Information

Contents: This page has links to more information on the petition’s topics. First: clips on the need to fully inform early vaccine recipients about risks. Second: an overview of why vaccine enhanced disease is a particular concern in this case. That includes clips from scientific articles that may be understandable to some educated people in the general public who have learned a few of the relevant terms like “antibody” and “spike protein”.

Third: a section of unorganized relevant clips. They include concerns from mathematicians looking at Pfizer’s data who question whether there is enough data to support claims of efficacy for those over 75. Vaccines in general are sometimes less effective in the elderly, and immunity may fade faster for them. A final brief comment on more information at the end.

People who take experimental treatments should be fully informed

Vaccines for other diseases have saved hundreds of millions of lives and hopefully COVID-19 vaccines will eventually add to that record. There is a difference between vaccines that have been fully tested, and those still in the early stages of being studied which are released under Emergency Use Authorization (EUA).

Most of the public seems to be reacting to allowing the general public to get the vaccine as if that indicated the vaccine were already proven certain to be safe. They don’t seem to truly grasp it was merely determined to be worth letting people choose to take the risk of using a product that isn’t yet fully tested. The FDA’s review said it hadn’t found evidence to date of vaccine enhanced disease: but the problem is more likely to arise later when the initial protection has faded. A statement regarding lack of evidence at this point parallels the old “joke” about someone jumping from a skyscraper and saying as they fell past the 2nd floor: “I’m fine so far!”. Hopefully this will have a more positive outcome.

A Japanese professor of Immunology who testified on the issue to Japan’s House of Representatives explained that in: “With vaccines there is a risk of antibody-dependent enhancement (ADE), in which antibodies acquired through past infections or vaccinations behave abnormally, causing the ailment in the patient to become severe. But during phase 3 trials, you can’t examine the possibility of ADE — that can only be done after it goes on sale.”

He placed the issue in perspective: ” Looking back on the history of the development of vaccines, only about 4% make it all the way from pre-clinical trials (on animals) to approval. So if there are 100 candidate vaccines, 96 of them will fall by the wayside. But this is not because they were unable to produce antibodies. Even if they are effective in triggering an immune response, the reality is that most of them are rejected due to side effects.”

An infectious disease professor noted: ““The great vaccinologist who created new vaccines — Maurice Hilleman — always said, and he created a whole series of vaccines that are now in use, he said he was always worried until the first 3 million doses had been administered,” […] “some experimental vaccines against SARS, the original cousin to the virus that causes COVID-19, showed evidence of vaccine enhanced disease.”

Journal of Virology article: “There is, however, a foreseeable outcome that could set back the wider vaccine field for decades. If the first-tested vaccines fail to protect most recipients but prime or trigger an antibody or other immune response that exacerbates COVID-19 disease in people who become infected, there will be a ferocious public backlash against vaccines in general.
 The consequences could be serious harm not just to the prospects for a successful COVID-19 vaccine but also for the uptake of the commonly used vaccines that are essential to the health and wellbeing of our children.”

International Journal of Clinical Practice article: “Informed consent disclosure to vaccine trial subjects of risk of COVID‐19 vaccines worsening clinical disease […] This risk is sufficiently obscured in clinical trial protocols and consent forms for ongoing COVID‐19 vaccine trials that adequate patient comprehension of this risk is unlikely to occur, obviating truly informed consent by subjects in these trials.[…]Given the strong evidence that ADE is a non‐theoretical and compelling risk for COVID‐19 vaccines and the “laundry list” nature of informed consents, disclosure of the specific risk of worsened COVID‐19 disease from vaccination calls for a specific, separate, informed consent form and demonstration of patient comprehension in order to meet medical ethics standards. The informed consent process for ongoing COVID‐19 vaccine trials does not appear to meet this standard. While the COVID‐19 global health emergency justifies accelerated vaccine trials of candidates with known liabilities, such an acceleration is not inconsistent with additional attention paid to heightened informed consent procedures specific to COVID‐19 vaccine risks.”

A viewpoint in the Journal of the American Medical Association: “If a vaccine is released under an EUA, clinicians should inform patients that the vaccine is not FDA licensed. Key questions will include why the vaccine is not licensed and what information FDA may be waiting for.”. A news article at from the journal Nature adds: “The vaccine has completed only a few months of the two-year clinical-trial period that it will need to complete before it is approved to be sold freely on the market. As a result, health officials, clinicians and people receiving the vaccine will be watching closely for as-yet unobserved signs of danger.”

As of Dec. 12th, 2020 the fact sheets about Pfizer’s vaccine provided by the US, UK and Canada for the public don’t mention vaccine-enhanced disease concerns, despite the FDA’s technical review acknowledging that to be an “important potential risk”.

Here are US FDA’s “FACT SHEET FOR HEALTHCARE PROVIDERS ADMINISTERING VACCINE” and its “FACT SHEET FOR RECIPIENTS AND CAREGIVERS”. Canada’s COVID-19 vaccine “Consumer Information” and a “PRODUCT MONOGRAPH”. The UK NHS’s COVID-19 vaccine info.

The journal Vaccine: “Safety surveillance must be capable of investigating adverse events of special interest (AESI)[…] For the COVID-19 vaccines, the AESIs could potentially include vaccine-enhanced disease (vaccination could make subsequent infection with SARS-CoV-2 more severe) […]Enhanced disease was seen in some preclinical studies with SARS-CoV vaccines and raised questions about other coronavirus vaccines showing a similar AESI.”

 A  meeting of  “experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns”  in March published a “Consensus Summary report” on “Assessment of risk of disease enhancement with COVID-19 vaccines” which said: “Data are needed on whether antibody waning could increase the risk of enhanced disease on exposure to virus in the long term.”

 A  meeting of  “experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns”  in March published a “Consensus Summary report” on “Assessment of risk of disease enhancement with COVID-19 vaccines” which said: “Data are needed on whether antibody waning could increase the risk of enhanced disease on exposure to virus in the long term.”
 
That meeting was sponsored by the  Coalition for Epidemic Preparedness which is funded by the EU, UK, Japan, Norway, Germany, the Bill and Melinda Gates Foundation, The Wellcome Trust.  Its described as “by far the largest vaccine development initiative ever against viruses that are potential epidemic threats.” It was co-sponsored by the Brighton Collaboration which is “a member of the WHO-led project Vaccine Safety Net”

Why Vaccine Enhanced Disease is of concern in this case

Most people who are infected with the virus SARS-COV-2 either have mild symptoms, or even no symptoms at all. Those who have severe cases of COVID-19 often have a strong immune response to the virus, but one which is dysfunctional for reasons they don’t yet understand. Many describe severe COVID-19 as being due to an over-reaction of the immune system, rather than a lack of reaction.

Sometimes a vaccine will initially train the body to have highly effective sterilizing immunity by producing enough neutralizing antibodies to prevent the virus from replicating in the body. It seems likely that is happening during the initial few weeks after people have received COVID-19 vaccines and its led to reports of early high levels of effectiveness. The problem is: over some as yet unknown period of time that level of protection is likely to fade.

Eventually someone who was vaccinated won’t be able to prevent the virus from infecting their cells. Other aspects of the immune system will then respond more quickly than if they hadn’t been vaccinated. With many diseases that would likely lead to a quicker recovery.

The question in the case of COVID-19 (where nature of the immune response seems to be what causes severe cases): might that immune reaction also be dysfunctional and trigger serious illness? Would the immune response be more likely to be a problem in someone who wasn’t vaccinated, or less likely? Would a booster help?

Its important to be aware there are different kinds of vaccine enhanced disease and not merely the most commonly referred to issue of Antibody Dependent Enhancement (ADE). News article from the National Academy of Sciences on the topic: “Avoiding pitfalls in the pursuit of a COVID-19 vaccine […] Some researchers argue that although ADE has received the most attention to date, it is less likely than the other immune enhancement pathways to cause a dysregulated response to COVID-19”

The authors of one study described the immune response in severe COVID-19 cases as “uncoordinated” where for instance “the antibodies might have risen to high levels while one of the cellular responses remained weak, for example.” A vaccine expert added that: “But she notes that some of the vaccine efficacy trials aren’t designed to even analyze T cell levels. And training an immune system to make strong T cell responses against SARS-CoV-2 ultimately may require using more parts of the virus in a vaccine than the spike protein alone.”

The article references the potential need to use “more parts of the virus in a vaccine” because the initial COVID-19 “vaccine candidates involve the full-length S-protein” and not the rest of the virus.

A review in the Journal of Virology: “What is also seen consistently is the lack of correlation between strong antibody responses and the amelioration of disease; indeed, the converse is true in that the highest antibody titers are seen in the patients who later develop the most severe disease and also in the oldest ones. In contrast, people with mildly symptomatic infection that did not require hospitalization generally have far weaker antibody responses. The same was seen in the SARS epidemic, where cases with the earliest and strongest NAb responses also had the poorest prognosis.”

It further notes reasons for concern regarding vaccines: “Taken together, there are concerns that the antibody responses to SARS-CoV-1 and -2 may not protect against disease but could even contribute to pathogenesis (see above). […] The risk of ADE for SARS-CoV-2 is a topic for serious discussion […]A rational approach to avoiding ADE is to minimize the induction of poorly or nonneutralizing antibodies by using the RBD to focus the antibody response on its key NAb epitopes (1687123147). However, all of the leading Warp Speed vaccine candidates involve the full-length S-protein, which expresses both NAb and non-NAb epitopes.”

Nature article: “The S protein is the major antigen in most COVID-19 vaccine candidates under development as it contains the major neutralizing epitopes and is located on the surface of the viral particle. However, the full-length S protein of SARS-CoV also contains several immunodominant sites that can induce non-neutralizing antibodies, including those associated with ADE, or harmful immune responses […] The phenomenon of VADE has, however, erected substantial barriers to the development of vaccines for some viruses, including, RSV, DENV, SARS-CoV and MERS-CoV. Currently, the unabated spread of COVID-19 has prompted several countries to rush into local vaccine approval without a comprehensive safety evaluation. Vaccines for viruses with high transmissibility but low case fatality, such as SARS-CoV-2, should usually have a higher bar for safety than those for viruses with low transmissibility but high case fatality, such as Ebola virus, because many more healthy individuals will have to use them.”

Unorganized clips on related issues

A concern regarding the initial level of evidence for the Pfizer vaccine. A mathematician analyzed the data and suggests the study didn’t include enough participants over 75 to be able to draw useful conclusions: “And when we get to people over 75, what they describe isn’t a confidence interval, it’s a joke. A confidence interval of -12.1 to 100 is a lot like saying they threw a bunch of darts at a dart board at random and did everything from hit bystanders (i.e. the vaccine made things worse) to a bullseye (perfect protection). They simply didn’t have enough cases to say anything meaningful and so what they say is just totally useless.”,

A retired physicist confirmed the mathematician’s analysis: “But when we consider the 95% confidence intervals, Pfizer’s own table tells us there is no reason to claim efficacy in 16-17 year olds, and in 75+ year olds.[…] This explains why some of the VRBPAC committee members balked at endorsing the vaccine for 16-17 year olds. They probably would not balk at 75+ year olds, since they desperately need a vaccine and have little other recourse.”

Cell journal article where the reference to “resolving an ongoing infection is more challenging than prophylaxis” refers to the immune response to a virus after initial sterilizing immunity fades and infections occur: ” Thus, fatal COVID-19 case C92 represented an uncoordinated adaptive immune response, with neutralizing antibodies but a largely undetectable SARS-CoV-2-specific CD4+ T cell and CD8+ T cell response.[…] A vaccine does not have to directly mimic protective immunity observed in natural infection, but should be informed by protective immunity observed in natural infection. Resolving an ongoing infection is more challenging than prophylaxis. The data presented here suggest that neutralizing antibodies play a role in resolving acute COVID-19, but statistical associations found less of a role for antibodies than SARS-CoV-2-specific CD4+ or CD8+ T cells”.

An old published article about the original SARS: “Combined, our results suggest that antibodies against SARS-CoV spike proteins may trigger ADE effects. The data raise new questions regarding a potential SARS-CoV vaccine”

An editorial in Science from July: “SARS-CoV2 vaccines: Slow is fast […] Many advocate “fast-tracking” these trials, and some wish to rely solely on evidence of induction of neutralizing responses. However, this could be catastrophic. In 1966, a large trial of a vaccine for respiratory syncytial virus (RSV) found that the immunized cohort actually faired significantly worse upon infection. There is some reason to worry that the same may occur with some SARS-CoV2 vaccines.”

Nature article: “Risk of ADE for SARS-CoV-2 vaccines […] Evidence for vaccine-induced ADE in animal models of SARS-CoV is conflicting, and raises potential safety concerns. ”

A preprint: “These results also suggest that ADE may be more likely to occur at later time points after recovery from COVID-19 when the concentration of neutralizing antibodies elicited by the primary SARS-CoV-2 infection have waned to suboptimal neutralizing level.”

Vaccine journal: “Consequently, vaccine-induced enhancement has been a major stumble block in the development of certain flavi-, corona-, paramyxo-, and lentivirus vaccines. “

A Royal Society collaborative group on: “SARS-CoV-2 Vaccine Development & Implementation; Scenarios, Options, Key Decisions […] While antibodies and T cells are often helpful, they can also be destructive and enhance inflammation if present in the wrong proportions or mis-targeted, or if they enhance entry of the virus into cells. Historically, this has occurred with some vaccines (which commonly focus on inducing high levels of a single type of immune response), leading to vaccine-enhanced disease. There is a risk that this could occur following vaccination against SARS-CoV-2.19 20 21 Antibody dependent enhancement (ADE) occurred following vaccination against a feline coronavirus20 22 and the potential for antibody enhanced uptake of virus can be demonstrated in the laboratory for the related MERS and SARS-CoV-1 viruses.23 24 25 Animal models of SARS-CoV-2 infection for vaccine development may prove useful for assessing safety in this context 26 but there is currently no reliable predictive measurement of immune enhanced disease, whether in all recipients or in individuals.2

Article in Science: “Although animal models of SARS-CoV-2 infection may elucidate mechanisms of immune protection, we need observations of enhanced disease in people receiving candidate COVID-19 vaccines to understand the risk of immune enhancement of disease. Neither principles of immunity nor preclinical studies provide a basis for prioritizing among the COVID-19 vaccine candidates with respect to safety at this time. Rigorous clinical trial design and post-licensure surveillance should provide a reliable strategy to identify adverse events, including the potential for enhanced severity of COVID-19 disease, following vaccination. […] Among the potential risks raised in the context of COVID-19 vaccine development is whether the immune responses elicited by a vaccine could enhance SARS-CoV-2 acquisition or make the disease worse when infection occurs after vaccination”

A Nature article: “A perspective on potential antibody-dependent enhancement of SARS-CoV-2…ADE of disease cannot be reliably predicted after either vaccination or treatment with antibodies—regardless of what virus is the causative agent—it will be essential to depend on careful analysis of safety in humans as immune interventions for COVID-19 move forward.”

A preprint: “Pre-existing T cell memory as a risk factor for severe 1 COVID-19 in the elderly […] Therefore the impact of pre-existing memory on 401 neoantigen exposure, including sensitizing antigens, infections or vaccinations, as well as for autoantigens has to be carefully evaluated in future studies.”

Some scientists are working to understand the reality that some immune system reactions, like those a vaccine teaches the body to produce, may be detrimental rather than protective: “However, it is currently not clear which type of adaptive immunity to SARS-CoV-2 is protective or detrimental. Thus, there is an enormous interest to decipher the anti-SARS-CoV-2 response, both to define parameters of immune protection versus pathology, as well as for the design of effective vaccination strategies. […] Furthermore, pre-existing immunity has also been described for several other pathogens and neoantigens with variable consequences, from protective to harmful”

A Nature article on the immune reaction to COVID-19: “However, it is unclear why some patients respond too little and some patients too much,”

A preprint: “However, the neutralization capacities of these specific antibodies is still under discussion, especially since non-neutralizing antibodies can enhance infection through a process called antibody-dependent enhancement (hereafter abbreviated ’ADE’) [5, 6, 7, 8]. This has been recently emphasized in the set up of clinical trials (see for example [9]), in a general discussion of the prospects of vaccination [10] and in a perspective accounting for the present situation in terms of SARS-CoV-2 vaccines, therapies and immunity”

A preprint notes: “Our results revealed that ADE mediated by SARS-CoV-2 spike-specific antibodies could result from binding to the receptor in slightly different pattern from antibodies mediating neutralizations.”

MedCityNews reported in July: “Some potential long-term complications really are cause for worry. For instance, the FDA expressed considerable concern for enhanced respiratory disease, or ERD, which happens when people who have been vaccinated contract the virus and, instead of fighting it off, experience heightened symptoms due to a dysfunctional immune response. This occurred in the late 1960s among several children who received vaccines against respiratory syncytial virus and, more recently, has been seen in animal models of vaccines against coronaviruses like the 2002-2004 severe acute respiratory syndrome and Middle East respiratory syndrome.”

An older Vaccine journal article providing background that: “Consequently, vaccine-induced enhancement has been a major stumble block in the development of certain flavi-, corona-, paramyxo-, and lentivirus vaccines. “

Science article: “although antibody-dependent infection enhancement (ADE) was not observed during our studies with the human and animal serum antibodies, this effect should be carefully addressed in vaccine development.”

Frontiers in Microbiology article: “Clinical evidence of enhanced illness by preexisting antibodies from vaccination, infection or maternal passive immunity is available for several viruses and is presumptively proposed for other viruses. […] Considering that antibody dependent enhancement (ADE) is a major obstacle in vaccine development, there are continues efforts to understand the underlying mechanisms through identification of the epitopes and antibodies responsible for disease enhancement or protection.”

Frontiers in Cellular and Infection Microbiology article: “Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine […] At 3 years post-dose 1, vaccinated children in the 2–5 year age group, were found to be nearly 8 times likely to be hospitalized for severe dengue, compared to children in the placebo group “

Virology blog: “A problem with dengue virus vaccine […] The numbers are small but significant. For example, during year 5 after the third dose of vaccine, 295 of 20,439 children (1.44%) were hospitalized with dengue virus infection. Severe dengue was also observed during years 2-4 after the third dose. Considering that millions of children will eventually receive this vaccine, serious disease occurring at a rate of 1.44% is not acceptable.”

The New England Journal of Medicine article: ” Although immunologic dysregulation has been observed in severe cases of Covid-19,26 it is not known whether immune hyperactivity or a failure to resolve the inflammatory response because of ongoing viral replication or immune dysregulation underlies severe cases.”

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