial.
    Preclinical studies have created hope that mRNA vaccines will fulfill many aspects of an ideal clinical vaccine: they have shown a favourable safety profile in animals, are versatile and rapid to design for emerging infectious diseases, and are amenable to scalable good manufacturing practice (GMP) production (already under way by several companies). Unlike protein immunization, several formats of mRNA vaccines induce strong CD8+ T cell responses, likely owing to the efficient presentation of endogenously produced antigens on MHC class I molecules, in addition to potent CD4+ T cell responses. Additionally, unlike DNA immunization, mRNA vaccines have shown the ability to generate potent neutralizing antibody responses in animals with only one or two low-dose immunizations. As a result, mRNA vaccines have elicited protective immunity against a variety of infectious agents in animal models and have therefore generated substantial optimism. However, recently published results from two clinical trials of mRNA vaccines for infectious diseases were somewhat modest, leading to more cautious expectations about the translation of preclinical success to the clinic (discussed further below).
    Two major types of RNA vaccine have been utilized against infectious pathogens: self-amplifying or replicon RNA vaccines and non-replicating mRNA vaccines. Non-replicating mRNA vaccines can be further distinguished by their delivery method: ex vivo loading of DCs or direct in vivo injection into a variety of anatomical sites. As discussed below, a rapidly increasing number of preclinical studies in these areas have been published recently, and several have entered human clinical trials.
  • Nucleoside-modified mRNA vaccines represent a new and highly efficacious category of mRNA vaccines. Owing to the novelty of this immunization platform, our knowledge of efficacy is limited to the results of four recent publications that demonstrated the potency of such vaccines in small and large animals. The first published report demonstrated that a single intradermal injection of LNP-formulated mRNA encoding Zika virus prM-E, modified with 1-methylpseudouridine and FPLC purification, elicited protective immune responses in mice and rhesus macaques with the use of as little as 50 μg (0.02 mg kg−1) of vaccine in macaques20. A subsequent study by a different group tested a similarly designed vaccine against Zika virus in mice and found that a single intramuscular immunization elicited moderate immune responses, and a booster vaccination resulted in potent and protective immune responses85. This vaccine also incorporated the modified nucleoside 1-methylpseudouridine, but FPLC purification or other methods of removing dsRNA contaminants were not reported. Notably, this report showed that antibody-dependent enhancement of secondary infection with a heterologous flavivirus, a major concern for dengue and Zika virus vaccines, could be diminished by removing a cross-reactive epitope in the E protein. A recent follow-up study evaluated the same vaccine in a model of maternal vaccination and fetal infection. Two immunizations reduced Zika virus infection in fetal mice by several orders of magnitude and completely rescued a defect in fetal viability.
  • mRNA-based cancer vaccines have been recently and extensively reviewed. Below, the most recent advances and directions are highlighted. Cancer vaccines and other immunotherapies represent promising alternative strategies to treat malignancies. Cancer vaccines can be designed to target tumour-associated antigens that are preferentially expressed in cancerous cells, for example, growth-associated factors, or antigens that are unique to malignant cells owing to somatic mutation. These neoantigens, or the neoepitopes within them, have been deployed as mRNA vaccine targets in humans. Most cancer vaccines are therapeutic, rather than prophylactic, and seek to stimulate cell-mediated responses, such as those from CTLs, that are capable of clearing or reducing tumour burden122. The first proof-of-concept studies that not only proposed the idea of RNA cancer vaccines but also provided evidence of the feasibility of this approach were published more than two decades ago. Since then, numerous preclinical and clinical studies have demonstrated the viability of mRNA vaccines to combat cancer.
  • As DCs are central players in initiating antigen-specific immune responses, it seemed logical to utilize them for cancer immunotherapy. The first demonstration that DCs electroporated with mRNA could elicit potent immune responses against tumour antigens was reported by Boczkowski and colleagues in 1996 (Ref. 124). In this study, DCs pulsed with ovalbumin (OVA)-encoding mRNA or tumour-derived RNAs elicited a tumour-reducing immune response in OVA-expressing and other melanoma models in mice. A variety of immune regulatory proteins have been identified in the form of mRNA-encoded adjuvants that can increase the potency of DC cancer vaccines. Several studies demonstrated that electroporation of DCs with mRNAs encoding co-stimulatory molecules such as CD83, tumour necrosis factor receptor superfamily member 4 (TNFRSF4; also known as OX40) and 4-1BB ligand (4-1BBL) resulted in a substantial increase in the immune stimulatory activity of DCs. DC functions can also be modulated through the use of mRNA-encoded pro-inflammatory cytokines, such as IL-12, or trafficking-associated molecules129,130,131. As introduced above, TriMix is a cocktail of mRNA-encoded adjuvants (CD70, CD40L and constitutively active TLR4) that can be electroporated in combination with antigen-encoding mRNA or mRNAs132. This formulation proved efficacious in multiple preclinical studies by increasing DC activation and shifting the CD4+ T cell phenotype from T regulatory cells to T helper 1 (TH1)-like cells. Notably, the immunization of patients with stage III or stage IV melanoma using DCs loaded with mRNA encoding melanoma-associated antigens and TriMix adjuvant resulted in tumour regression in 27% of treated individuals. Multiple clinical trials have now been conducted using DC vaccines targeting various cancer types, such as metastatic prostate cancer, metastatic lung cancer, renal cell carcinoma, brain cancers, melanoma, acute myeloid leukaemia, pancreatic cancer and others (reviewed in Refs 51,58).
    A new line of research combines mRNA electroporation of DCs with traditional chemotherapy agents or immune checkpoint inhibitors. In one trial, patients with stage III or IV melanoma were treated with ipilimumab, a monoclonal antibody against CTL antigen 4 (CTLA4), and DCs loaded with mRNA encoding melanoma-associated antigens plus TriMix. This intervention resulted in durable tumour reduction in a proportion of individuals with recurrent or refractory melanoma.
  • The route of administration and delivery format of mRNA vaccines can greatly influence outcomes. A variety of mRNA cancer vaccine formats have been developed using common delivery routes (intradermal, intramuscular, subcutaneous or intranasal) and some unconventional routes of vaccination (intranodal, intravenous, intrasplenic or intratumoural).
    Intranodal administration of naked mRNA is an unconventional but efficient means of vaccine delivery. Direct mRNA injection into secondary lymphoid tissue offers the advantage of targeted antigen delivery to antigen-presenting cells at the site of T cell activation, obviating the need for DC migration. Several studies have demonstrated that intranodally injected naked mRNA can be selectively taken up by DCs and can elicit potent prophylactic or therapeutic antitumour T cell responses62,66; an early study also demonstrated similar findings with intrasplenic delivery141. Coadministration of the DC-activating protein FMS-related tyrosine kinase 3 ligand (FLT3L) was shown in some cases to further improve immune responses to intranodal mRNA vaccination142,143. Incorporation of the TriMix adjuvant into intranodal injections of mice with mRNAs encoding tumour-associated antigens resulted in potent antigen-specific CTL responses and tumour control in multiple tumour models133. A more recent study demonstrated that intranodal injection of mRNA encoding the E7 protein of human papillomavirus (HPV) 16 with TriMix increased the number of tumour-infiltrating CD8+ T cells and inhibited the growth of an E7-expressing tumour model in mice67.
    The success of preclinical studies has led to the initiation of clinical trials using intranodally injected naked mRNA encoding tumour-associated antigens into patients with advanced melanoma (NCT01684241) and patients with hepatocellular carcinoma (EudraCT: 2012-005572-34). In one published trial, patients with metastatic melanoma were treated with intranodally administered DCs electroporated with mRNA encoding the melanoma-associated antigens tyrosinase or gp100 and TriMix, which induced limited antitumour responses144.
    Intranasal vaccine administration is a needle-free, noninvasive manner of delivery that enables rapid antigen uptake by DCs. Intranasally delivered mRNA complexed with Stemfect (Stemgent) LNPs resulted in delayed tumour onset and increased survival in prophylactic and therapeutic mouse tumour models using the OVA-expressing E.G7-OVA T lymphoblastic cell line145.
  • Intratumoural mRNA vaccination is a useful approach that offers the advantage of rapid and specific activation of tumour-resident T cells. Often, these vaccines do not introduce mRNAs encoding tumour-associated antigens but simply aim to activate tumour-specific immunity in situ using immune stimulatory molecules. An early study demonstrated that naked mRNA or protamine-stabilized mRNA encoding a non-tumour related gene (GLB1) impaired tumour growth and provided protection in a glioblastoma mouse model, taking advantage of the intrinsic immunogenic properties of mRNA146. A more recent study showed that intratumoural delivery of mRNA encoding an engineered cytokine based on interferon-β (IFNβ) fused to a transforming growth factor-β (TGFβ) antagonist increased the cytolytic capacity of CD8+ T cells and modestly delayed tumour growth in OVA-expressing lymphoma or lung carcinoma mouse models147. It has also been shown that intratumoural administration of TriMix mRNA that does not encode tumour-associated antigens results in activation of CD8α+ DCs and tumour-specific T cells, leading to delayed tumour growth in various mouse models.
  • Systemic administration of mRNA vaccines is not common owing to concerns about aggregation with serum proteins and rapid extracellular mRNA degradation; thus, formulating mRNAs into carrier molecules is essential. As discussed above, numerous delivery formulations have been developed to facilitate mRNA uptake, increase protein translation and protect mRNA from RNases. Another important issue is the biodistribution of mRNA vaccines after systemic delivery. Certain cationic LNP-based complexing agents delivered intravenously traffic mainly to the liver, which may not be ideal for DC activation. An effective strategy for DC targeting of mRNA vaccines after systemic delivery has recently been described. An mRNA–lipoplex (mRNA–liposome complex) delivery platform was generated using cationic lipids and neutral helper lipids formulated with mRNA, and it was discovered that the lipid-to-mRNA ratio, and thus the net charge of the particles, has a profound impact on the biodistribution of the vaccine. While a positively charged lipid particle primarily targeted the lung, a negatively charged particle targeted DCs in secondary lymphoid tissues and bone marrow. The negatively charged particle induced potent immune responses against tumour-specific antigens that were associated with impressive tumour reduction in various mouse models. As no toxic effects were observed in mice or non-human primates, clinical trials using this approach to treat patients with advanced melanoma or triple-negative breast cancer have been initiated (NCT02410733 and NCT02316457).
  • A variety of antigen-presenting cells reside in the skin, making it an ideal site for immunogen delivery during vaccination. Thus, the intradermal route of delivery has been widely used for mRNA cancer vaccines. An early seminal study demonstrated that intradermal administration of total tumour RNA delayed tumour growth in a fibrosarcoma mouse model. Intradermal injection of mRNA encoding tumour antigens in the protamine-based RNActive platform proved efficacious in various mouse models of cancer and in multiple prophylactic and therapeutic clinical settings. One such study demonstrated that mRNAs encoding survivin and various melanoma tumour antigens resulted in increased numbers of antigen-specific T cells in a subset of patients with melanoma. In humans with castration-resistant prostate cancer, an RNActive vaccine expressing multiple prostate cancer-associated proteins elicited antigen-specific T cell responses in the majority of recipients. Lipid-based carriers have also contributed to the efficacy of intradermally delivered mRNA cancer vaccines. The delivery of OVA-encoding mRNA in DOTAP and/or DOPE liposomes resulted in antigen-specific CTL activity and inhibited growth of OVA-expressing tumours in mice. In the same study, coadministration of mRNA encoding granulocyte–macrophage colony-stimulating factor (GM-CSF) improved OVA-specific cytolytic responses. Another report showed that subcutaneous delivery of LNP-formulated mRNA encoding two melanoma-associated antigens delayed tumour growth in mice, and co-delivery of lipopolysaccharide (LPS) in LNPs increased both CTL and antitumour activity. In general, mRNA cancer vaccines have proved immunogenic in humans, but further refinement of vaccination methods, as informed by basic immunological research, will likely be necessary to achieve greater clinical benefits.
  • Once the mRNA is synthesized, it is processed though several purification steps to remove reaction components, including enzymes, free nucleotides, residual DNA and truncated RNA fragments. While LiCl precipitation is routinely used for laboratory-scale preparation, purification at the clinical scale utilizes derivatized microbeads in batch or column formats, which are easier to utilize at large scale. For some mRNA platforms, removal of dsRNA and other contaminants is critical for the potency of the final product, as it is a potent inducer of interferon-dependent translation inhibition. This has been accomplished by reverse-phase FPLC at the laboratory scale, and scalable aqueous purification approaches are being investigated. After mRNA is purified, it is exchanged into a final storage buffer and sterile-filtered for subsequent filling into vials for clinical use. RNA is susceptible to degradation by both enzymatic and chemical pathways. Formulation buffers are tested to ensure that they are free of contaminating RNases and may contain buffer components, such as antioxidants and chelators, which minimize the effects of reactive oxygen species and divalent metal ions that lead to mRNA instability.
  • Several different mRNA vaccines have now been tested from phase I to IIb clinical studies and have been shown to be safe and reasonably well tolerated. However, recent human trials have demonstrated moderate and in rare cases severe injection site or systemic reactions for different mRNA platforms. Potential safety concerns that are likely to be evaluated in future preclinical and clinical studies include local and systemic inflammation, the biodistribution and persistence of expressed immunogen, stimulation of auto-reactive antibodies and potential toxic effects of any non-native nucleotides and delivery system components. A possible concern could be that some mRNA-based vaccine platforms induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity. Thus, identification of individuals at an increased risk of autoimmune reactions before mRNA vaccination may allow reasonable precautions to be taken. Another potential safety issue could derive from the presence of extracellular RNA during mRNA vaccination. Extracellular naked RNA has been shown to increase the permeability of tightly packed endothelial cells and may thus contribute to oedema. Another study showed that extracellular RNA promoted blood coagulation and pathological thrombus formation. Safety will therefore need continued evaluation as different mRNA modalities and delivery systems are utilized for the first time in humans and are tested in larger patient populations.
  • The fast pace of progress in mRNA vaccines would not have been possible without major recent advances in the areas of innate immune sensing of RNA and in vivo delivery methods. Extensive basic research into RNA and lipid and polymer biochemistry has made it possible to translate mRNA vaccines into clinical trials and has led to an astonishing level of investment in mRNA vaccine companies. Moderna Therapeutics, founded in 2010, has raised almost US$2 billion in capital with a plan to commercialize mRNA-based vaccines and therapies. The US Biomedical Advanced Research and Development Authority (BARDA) has committed support for Moderna's clinical evaluation of a promising nucleoside-modified mRNA vaccine for Zika virus (NCT03014089). In Germany, CureVac AG has an expanding portfolio of therapeutic targets, including both cancer and infectious diseases, and BioNTech is developing an innovative approach to personalized cancer medicine using mRNA vaccines. The translation of basic research into clinical testing is also made more expedient by the commercialization of custom GMP products by companies such as New England Biolabs and Aldevron. Finally, the recent launch of the Coalition for Epidemic Preparedness Innovations (CEPI) provides great optimism for future responses to emerging viral epidemics. This multinational public and private partnership aims to raise $1 billion to develop platform-based vaccines, such as mRNA, to rapidly contain emerging outbreaks before they spread out of control.

History of vaccination (Aug 26, 2014)

Stanley Plotkin, ”History of vaccination”, Proc Natl Acad Sci U S A. 2014 Aug 26; 111(34): 12283–12287.

  • Vaccines have a history that started late in the 18th century. From the late 19th century, vaccines could be developed in the laboratory. However, in the 20th century, it became possible to develop vaccines based on immunologic markers. In the 21st century, molecular biology permits vaccine development that was not possible before.
    One of the brightest chapters in the history of science is the impact of vaccines on human longevity and health. Over 300 years have elapsed since the first vaccine was discovered.
  • In current articles that describe novel technologies, it is often said that they will enable “rational” development of vaccines. The opposite of rational is irrational, but presumably the writers mean to contrast rational with “empiric.” However, in fact, vaccine development has been based on rational choices ever since the mid-20th century, when immunology advanced to the point of distinguishing protection mediated by antibody and that mediated by lymphocytes, and when passage in cell culture permitted the selection of attenuated mutants. After that point, successful vaccines have been “rationally” developed by protection studies in animals; by inference from immune responses shown to protect against repeated natural infection (the so-called mechanistic correlates of protection); and from the use of passive administration of antibodies against specific antigens to show that those antigens should be included in vaccines.
  • The idea of attenuation of virulent infections developed slowly over the course of centuries. Variolation was analogous to the use of small amounts of poison to render one immune to toxic effects. Jenner's use of an animal poxvirus (probably horsepox) to prevent smallpox was essentially based on the idea that an agent virulent for animals might be attenuated in humans. This idea played a role in the development of bacillus Calmette–Guérin but is even more obvious in the selection of rhesus and bovine rotavirus strains to aid the creation of human rotavirus vaccines as mentioned below under Reassortment.
    It was Pasteur and his colleagues who most clearly formulated the idea of attenuation and demonstrated its utility, first with Pasteurella multocida, the cause of a diarrheal disease in chickens, then anthrax in sheep and most sensationally rabies virus in animals and humans. Their first approaches involved exposure to oxygen or heat, both of which played a role in the development of the rabies vaccine and in the famous anthrax challenge experiment at Pouilly-le-Fort. However, the more powerful technique of serial cultivation of a pathogen in vitro or in inhabitual hosts originated with Calmette and Guérin, who passaged bovine tuberculosis bacteria 230 times in artificial media to obtain an attenuated strain to protect against human tuberculosis. Later in the 20th century, Sellards and Laigret and, more successfully, Theiler and Smith attenuated yellow fever virus by serial passage in mice and in chicken embryo tissues, respectively.
  • By the 1940s, virologists understood that attenuation could be achieved by passage in abnormal hosts. Notably, Hilary Koprowski and coworkers developed rabies and oral polio vaccines by passage in chicken embryo or mice. However, this method was inefficient, and mice were not a sterile medium. A revolution happened with the discovery that cells could be cultured in vitro and used as substrates for viral growth. Enders, Weller, and Robbins showed that many viruses could be grown in cell culture, including polio and measles, and this method was vigorously taken up by vaccine developers. The oral polio vaccine of Albert Sabin and the measles, rubella, mumps, and varicella vaccines were all made possible through selection of clones by cell-culture passage in vitro. In essence, passage in cell culture leads to adaptation to growth in that medium, and the mutants best capable of growth have often lost or modified the genes that allow them to infect and spread within a human host. The oral polio vaccine is a good example, in that the mutants that occur in cell-culture passage that confer inability to cause paralysis were isolated by selection of clones with low neurovirulence in monkeys. These mutations are at least partly lost after replication of attenuated strains in the human intestine, leading to rare cases of paralysis after vaccination. Adaptation of viruses to growth at temperatures below 37 °C, the normal temperature of humans, also is attenuating, as was the case for rubella vaccine. Another live vaccine, thus far used only in the military to prevent epidemic pneumonia, consists of adeno 4 and 7 viruses grown in human diploid cell strains and administered orally to replicate in the intestine. Other live vaccines attenuated in cell-culture passage are the monovalent rotavirus vaccine attenuated by passage in Vero cells and the Japanese encephalitis strain SA14-14-2.
  • Certain RNA viruses have segmented genomes that can be manipulated in a way similar to the chromosomes of eukaryotes. Cocultivation of two viruses in cell culture with clone selection by plaque formation allows isolation of viruses with RNA segments from both viruses. Reassortment has enabled the creation of three major vaccines: live and inactivated influenza, as well as one of the two rotavirus vaccines. In the case of inactivated influenza, the objective is to select the segments coding for hemagglutinin and neuraminidase and to combine them with segments coding for the internal genes of viruses that grow well. Thus, one obtains a vaccine virus that is safe to handle but still generates functional antibodies against virulent influenza strains.
  • Another discovery toward the end of the 19th century was that immunogenicity could be retained if bacteria were carefully killed by heat or chemical treatment. The first inactivated vaccines were developed more or less simultaneously by Salmon and Smith in the United States and the Pasteur Institute group (Roux and Chamberland) in France. Inactivation was first applied to pathogens such as the typhoid, plague, and cholera bacilli. This era was marked by competition between French, German, and English workers to develop antibacterial vaccines. Inactivated vaccines against typhoid were first applied by Wright and Semple in England and Pfeiffer and Kolle in Germany. Humans were vaccinated against plague by Haffkine, using inactivated plague bacilli. Live vaccines against cholera were developed by Ferran in Spain and Haffkine in France, but it was ultimately the vaccine developed by Kolle using heat-inactivated cholera bacilli that came into general use. That vaccine was given parenterally but was painful and did not give long-lasting immunity. More recently, a vaccine was developed that consists of orally administered killed cholera bacteria, with or without the B subunit of cholera toxin. Formalin-inactivated whole-cell pertussis vaccine was first tested by Madsen and was later shown to be relatively successful in controlling serious disease. However, it was the later work of Kendrick and Eldering that permitted standardization and safety of a whole-cell vaccine.
    In 1923, Glenny and Hopkins made diphtheria toxin less toxic by formalin treatment. Ramon improved on this discovery and showed it was possible to inactivate the toxicity of those molecules yet retain their ability to induce toxin-neutralizing antibodies.
    In the 20th century, chemical inactivation was also applied to viruses. Influenza vaccine was the first successful inactivated virus vaccine, and experience with that vaccine served Salk well in his successful effort to develop an inactivated polio vaccine. Later, hepatitis A vaccine was prepared by Provost and coworkers, also based on chemical inactivation. The excellent efficacy of the latter testifies to the ability of careful inactivation to maintain immunogenicity.
    Whole inactivated viruses or subunits of virus have been used to make successful vaccines against Japanese encephalitis virus and tick-borne encephalitis virus.
  • Early in the history of bacteriology, morphological studies and chemical analysis showed that many pathogens were surrounded by a polysaccharide capsule and that antibodies against the capsule could promote phagocytosis. The first use of this information to make a vaccine was the development of meningococcal polysaccharide vaccine by Artenstein, Gottschlich, and coworkers. This vaccine controlled epidemic and endemic disease in military recruits. Basic bacteriology also suggested that pneumococcal polysaccharides were immunogenic although there were chemical differences between the multiple serotypes. Heidelberg and Macleod and later Austrian fostered the creation of combinations of multiple pneumococcal polysaccharides to prevent invasive infections. This principle was then applied to Hemophilus influenzae type b capsular polysaccharide by Anderson, Smith, Schneerson, Robbins, and coworkers. The Vi antigen present in the capsule of the typhoid bacillus was made into a vaccine by Landy and coworkers.
    All of the capsular polysaccharide vaccines generated serum antibodies that prevented bacteremia and thus end-organ disease in adults, but they were not immunogenic in infants, who are unable to mount a B-cell response to polysaccharide alone. This problem was solved by coupling the polysaccharides to proteins, which allowed T-cell help to B cells. In addition, whereas the polysaccharide vaccines did not prevent nasopharyngeal carriage of the bacilli, conjugated vaccines did prevent carriage and thus added the dimension of herd immunity to immunization against the three major bacterial pathogens of infancy. Curiously, the utility of protein conjugation of polysaccharides had been shown by Avery and Goebel in 1929, but this discovery was not taken advantage of until Schneerson, Robbins, and coworkers made a conjugated H. influenzae type b vaccine. Eventually, this principle was applied to meningococcal and pneumococcal vaccines, with resulting control of both invasive infections and spread of the organisms. Hib and some meningococcal serogroups have been completely controlled whereas pneumococcal serogroups in vaccines have greatly diminished disease causation.
  • Aside from tetanus and diphtheria toxoids, mentioned above under Inactivation, several vaccines consist of partly or fully purified proteins. Most inactivated influenza vaccines used today are generated by growing the viruses in embryonated eggs and then breaking up the whole virus with detergents. The viral hemagglutinin (HA) protein is purified to serve as the vaccine antigen although other components of the influenza virus may be present in the final product.
    Acellular pertussis vaccines have replaced whole-cell pertussis vaccines in many countries to reduce reactions to the latter. The licensed acellular vaccines consist of one to five proteins from the pertussis bacillus, which are meant to reconstitute efficacy of the whole-cell vaccine without generating febrile reactions. Sato and Sato created the first such vaccine for use in Japan in 1981, but many other acellular vaccines were licensed after extensive trials conducted in the 1990s.
    Although Pasteur and coworkers made inactivated whole-cell anthrax vaccine early in the history of vaccinology, it was only in the early 1960s that a vaccine was developed for biodefense by the US Army, based on anthrax protective antigen protein secreted by the organism. Another improvement on a vaccine originally developed by Pasteur was the creation of a cell culture-produced rabies vaccine by Wiktor, Koprowski, and coworkers in the 1970s. Human, monkey, or chicken cells are used to grow the virus, which is then purified and inactivated. The rabies glycoprotein is the protective antigen in the vaccine.
  • The revolution of genetic engineering toward the end of the 20th century has greatly impacted vaccine development. The first fruit of that revolution was the vaccine against hepatitis B. Initially, Hilleman and coworkers had purified the hepatitis B surface antigen particles from the serum of naturally infected patients and inactivated any residual live virus. However, this type of vaccine could not be practical in the long term. Valenzuela et al. placed the coding sequence for the S antigen into yeast cells and were able to produce large quantities of surface-antigen particles in vitro. Genetic engineering has been used to produce many candidate antigens for vaccines in yeast, animal cells, or insect cells producing an antigen in culture.
    Two bacterial live-virus vaccines are administered orally: the Ty21a vaccine against typhoid, which is a strain mutated chemically to deprive the organism of enzymes that contribute to virulence, and the CVD103-HgR cholera vaccine, which is unable to synthesize complete cholera toxin. Both of these vaccines were made possible after genetic engineering provided the tools for excision of bacterial DNA.
  • Many viruses and bacteria are under active study as vectors for vaccine antigens. Poxviruses, adenoviruses, bacillus Calmette–Guérin, and other relatively attenuated microbes have had genes for protective antigens from pathogens inserted into their genomes. The vectors are then injected and undergo either abortive or complete replication, expressing the inserted genes in both cases. The first licensed vector is the 17D yellow fever attenuated strain, which serves as a vector for the prM and E genes of Japanese encephalitis virus, thus immunizing against the latter.
    The development of the human papilloma virus (HPV) vaccine was made possible because of the properties of the L1 protein of the virus. This protein induces protective antibodies, but what makes it particularly immunogenic is that it aggregates to form virus-like particles (VLPs) that are much more immunogenic than the soluble protein. L1 is produced in yeast or insect cells, and the VLPs produced therein form the basis of the current vaccines.
    Influenza HA has been produced in insect cells and induces antibodies without the risk of allergy to egg proteins.
    A vaccine against Lyme disease was on the market briefly. The vaccine consisted of the OspA protein of Borrelia burgdorferi, produced in Escherichia coli.
    Most recently, a meningococcal group B vaccine has been licensed, consisting of four proteins identified by genomic analysis that induce bactericidal antibodies together with an outer membrane vesicle of the organism (74). This is the first vaccine developed by so-called reverse vaccinology, pioneered by Rappuoli and coworkers (75), by which genomic analysis enables selection of proteins that induce protective immune responses.
  • Many have pointed out that it is easier to foretell the past than the future! Be that as it may, the current tendencies in vaccine development are reasonably clear. Although the older methods described above continue to be used, as for example inactivation of whole virus to make vaccines against enterovirus 71 (76), expression of proteins by transcription and translation from either DNA or RNA coding for those proteins will be a widely used approach (77, 78). Attenuated viral or bacterial vectors carrying genetic information for a foreign vaccine antigen is a prominent strategy, exemplified by candidate HIV and dengue vaccines (79, 80). As described above, replicating organisms often make good vaccines, but ways are available to allow only one replication cycle to produce so-called replication-defective agents that maximize safety (81). To generate higher immune responses, stronger adjuvants than aluminum salts are coming into use, including oil-in-water preparations and Toll-like receptor agonists, and their use will surely increase (82).
    Meanwhile, structural biology and systems biology are enabling us to identify critical protective antigens and the immune responses they generate, including those that are innate (83, 84). Major unsolved problems remain, including how to deal with immaturity and postmaturity of immune responses in the young and old, respectively; how to induce mucosal responses with nonliving antigens; how to prolong immune memory; and genetic variability as it affects both the safety and efficacy of vaccines. Future vaccines are likely to have a more complex composition than heretofore, but the principles elucidated by past successes will have continued importance as vaccination is extended to more diseases and to all age groups.

“Inactivated Viral Vaccines” (Nov 28, 2014)

Barbara Sanders, Martin Koldijk, and Hanneke Schuitemaker, “Inactivated Viral Vaccines”, Vaccine Analysis: Strategies, Principles, and Control. 2014 Nov 28 : 45–80.

  • Inactivated vaccines have been used for over a century to induce protection against viral pathogens. This established approach of vaccine production is relatively straightforward to achieve and there is an augmented safety profile as compared to their live counterparts. Today, there are six viral pathogens for which licensed inactivated vaccines are available with many more in development. Here, we describe the principles of viral inactivation and the application of these principles to vaccine development. Specifically emphasized are the manufacturing procedure and the accompanying assays, of which assays used for monitoring the inactivation process and preservation of neutralizing epitopes, are pivotal. Novel inactivated vaccines in development and the hurdles they face for licensure are also discussed as well as the (dis)advantages of inactivation over the other vaccine production methodologies.
  • The first report of “virus” inactivation for vaccine purposes was described in 1886 when Daniel Elmer Salmon and Theobald Smith immunized pigeons with what they thought was a heat-killed hog cholera “virus” (Salmon and Smith 1886). Although in reality it was a cholera-like bacterium, it seeded the scientific community with evidence that immunization with inactivated pathogens can provide protection against infectious disease. Research continued for at least 15 years when at the beginning of the twentieth century the first killed (bacterial) vaccines for humans were developed for typhoid fever, cholera, and plague (Wright and Semple 1897; Haffkine 1899). The foundations of immunization with inactivated virus preparations were also laid at the end of the nineteenth century with Pasteur’s partially inactivated rabies virus (Pasteur et al. 1885), which was cultured in rabbit spinal cords. However, inactivated viral vaccine development was only truly launched with the discovery of cell culture procedures that supported the replication of viral pathogens in vitro, outside the host organism, thus allowing the large scale production of viruses as a source for whole inactivated vaccines. This breakthrough was attributed to Enders, Weller, and Robbins who received the Nobel Prize in 1954 for their discovery on how to cultivate poliovirus in fibroblasts in vitro (Enders et al. 1949; Weller et al. 1949).
    In general, all inactivated viral vaccines follow a similar production course in which the pathogen is first cultivated on a substrate to produce large quantities of antigen. Historically, vaccine manufacturers have been using primary cells, tissues, fertilized eggs, and even whole organisms as substrates for virus propagation (Hess et al. 2012; Barrett et al. 2009). Today, vaccine manufacturers are increasingly shifting toward virus growth on continuous cell lines. This brings certain advantages such as reduced production costs, increased vaccine safety, and relatively straightforward upscaling (Barrett et al. 2009). Once the virus has been propagated, it is often purified and concentrated prior to inactivation. Inactivation can be performed using chemical or physical methods or a combination of the two. A wide range of well-established and novel inactivation agents or methods have been described to successfully inactivate viruses for vaccine purposes. Examples are ascorbic acid (Madhusudana et al. 2004), ethylenimine derivatives (Larghi and Nebel 1980), psorlens (Maves et al. 2011), hydrogen peroxide (Amanna et al. 2012), gamma irradiation (Martin et al. 2010a; Alsharifi and Mullbacher 2010), UV treatment (Budowsky et al. 1981), heat (Nims and Plavsic 2012), and many more (Stauffer et al. 2006). Nonetheless, only formaldehyde and β-Propiolactone (BPL) are widely used for inactivation of licensed human viral vaccines for decades.
  • Not only do inactivated vaccines possess a higher safety profile as compared to live vaccines, they are also generally less reactogenic, relatively straightforward, and technically feasible to produce with fewer regulatory hurdles for licensure (Zepp 2011). However, inactivated vaccines are typically associated with a lower immunogenicity which can imply the necessity of multiple doses or adjuvant addition which consequently raises the costs of goods and vaccine pricing. Therefore, choosing an inactivated vaccine approach is in general a trade-off with on one hand increased safety (if inactivation is of course complete) and a fast pathway to regulatory approval, but on the other hand the risk of reduced antigenicity of the immunogen which often requires adjuvant addition and/or multiple doses which not only raises production costs but also the complexity of formulation and administration.
  • The first reports of vaccination against influenza stem from the 1930s (Stokes et al. 1937) which ultimately lead to the licensure of the first inactivated influenza vaccine in 1945 in the US (Francis et al. 1946; Salk and Francis 1946). Over the course of more than 80 years, the currently available inactivated influenza vaccines have undergone several improvements and have shown significant benefits for society (Clover et al. 1991; Edwards et al. 1994; Gruber et al. 1990; Neuzil et al. 2001; Wilde et al. 1999), however, breadth of protection and efficacy of currently available vaccines are still insufficient to diminish the current annual health burden induced by the virus. Differences in protective efficacy may result from continuing antigenic variation in the prevalent epidemic strains. Due to this variation, the composition of inactivated influenza virus vaccine, unlike that of most viral vaccines, must be kept constantly under review. Accordingly, WHO publishes recommendations concerning the strains to be included in the vaccine twice annually (WHO 2000, 2009a; Ghendon 1991).
    Until recently inactivated influenza vaccines consisted of three inactivated viruses; two Influenza A strains and one B strain, however, a new pattern of influenza B circulation has rendered it troublesome to predict the global dominance of one of the two influenza B lineages (Paiva et al. 2013). Therefore, quadrivalent influenza vaccines have been developed to ensure broader protection against Type B influenza viruses as compared to the trivalent vaccines which contained only one Type B influenza strain from one lineage. The licensed quadrivalent inactivated influenza vaccines are formulated in the same way as their trivalent counterparts, however, two influenza B strains, one from the Victoria lineage and one from the Yamagata lineage, are included in the formulation.
    After inactivation the vaccine strains are either formulated as virosomes (Herzog et al. 2009), whole inactivated virus (WIV), or detergent-treated “split” vaccines, where the viral envelope is disrupted after inactivation (Wood 1998; Schultz-Cherry and Jones 2010). All the US-licensed inactivated influenza vaccines are split vaccines as “splitting” of the virus is thought to reduce reactogenicity, especially in children (Verma et al. 2012; Nicholson et al. 2003). However, WIV vaccines have been reported to induce stronger immune responses in immunologically naive individuals than split-virus or subunit vaccines (Beyer et al. 1998; Nicholson et al. 1979). Budimir et al. have recently shown that only WIV influenza vaccines, and not split or subunit vaccines, are capable of inducing cross-protection against heterosubtypic challenge due to elicitation of a strong CTL response in mice as whole (BPL) inactivated vaccines are capable of endosomal fusion into the cell cytoplasm (Budimir et al. 2012). The necessity of an influenza vaccine that can elicit cell-mediated immunity and the superiority of WIV vaccines over split vaccine variants has recently been reviewed (Furuya 2012).
  • The second currently licensed BPL-inactivated viral vaccine is a rabies vaccine which has an equally rich history of development. Pasteur introduced an experimental rabies vaccine in 1885 when he observed the rapid decrease of rabies virus virulence upon air drying of rabies-infected rabbit spinal cords. Serially less dried rabies-infected rabbit spinal cords containing inactivated—or at least partially inactivated—rabies viruses induced protection of dogs and later humans against challenge following inoculation (Bazin 2011; Pasteur et al. 1885). This method of vaccination, although it was considered a treatment for infected people at the time, was the foundation for rabies vaccines. However, Pasteur faced significant criticism from the scientific community as recipients were essentially inoculated with virulent virus at the end of the treatment (Burke 1996; Gelfand 2002; Wu et al. 2011). This set the incentive to chemically inactivate the rabies virus with phenol in 1908 leading to the first completely inactivated rabies vaccine, despite the disruptive action of phenol on the antigenic sites on the proteins (Fermi 1908; Semple 1911; Briggs 2012).
  • In the 1950s and 1960s the vaccine was further improved by using alternative substances to cultivate rabies virus, such as chicken and duck embryos (Peck et al. 1955). This due to the fact that vaccines based on adult mammalian nerve tissue were associated with effects such as encephalomyelitis and demyelination lesions in the CNS due to the presence of myelin (Bonito et al. 2004; Bahri et al. 1996). Therefore, the WHO currently does not recommend the use and production of nerve tissue vaccines (WHO 2005) and has been advocating use of cell culture or embryonated eggs as production platforms since 1983 (WHO 1984). In the US, only cell culture derived rabies vaccines are approved for commercial use, however, some African and Latin American countries continue to produce and use nerve tissue vaccines by phenol inactivation, where the vaccine production protocol resembles the methods from a century ago (Briggs 2012). Today, there are two primary avian cell lines used for rabies vaccine production; purified chick embryo cell vaccine (PCECV) and purified duck embryo rabies vaccine (PDEV) and multiple continuous cell lines such as MRC-5, Vero, and primary hamster kidney cells. However, inactivated vaccines produced on continuous cell lines are not completely free from adverse reactions. There are reports on reactogenicity in response to vaccination with the human diploid cell rabies vaccine (HDCRV) which may relate to the presence of BPL-altered human albumin, added as a stabilizer to vaccine preparations (Anderson et al. 1987; Swanson et al. 1987). Nonetheless, cell culture based vaccines are still vastly preferred over nerve tissue vaccines. Moreover, an additional advantage of the use of a cell line platform, for instance Vero cells, is that they can be cultured in large scale in fermenters on microcarriers which contributes to standardization, safety, and upscaling of the production system resulting in constant yields.
    Despite the variation in vaccine cell substrates, the majority of the rabies vaccines are inactivated in a similar manner using a concentration of not more than 1:3,500 and up to 1:5,000 v/v of BPL at 2–8 °C for 24 h (WHO 2007a; Ph. Eur. 2011e). However, there are exceptions such as the use of formalin for Primary Hamster kidney cell culture vaccine (PHKCV). As with the formalin-inactivated vaccines, the inactivation curves have to be validated and approved by the regulatory body. After inactivation, different purification standards can be used such as ultrafiltration, ultracentrifugation, zonal centrifugation, or chromatography. Once formulated, the vaccine potency for all these vaccines is determined by quantifying the degrees of protection against rabies following immunizing and intracerebral challenge of mice (de Moura et al. 2009; Fitzgerald et al. 1978). Based on the results of this National Institutes of Health (NIH) test, the vaccine dosing is set at 2.5 International Units/dose. Many regulatory authorities, including the Ph. Eur. and WHO, have adopted the NIH potency test as the only assay for potency quantification of inactivated Rabies vaccines, despite the recognition of the fact that the animal test should be replaced by an antigen quantification procedure (Bruckner et al. 2003). The vaccine is further tested for complete inactivation by inoculating the cell substrate used for manufacturing with 25 human vaccine doses or more. Cultures are examined for the presence of newly produced rabies virus using immunofluorescence.
  • The century old concept of the use of inactivating viruses to elicit protection against the virulent pathogen continues to bear fruit for humanity. Countless improvements and innovations in the field of vaccinology, such as the introduction of recombinant, DNA-based, and vectored vaccines have not stopped the use and development of inactivated vaccines. The relative straightforwardness in which an inactivated vaccine is produced and licensed, accompanied by the fact that inactivated vaccines cannot revert as their replication competent counterparts can do, explains the fact that there are new inactivated pathogens that are being evaluated as vaccine candidates. However, inactivation does not always guarantee the creation of a suitable vaccine as was observed with pathogens such as RSV and measles, therefore immunogenicity of the novel inactivated particle must always be thoroughly tested. Furthermore, new inactivation methods are also being investigated to circumvent the disadvantages of formalin and BPL such as altered immunogenicity due to epitope masking. This section will provide an overview of novel inactivated vaccines in development as well as new inactivation methods.
  • The increased safety associated with inactivated vaccines does not entail a spotless track record, as was described for the formalin-inactivated RSV and measles vaccines. The inadequate immune response induced with inactivated viruses is thought to be due to masking of essential epitopes. This drives the investigation of alternative inactivation methods that do not alter epitopes or skew immune responses to ensure a protective vaccine with high efficiency. Three new inactivation methods, being hydrogen peroxide treatment, zinc-finger reactive treatment, and gamma irradiation are described in more detail below. Whether these inactivation methods will be implemented in the manufacturing of vaccines remains to be determined.
  • The oral polio vaccine (OPV) displays frequent reversion to virulence in vaccine recipients and there are estimates of approximately 400–800 vaccine-associated paralytic poliomyelitis (VAPP) cases per year globally (John 2002). Despite the immediate recognition of the fact that OPV strains can revert readily into a pathogenic phenotype (Henderson et al. 1964), OPV has been used since the 1960s and still is being used extensively. However, recently, it has been acknowledged that use of the oral live attenuated vaccine is at odds with global eradication of poliomyelitis. Indeed, the number of vaccine-associated poliomyelitis cases is in the range of wild-type PV induced poliomyelitis cases (WHO 2006a). Although IPV is a safe alternative, the costs of currently available IPV are too high to implement its use in low income countries (Heinsbroek and Ruitenberg 2010; Zehrung 2010) and several options to reduce costs of IPV are being considered (WHO 2009b). In the era after eradication, IPV use will have to be continued at least for a certain amount of time. At that time, production of IPV from wild-type PV strains will fall under strict biosafety measures (WHO 2009c). Even though it is currently not clear whether an IPV based on OPV strains may be produced at lower biosafety level after eradication as compared to a wild-type based IPV, there is much research going on to the inactivation of the OPV strains with formalin to eventually replace the inactivated PV vaccine based on the wild-type strains. Not only would the lowering of biosafety level decrease potential costs of goods, replacing the wild-type strains greatly reduces the risks of poliomyelitis upon accidental outbreaks from the manufacturing facility, after eradication. The manufacture of Sabin-IPV is essentially identical to the Salk-IPV process with slight modifications (Westdijk et al. 2011). The WHO encourages the development of this Sabin-IPV vaccine (Bakker et al. 2011) and multiple clinical trials have been or are being performed (Verdijk et al. 2011), moreover, in Japan a Sabin based IPV has recently been licensed in combination with diphtheria, tetanus, and acellular pertussis (DTaP-Sabin IPV) (Mahmood et al. 2013). In general, Sabin-IPV displays higher immunogenicity for serotype 1, lower for type 2, and similar for type 3 in comparison to Salk-IPV, licensure of more Sabin derived IPV’s is foreseen in the near future.
    Monath et al. describe the results of a Phase I study of a BPL-inactivated Yellow Fever (YF) vaccine, based on the licensed attenuated 17D strain (Monath et al. 2011). The 17D vaccine was developed in 1936 by Max Theiler and today 20 million doses are issued per year. However, yellow fever vaccine-associated viscerotropic disease (YF-AVD) and yellow fever vaccine-associated neurological disease (YF-AND) occurring at a frequency of 0.4 and 1.8 per 100,000 doses, respectively (Lindsey et al. 2008), instigate a need for safer vaccines. Inactivated vaccines will reduce the adverse effects associated with the vaccine and is predicted to be less reactogenic as it has been cultivated on Vero cells instead of eggs (Hayes 2010). The alum-adjuvanted, BPL-inactivated vaccine induced neutralizing antibodies in a high percentage of subjects, albeit lower titers than the live vaccine, whether the lower titers will be compensated for by the higher safety profile is yet to be determined (Monath et al. 2011).

“Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity” (Dec 2, 2017)

John J Suschak, James A Williams, Connie S Schmaljohn; “Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity”, Hum Vaccin Immunother, 2017 Dec 2;13(12):2837-2848.

  • A major advantage of DNA vaccination is the ability to induce both humoral and cellular immune responses. DNA vaccines are currently used in veterinary medicine, but have not achieved widespread acceptance for use in humans due to their low immunogenicity in early clinical studies. However, recent clinical data have re-established the value of DNA vaccines, particularly in priming high-level antigen-specific antibody responses. Several approaches have been investigated for improving DNA vaccine efficacy, including advancements in DNA vaccine vector design, the inclusion of genetically engineered cytokine adjuvants, and novel non-mechanical delivery methods. These strategies have shown promise, resulting in augmented adaptive immune responses in not only mice, but also in large animal models. Here, we review advancements in each of these areas that show promise for increasing the immunogenicity of DNA vaccines.
  • The constant emergence, and re-emergence, of known and novel pathogens challenges researchers to develop new vaccination technologies that allow for the rapid development of safe and effective vaccines. Nucleic acid (DNA and RNA) vaccines have characteristics that meet these challenges, including ease of production, scalability, consistency between lots, storage, and safety. DNA vaccine technology usually is based on bacterial plasmids that encode the polypeptide sequence of candidate antigens. The encoded antigen is expressed under a strong eukaryotic promoter, yielding high levels of transgene expression.1 Inclusion of transcriptional enhancers, such as Intron A, enhance the rate of polyadenylation and nuclear transport of messenger RNA (mRNA). The vaccine plasmids are generally produced in bacterial culture, purified, and then used to inoculate the host.
    Modern DNA vaccine design generally relies on synthesis of the nucleic acid and possibly one-step cloning into the plasmid vector, reducing both the cost and the time to manufacture. Plasmid DNA is also extremely stable at room temperature, reducing the need for a cold chain during transportation. Vaccination with DNA plasmid removes the necessity for protein purification from infectious pathogens, improving safety. Furthermore, DNA vaccination has an excellent safety profile in the clinic, with the most common side effect being mild inflammation at the injection site. Importantly, DNA vaccines provide a safe, non-live vaccine approach to inducing balanced immune responses, as the in vivo production of antigen allows for presentation on both class I and class II major histocompatibility complex (MHC) molecules (Fig. 1). This elicits antigen specific antibodies, as well as cytotoxic T lymphocyte responses (CTL), something that remains elusive in most non-live vaccines. DNA vaccines have also demonstrated the ability to generate follicular T helper populations, which are critical for the induction of high quality antigen-specific B cell responses.
  • DNA vaccination has proven successful in several animal models for preventing or treating infectious diseases, allergies, cancer, and autoimmunity. The early success of small animal studies led to several human clinical trials. However, the protective immunity observed in small animals and non-human primates was not observed in human studies when DNA vaccines were administered alone by needle delivery. Like the more conventional protein-based vaccines, DNA can be delivered by a variety of routes, including intramuscular (IM), intradermal (ID), mucosal, or transdermal delivery. Because DNA plasmids must enter host cell nuclei to be transcribed into mRNA, the early failure of DNA vaccines to elicit strong responses in humans was largely due to their delivery by needle injection, which deposits the DNA in intracellular spaces, rather than within cells. Improved delivery technologies, such as intramuscular or intradermal electroporation, have been used to facilitate transport of DNA into cells, resulting in much better immunogenicity in both clinical and non-clinical studies. In one study, electroporation-enhanced DNA vaccination resulted in increased polyfunctional antigen-specific CD8+ T cells in patients receiving a HPV DNA vaccine expressing the E6 and E7 genes of HPV16 and HPV18 respectively. The majority of DNA vaccinated patients displayed complete regression of their cervical lesions, as well as viral clearance, following DNA delivery. Other mechanical delivery approaches use physical force such as particle bombardment (gene gun) to deliver the DNA plasmids into targeted tissues or cells, with some clinical successes. Delivery of a Hepatitis B DNA vaccine by particle bombardment resulted in sustained antibody titers in subjects who had previously failed to respond to a licensed subunit vaccine. Needle-free pneumatic or jet injectors have also shown promise in both animal and human clinical trials, and function by injecting a high-pressure, narrow stream of injection liquid into the epidermis or muscles of test subjects. In addition to these improved mechanical delivery methods, several other approaches are being explored to increase the immunogenicity of DNA vaccines in humans. Here we review 3 of these approaches which show promise for advancing DNA vaccines: non-mechanical delivery, inclusion of molecular adjuvants, and improvements in DNA vaccine vectors.
  • As already mentioned, the greatest impediment to DNA vaccination is low immunogenicity due to difficulties in delivering DNA plasmid into the host cell. The transportation of DNA vaccine plasmids into cellular nuclei requires the crossing of several barriers. Vaccine plasmid must cross the phospholipid cellular membrane through endocytosis or pinocytosis, escape degradation in endosomes and lysosomes, survive cytosolic nucleases, and translocate across the nuclear envelope. In contrast to physical delivery systems, chemical delivery approaches use biopharmaceuticals to increase DNA vaccine transfection efficiency.
  • The use of liposomes as a carrier molecule has become a popular DNA vaccine delivery method as liposomes not only enhance transfection efficiency, but also have an adjuvant effect. Liposomes are spherical vesicles composed of phospholipids and cholesterol arranged into a lipid bilayer, allowing for fusion with cellular lipid membranes. DNA plasmid can be either bound to the liposome surface, or encased within the hydrophobic core of the liposome. This facilitates delivery of the DNA vaccine plasmid into the cells. Importantly, lipid vesicles can be formulated as either unilamellar or multilamellar. Multilamellar vesicles allow for sustained delivery of vaccine over an extended period of time. While the use of liposomes for IM injection has resulted in some reactogenicity issues, liposome/DNA vaccine complexes have demonstrated an immunological benefit. IM injection of a liposome/influenza nucleoprotein formulation increased antibody titers 20-fold compared with vaccine alone. Boosting of antibody titers did not diminish the cytotoxic T cell response. Likewise, inclusion of a liposome formulation in a P. falciparum vaccine enhanced the IFN-γ production. An ensuing human trial involving DNA plasmids encoding the influenza H5 HA, nucleoprotein, and M2 genes reported cellular immune response rates and antibody titers comparable to that of the currently available inactivated protein-based H5 vaccines. Additionally, liposomes have shown promise as a candidate for delivery of DNA vaccines to mucosal tissue. A recent study demonstrated that vaccination with liposome encapsulated influenza A virus M1 induced both humoral and cellular immune responses that protected against respiratory infection. Liposomes have also been shown to be an effective delivery method for intranasal DNA vaccination, conferring protective immune responses against infection.
  • DNA vaccine delivery can also be accomplished through the use of biodegradable polymeric micro- and nanoparticles consisting of amphiphilic molecules between 0.5–10 µm in size. Similar to loading of DNA plasmid on liposomes, plasmid molecules can be either encapsulated or adsorbed onto the surface of the nanoparticles. These particles function as a carrier system, protecting the vaccine plasmid from degradation by extracellular deoxyribonucleases. In addition to shielding plasmid DNA from nucleases, micro- and nanoparticles promote the sustained release of vaccine instead of the bolus type of delivery characteristic of larger submicrometer complexes. High molecular weight cationic polymers have proven significantly more effective than cationic liposomes in aggregating DNA vaccine plasmid. Plasmid DNA immobilized within biodegradable chitosan-coated polymeric microspheres (ranging from 20 to 500 μm) can induce both mucosal and systemic immune responses. Microspheres may be delivered either by the oral or intraperitoneal route, allowing for direct transfection of dendritic cells (DC), thereby increasing DC activation. The benefits of microsphere formulations have been shown in mice, non-human primates, and humans against a wide range of diseases including hepatitis B, tuberculosis, and cancer. These results suggest that microparticle-based delivery systems are capable of significantly improving DNA vaccine immunogenicity, and boosting cellular and humoral immune responses.
    The use of liposomes or nanoparticles appears to be safe and well tolerated in clinical studies. Microparticle-based delivery systems can increase gene expression, as well as, DNA vaccine immunogenicity. Although many of the earliest carrier formulations did not show a significant clinical benefit, more recent studies highlighted herein yielded promising clinical data. As microparticles can be prepared with significant structural diversity (size, surface charge, lipid content), they offer considerable flexibility of vaccine formulation. This allows for optimization of the vaccine based on the specific needs of the clinician.
  • A major advantage of DNA vaccination is the ability of multiple molecules such as molecular adjuvants to be inserted into the plasmid. Unlike the addition of recombinant cytokines, co-stimulatory molecules, and TLR ligands, which have a limited duration due to the short half-life of recombinant protein in vivo, molecular adjuvant-encoding plasmids will express protein for the same duration as the antigen, stimulating the immune system for a greater length of time. This can be done without fear of eliciting a cytokine storm, as generation of the adjuvanting signal will be localized to the site of vaccination. Of note, homologous recombination between plasmid-encoded cytokines and the host gene sequence does not appear to be a significant concern, as multiple studies have shown that only extrachromosomal plasmid DNA has been identified following intramuscular injection. Furthermore, many current plasmids have been-codon optimized to improve gene expression in mammalian cells. This has resulted in changes to the cytokine gene sequence, limiting the possibility for homologous recombination and/or integration. Molecular adjuvants therefore show great promise for both increasing immunogenicity and extending the longevity of the immune response.
  • Another approach to improve DNA vaccines is to engineer the vector to increase innate immune activation. DNA vaccines are potent triggers of innate immunity. Various studies have determined several innate immune pathways are activated by DNA vaccination (Fig. 2). Most of the intrinsic adjuvant effect of DNA is mediated by cytoplasmic innate immune receptors that nonspecifically recognize B DNA and activate Sting or Inflammasome mediated signaling, but unmethylated CpG sequences specific for TLR9 activation may also be important for priming CD8 T cell responses. Along these lines, DNA vaccine vectors may be sequence modified to introduce immunostimulatory xxCGxx TLR9 agonists into the vector to increase innate immune activation. This approach has been used to improve DNA vaccine immunogenicity, but the results are variable. Some of the variability may be due to unintended inhibition of the eukaryotic promoter expression resulting from integration of CpG motifs into non-permissive sites in the vector. As well, certain DNA delivery methods may not transfer DNA to the endosome as effectively as other deliveries (e.g. liposomes), preventing unmethylated CpG interaction with, and activation of, TLR9. Part of the complexity is that optimal TLR9 activating xxCGxx motifs are species-specific; different xxCGxx agonist motifs differentially modulate the immune response and many xxCGxx motifs are immunosuppressive.
  • DNA vaccines encoding immunostimulatory sequences that selectively improve CTL responses to encoded antigen may have niche application in vaccines for intracellular pathogens or cancer. Innovations that increase transgene expression may be used to improve the performance of immunomodulatory molecular adjuvant plasmids, in addition to traditional antigen expressing DNA vaccine plasmids. Collectively, vector design innovations that improve transgene expression level and innate immune activation are complementary to improved mechanical and non-mechanical DNA vaccine delivery platforms. Combining improved vectors with liposome or polymeric particle non-mechanical delivery, or with needle free injector device delivery, has the potential to increase immunogenicity with these well tolerated, safe, delivery platforms.
  • While DNA vaccination provides several advantages over more conventional vaccination strategies, further optimization is necessary before it becomes the predominant strategy in human patients. Despite initial setbacks, significant progress has been made in overcoming the problem of low immunogenicity in humans. A clearer understanding of the immune mechanisms governing DNA vaccine immunogenicity has illuminated several pathways that may be useful in further improving DNA vaccine efficacy. A large catalog of cytokines, chemokines, adhesion molecules, and transcription factors are in the process of being tested as molecular adjuvants, although it is likely that each will need to be carefully assessed for safety and tolerability. Likewise, continued development of vaccine delivery methods appears promising. New formulations exploiting sustained vaccine delivery methods, such as slow-releasing micropatches or multilamellar vesicles, are on the horizon. The strong appeal of needle-free injection and mucosal delivery, the ease of design, and the recent clinical successes with DNA vaccines suggests that this approach is on the precipice of redefining the field of vaccinology.

"Vaccine ingredients" (February 5, 2019)

"Vaccine ingredients". "Vaccine ingredients". Retrieved February 5, 2019.

  • The key ingredient in all vaccines is one or more active ingredients (see below). Apart from this, the main ingredient in vaccines is water. Most injected vaccines contain 0.5 millilitres of liquid, in other words, a few drops. All other ingredients weigh a few milligrams (thousandths of a gram) or even less.
    Unlike food products, the list of vaccine ingredients may include products used during the manufacturing process, even if they do not remain in the finished product. Added ingredients are present in very small quantities (usually a few milligrams). Products used in making vaccines or growing the active ingredients may not remain in the final vaccine at all. If they do, they are present only in trace amounts.
    Vaccine ingredients can look unfamiliar. However, it is important to remember that many of the substances used in vaccines are found naturally in the body. For example, many vaccines contain salts based on sodium and potassium (see the section on 'Acidity regulators'), which are essential for life. People may think of formaldehyde as a man-made chemical, but in small quantities, it is also found naturally in the bloodstream.
    All vaccine ingredients are present in very small quantities, and there is no evidence that they cause harm in these amounts. The exception to this is the small number of people who may be severely allergic to a vaccine ingredient, even if it is present only in trace amounts (for example, egg proteins or antibiotics used in vaccine manufacture).
    If you look up some vaccine ingredients on the internet you may read that they could be harmful, but most of them are present in vaccines in amounts that are completely normal for our bodies. Even common salt (sodium chloride), which is essential for the normal functioning of the body, is harmful in large quantities.
  • The active ingredients are the parts of the vaccine made from viruses or bacteria, sometimes also called ‘antigens’. They challenge the immune system so that it makes antibodies to fight the disease.
  • Vaccines contain tiny quantities of active ingredients – just a few micrograms (millionths of a gram) per vaccine. To give some idea of how small these quantities are, one paracetamol tablet contains 500 milligrams of the drug. This is several thousand times more than the quantity of the active ingredient you would find in most vaccines. Hundreds of thousands of individual vaccines could be made from a single teaspoon of active ingredient.
    Some vaccines contain whole bacteria or viruses. In these cases, the bacteria or viruses will either be severely weakened (attenuated) so that they cannot cause disease in healthy people, or killed altogether (inactivated). Many vaccines contain only parts of viruses or bacteria, usually proteins or sugars from the surface. These stimulate the immune system but cannot cause disease.
  • Compared with the number of viruses and bacteria in the environment that our bodies have to deal with every day, the amount of active ingredient in a vaccine is very small indeed. Most bacterial vaccines contain just a few proteins or sugars from the relevant bacterium. By contrast, it is estimated that 100 trillion bacteria live on the skin of the average human being, each of them containing many thousands of proteins which constantly challenge our immune systems.
    A few vaccines in the UK schedule are made using recombinant DNA technology. Only one vaccine used in the UK contains genetically modified organisms (GMOs).
  • Like vaccines, most of the medicines we use also contain excipients.
  • Unlike food products or other drug product listings, substances used in the production of a vaccine may also be listed under ‘excipients’, even though they are not added to the vaccine. However, many of the items listed do not actually remain in the finished vaccine. If they do, they will often be present in trace amounts.
  • For some vaccines, the active ingredient is grown in laboratories on cultures that contain human cells. Some viruses, such as chickenpox (varicella), grow much better in human cells. After they are grown, the viruses are purified several times to remove the cell culture material. This makes it unlikely that any human material remains in the final vaccine.
    For vaccines used in the UK, human cell lines are used to grow viruses for these vaccines:
    *the rubella part of both MMR vaccines (MMRVaxPro and Priorix)
    *the shingles vaccine (Zostavax)
    *both chickenpox vaccines (Varivax and Varilrix)
    The cell lines currently used (called WI-38 and MRC-5) were started in the 1960s using lung cells taken from two aborted foetuses. The abortions were legal and agreed to by the mothers, but they were not performed for the purpose of vaccine development.
    Some people may have moral concerns about using a vaccine produced in this way. In 2005 the Vatican’s Pontifical Academy for Life issued a statement  called ‘Moral reflections on vaccines prepared from cells derived from aborted human foetuses’. This statement says that they believe it is wrong to make vaccines using human cell strains derived from foetuses, and that there is a ‘moral duty to continue to fight’ against the use of such vaccines and to campaign for alternatives. However, it also states that if the population is exposed to ‘considerable dangers to their health’ through diseases such as rubella (German measles), then ‘vaccines with moral problems pertaining to them may also be used on a temporary basis’.
  • The manufacturing process for the Oxford-AstraZeneca vaccine involves the production of a virus, the adenovirus, which carries the genetic material to the cells inside the body. To produce this virus in the laboratory, a “host” cell line is needed. The Oxford-AstraZeneca vaccine uses a cell line called HEK-293 cells. HEK-293 is the name given to a specific line of cells used in various scientific applications. The original cells were taken from the kidney of a legally aborted foetus in 1973. HEK-293 cells used nowadays are clones of those original cells, but are not themselves the cells of aborted babies.
    The Department for Social Justice of the Catholic Bishops’ Conference of England and Wales released a statement addressing the use of HEK-293 cells in the COVID-19 vaccine. They say that “one may in good conscience and for a grave reason receive a vaccine sourced in this way”, and “that one does not sin by receiving the vaccine”.
    Other therapeutic products which use HEK-293 cells as a producer cell line include Ad5 based vaccines, such as Cansino’s COVID-19 vaccine, Adeno associated viruses (AAV) and lentiviruses as gene therapy vectors for various diseases. Many of these products are in clinical trials.
  • Viruses for some vaccines are grown in laboratories using animal cell cultures. This is because viruses will only grow in human or animal cells. In the UK schedule this applies to these vaccines:
    *The polio part of the 6-in-1 vaccine (Infanrix Hexa), the pre-school booster vaccines (Repevax, Infanrix IPV and Boostrix-IPV) and the teenage booster vaccine (Revaxis)
    *The Rotavirus vaccine (Rotarix)
    *One of the Inactivated flu vaccines (QIVc) 
    Viruses for these vaccines are grown on Vero cells. This is a cell line started in the 1960s using kidney cells from an African green monkey.
    The measles and mumps parts of the MMR vaccines (MMRVaxPro and Priorix) are grown on a culture which began with cells taken from a chick embryo.
    There is no evidence of any risk that animal diseases can be transmitted by vaccines grown on animal cell lines.
  • The only vaccine in the UK schedule which contains GMOs is the Nasal Flu vaccine (Fluenz). The viruses for flu vaccines are usually made by injecting two flu virus strains into an egg and letting them recombine naturally to make new strains. Researchers then look through all the new viruses to see which one has the features they are looking for to make this year’s vaccine. The viruses used to make Fluenz are custom-made by putting together individual genes that will give the right features. This is a quicker and more accurate process.
    The Oxford-AstraZeneca vaccine for COVID-19, ChAdOx1 nCoV-19, is made using a modified adenovirus, which is used to carry the genetic code for the coronavirus spike protein. This means that the vaccine is a GMO. The adenovirus has been modified in this way to prevent it from replicating inside the body so that it cannot cause an infection.
  • Recombinant vaccines are made using bacterial or yeast cells to manufacture the vaccine. A small piece of DNA is taken from the virus or bacterium that we want to protect against. This is inserted into other cells to make them produce large quantities of active ingredient for the vaccine (usually just a single protein or sugar).
    For example, to make the hepatitis B vaccine, part of the DNA from the hepatitis B virus is inserted into the DNA of yeast cells. These yeast cells are then able to produce one of the surface proteins from the hepatitis B virus, and this is purified and used as the active ingredient in the vaccine. Proteins for the HPV vaccine, part of the MenB vaccine and the hepatitis B part of the 6-in-1 vaccine are produced using a similar technique.
  • ‘Bovine products’ refers to any product that is derived from a cow or calf (such as bovine serum, which comes from cow's blood). Some sources state that bovine products may be present in the media that are used to grow the viruses or bacteria that are used to make the components of some vaccines. The Vaccine Knowledge Project has only been able to find two vaccines currently used in the UK which states that bovine products are used in their manufacture. These are Repevax, one of the Pre-school Booster vaccines and Vaxelis, one of the 6-in-1 vaccines available in the UK. The Summary of Product Characteristics sheets (SPC) for Repevax and Vaxelis states that bovine serum albumin is used in the manufacture of the vaccine and that trace amounts may remain in the vaccine. This is potentially a risk for people who are severely allergic to bovine products. Other vaccines in use in the UK may use bovine products in their manufacture, but this is not stated on their SPCs.
    The European Medicines Agency (EMA) has issued a series of statements and Q&Asheets on the risk posed by bovine products used in vaccine manufacture. These have been prepared in response to the recognition of BSE in the 1980s and are regularly updated.
  • Some bacteria do not need to be grown on human or animal cells. Instead they can be grown on cultures that are rich in proteins, vitamins and salts. Cultures that are often used in the production of vaccines are Medium 199, Eagle Medium and Minimum Essential Medium.

“How healthcare professionals respond to parents with religious objections to vaccination: a qualitative study” (2012 Aug 1)

Wilhelmina L M Ruijs, Jeannine L A Hautvast, Giovanna van Ijzendoorn, Wilke J C van Ansem, Glyn Elwyn, Koos van der Velden, Marlies E J L Hulscher; “How healthcare professionals respond to parents with religious objections to vaccination: a qualitative study”, BMC Health Serv Res. 2012 Aug 1:12:231. doi: 10.1186/1472-6963-12-231.

  • Background: In recent years healthcare professionals have faced increasing concerns about the value of childhood vaccination and many find it difficult to deal with parents who object to vaccination. In general, healthcare professionals are advised to listen respectfully to the objections of parents, provide honest information, and attempt to correct any misperceptions regarding vaccination. Religious objections are one of the possible reasons for refusing vaccination. Although religious objections have a long history, little is known about the way healthcare professionals deal with these specific objections.
    • p.1
  • Results: Three manners of responding to religious objections to vaccination were identified: providing medical information, discussion of the decision-making process, and adoption of an authoritarian stance. All of the HCPs provided the parents with medical information. In addition, some HCPs discussed the decision-making process. They verified how the decision was made and if possible consequences were realized. Sometimes they also discussed religious considerations. Whether the decision-making process was discussed depended on the willingness of the parents to engage in such a discussion and on the religious background, attitudes, and communication skills of the HCPs. Only in cases of tetanus post-exposure-prophylaxis, general practitioners reported adoption of an authoritarian stance. Conclusion: Given that the provision of medical information is generally not decisive for parents with religious objections to vaccination, we recommend HCPs to discuss the vaccination decision-making process, rather than to provide them with extra medical information
    • p.1
  • Vaccination programs have successfully controlled many infectious diseases. In recent years, however, healthcare professionals (HCPs) have faced increasing concerns about the value of childhood vaccination. Parental decision making with regard to vaccination is complex. Medical, psychological, social, and cultural aspects can play a role. Moreover, the medical information provided and trust in the HCP can play a role as well.
    Although not all HCPs recommend childhood vaccinations according to the national immunization schedule, most are convinced of the value of vaccination and many find it difficult to deal with parents who object to vaccination.
    • p.2
  • Religious objections are one of the possible reasons for refusing vaccination. In the Netherlands, an orthodox Protestant minority of about 250,000 members has religious objections to vaccination. Forty percent of them has been found to not be vaccinated at all. Epidemics of polio, measles, rubella, and mumps have broken out among this group and spread to their relatives in Canada. Orthodox Protestant objections to vaccination focus on the necessity of trust in divine providence. On biblical grounds arguments for vaccination are put forward as well: vaccination may be considered as a gift of God to be used in gratitude. Orthodox Protestant churches leave it up to parents to decide to have their children vaccinated or not.
    During the polio epidemic of 1978, Veenman and Jansma identified among orthodox Protestants religious objections, family tradition, and fear of possible sideeffects as major reasons for not being vaccinated. More recently, we performed a study on vaccination decision-making among orthodox Protestant parents and found that vaccinating as well as non-vaccinating parents predominantly used religious arguments to justify their decision. If side-effects of vaccination were mentioned, they often had a religious connotation. Nonvaccinating parents who primarily refused vaccination because of interference with divine providence, also mentioned that man is not allowed to cause disease in a by God given healthy body. On the other hand orthodox Protestant parents who broke with tradition and participated in the National Immunization Program (NIP), interpreted side-effects as a sign of God that they had made the wrong choice.
    • p.2
  • Religious objections to vaccination have a long history, nevertheless little is known about the way HCPs deal with these specific objections. The American Academy of Pediatrics issued a guideline “Responding to parental refusals of immunization of children” which advises to listen respectfully to all objections, provide honest information, and attempt to correct any misperceptions. A Dutch brochure on objections to vaccination advises largely the same. Few papers were published on the actual response of health care professionals to parents with objections to vaccination. The objections in these studies concerned vaccine safety and HCPs responded to them by trying to convince the parents of the medical benefits of vaccination. The response of health care professionals to parents with religious objections to vaccination has -to our knowledge- never been studied
    • pp.2-3
  • We identified three manners of responding to parents with religious objections to vaccination: the provision of medical information, the discussion of the vaccination decision-making process, and adoption of an authoritarian stance. The manner of responding was shown to depend on characteristics of the child, the willingness of the parents to engage in a discussion of the vaccination decision, and some personal characteristics of the HCPs themselves.
    The three manners of responding to religious objections to vaccination resemble to recent models of medical decision making (in the context of the doctorpatient relationship) in which the informative, the shared decision-making, and the paternalistic approaches are distinguished. There is, however, a major difference: while providing medical information on vaccination fits into the informative approach, and the doption of an authoritarian stance on tetanus postexposure prophylaxis fits into the paternalistic approach, discussing the vaccination decision-making process cannot be considered as shared decision-making. Shared decision making means that patient’s preferences are taken into account in a final decision that is endorsed by both the doctor and the patient. A prerequisite for shared decision making is that the available options be medically equivalent. This is questionable in cases of vaccination and simply untenable in cases of tetanus postexposure prophylaxis where refusal has a high risk of adverse outcome. Thus, the aim of discussing the vaccination decision-making process with parents who refuse vaccination is to help them make a well-considered decision; that is not necessarily a decision endorsed by the HCP .
    • pp.6-7
  • All HCPs primarily responded by providing medical information and correcting any misconceptions regarding vaccination. They considered the provision of medical information a key competence of HCPs, and their most important contribution to acceptance of vaccination. Orthodox Protestant youngsters, however, are more interested in religious aspects of vaccination than in medical aspects. And orthodox Protestant parents predominantly use religious arguments to justify their decision on vaccination. Therefore the influence of medical information on parents’ final decisions is expected to be limited, as was noticed by some HCPs in the present study.
    • p.7
  • The religious background of HCPs influences their attention to religious considerations in general clinical practice. In a recent study in the USA, older pediatricians with Christian backgrounds paid more attention to religious considerations than younger, non-religious pediatricians. Similarly, GPs with a Protestant background in the Netherlands have been found to pay more attention to religious considerations in their practice than GPs with a Catholic background. While to our knowledge the present study is the first to focus on the influence of religious background on vaccination discussions, our finding that in particular the HCPs with an (orthodox) Protestant background discussed the decision-making process and the religious considerations involved are in line with these studies. Some extra education on religious aspects of vaccination and training in communication skills could for the other HCPs possibly facilitate the discussion of the decision-making process with orthodox Protestant parents, however the effects of such discussions should be evaluated.
    • p.7
  • In this study, we identified three manners in which HCPs respond to parents with religious objections to vaccination: provision of medical information, discussion of the vaccination decision-making process, and adoption of an authoritarian stance. The choice of approach depends on the medical condition of the child, the willingness of the parents to engage in discussion, and the personal characteristics of the HCPs themselves. Given that for parents with religious objections to vaccination medical information is generally not decisive, we recommend HCPs to discuss the vaccination decision-making process – if parents are willing to engage in such a discussion- rather than to provide them with extra medical information.
    • pp.7-8

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