Re: Covid-19 Vaccine Efficacy and Safety
We understand you are extremely busy, both with normal activities associated with your electorate and important portfolio, but especially with matters related to the COVID-19 crisis. Given these obligations, we would not normally write to you directly appealing for your immediate consideration, unless we believed the issue was critical to public health and safety of all Australians.
Patrons of Chiropractic Science (PCS) is an Australian research charity, with a particular focus on promotion and funding for research to support of the validity and efficacy of Chiropractic sciences. In its role as a primary contact health care service, the Chiropractic profession is obliged to also be involved in general public health matters.
PCS is supportive of vaccination programs. While some vaccinations may have a history of adverse reactions, many have contributed to measurable improvements in public health across the globe. PCS acknowledges it may be possible, and even desirable, that the COVID-19 crisis be resolved with a safe and effective vaccine, particularly if the public broadly accept its implementation. However, an absolute guarantee of safety by the manufacturer, critically confirmed by your health department, will be the major factor for adequate uptake (1).
It is therefore fundamental for you and the various Australian health authorities, fully understand the historic issues that have accompanied all previous, but failed attempts, to develop and gain approval for coronavirus vaccines, as well as a number of other similar, viral based, communicable disease vaccines.
There are many mechanisms at play with the concerning negative responses to vaccines, but the two considered to be most relevant to COVID-19 have been termed pathogenic priming and enhanced immune responses (EIR).
During a number of SARS-CoV-1 (SARS) vaccine trials on test animals, where lung tissue was engineered to closely resembled human lung tissue (mice and then ferrets), the test subjects all accommodated the vaccine without significant adverse reactions, and also confirmed production of the appropriate antibodies. However, when these test animals were exposed to the wild virus, most developed extreme symptoms of lung, and in some cases liver disease, with many dying (2, 3). This disturbing pattern was later repeated with the Middle Eastern Respiratory Syndrome (MERS, also a coronavirus) vaccine studies (4).
Researchers believed a type of “priming” of the immune system was observed during these animal studies of SARS spike protein-based vaccines (viruses nearly identical to SARS-CoV-2; COVID-19), leading to increased morbidity and mortality in vaccinated animals when subsequently exposed to the wild virus. This serious reaction only became obvious following post-vaccination challenge with the live virus, where the recombinant SARS spike-protein-based vaccines not only failed to provide protection from SARS-CoV-1 infection, but also the test animals experienced increased immunopathology with eosinophilic infiltrates in their lungs (5). Similarly, further trials found that ferrets previously vaccinated against SARS-CoV-1 also developed strong inflammatory responses in liver tissue.
Both studies appear to have confirmed a cellular immune response, or pathogenic priming, allowing significant susceptibility to the actual pathogen due to an over-reaction by the immune system, described as EIR, or antigen-dependent enhancement (ADE), where antibodies created during a first-time infection to the body, even a vaccine, could end up enhancing virus entry into host cells. The vaccine and the subsequent immune responses then triggered symptoms and outcomes on par or worse than naturally acquired disease, rather than protecting against a real infection (6). The precise mechanism for these negative reactions is not fully understood and is disputed by experts, which actually makes the risk even greater.
Such findings are not new. Since the 1960s, tests of various vaccine candidates for diseases, such as dengue fever and respiratory syncytial virus (RSV), have shown a similar paradoxical phenomenon to the SARS and MERS trials (7, 8), where some test animals or people who received the vaccine and later exposed to the virus, developed more severe disease than those who had not been vaccinated. The vaccine-primed immune system, in certain cases, seemed to launch extreme reactions, often involving cytokine inflammatory responses to the natural infection, known as a cytokine storm. If this is repeated with a COVID-19 vaccine, it could directly lead to patients effectively drowning in the inflammatory liquids generated by the body as part of its excessive, primed immune response.
It is now widely accepted that serious complications and death associated with COVID-19 impacts a very specific group, largely those over 70 years of age, generally with one of more co-morbidities, and some younger people also with notable co-morbidities, that render them immuno-compromised to one degree or another. 80% of the population suffers no or very mild symptoms from COVID-19, and around 18% suffer more serious symptoms, some requiring hospitalisation, but they recover. A small percentage, probably less than 1% of those infected die, nearly all elderly, each suffering with more serious associated co-morbidities.
One can only imagine the repercussions, if a rushed or poorly tested vaccine was broadly introduced to Australians, and forced under any form of mandate, to effectively protect 1% of the population, that ultimately triggered pathogenic priming/EIR/ADE. This could lead to significant deaths across a larger cross-section of the general population, including the group who had not previously suffered significant symptoms or negative outcomes. This could even start to trigger deaths in our children if they are vaccinated.
Many independent experts generally agree that detailed animal experiments and extended human clinical trials of candidate vaccines for COVID-19, which is caused by the coronavirus SARS-CoV-2, must include a careful assessment of possible immune complications before releasing the vaccine to the public. This will require greater standards of research.
PCS suggests that any valid assessment of a proposed COVID-19 vaccine for Australia must be independent of the pharmaceutical company developing the vaccine, using parties selected by you that are provided with full access to all of the trial data and outcomes. Unfortunately, there has been a long history of data “cherry picking” by these companies as they rush to meet a market demand. For these companies, this is a multi-billion dollar business, so we believe it would be unwise to totally depend on their philanthropic tendencies.
Additionally, the vaccine industry and its supporters have now managed over time to convince most regulatory and approval bodies that full, randomised human trials, over extended periods are no longer necessary. They claim responses to the vaccines are now well understood, once it is confirmed that the test subjects generated suitable antibodies within a few days (9). Such an approach is inappropriate for COVID-19, particularly in the light of the earlier SARS and MERS vaccine failures. To further complicate the matter is the insistence on indemnities for vaccine producers in the event any recipients ultimately suffer serious or even life threatening adverse reactions. Given the vast amount of risk funding having been granted by many governments to such producers, this requirement appears to be counter-intuitive.
PCS already has significant concerns with the AstraZeneca/Oxford University vaccine trials, as very little extended animal testing was undertaken. However, the Oxford University trial using rhesus macaque monkeys, did not appear to stop them from getting coronavirus once vaccinated, although there may be some anecdotal evidence in reducing the severity of the disease. The trials then advanced to human subjects, who appeared to present with “acceptable levels of adverse reactions” and triggering the required antibody production. Unfortunately, the next phase of testing has been suspended as subjects of this first human trial later suffered severe adverse reactions that are often linked to vaccines. PCS believes the subjects may have been later exposed to the wild virus, and these reactions could be EIR/ADE. It is fundamental that full disclosure of these unfortunate subjects symptoms be made available to your department. This setback could delay approval of this vaccine by up to eighteen months.
Had the next phase of AstraZeneca trials advanced, PCS still harboured significant concerns as initially, it was claimed by the researchers the vaccine would be trialled against a saline placebo as a control. This plan was later changed, so that the control group would be administered a meningococcal vaccine as the control, a vaccine noted for its serious levels of adverse reactions. It is rather obvious why Oxford/AstraZeneca changed this aspect; to mask the already observed adverse reactions of their trial vaccine.
However, there do appear to be positive examples by some vaccine developers, who may be using acceptable trial procedures, that will test the risks for these concerning reactions associated with post-vaccination exposure to a wild viral infection. The Moderna Phase 3 trials are about to begin, which will involve ~30,000 subjects who have not contracted SARS-CoV-2, where the control group will be administered a saline placebo. Further, these subjects will circulate as normal in the USA community for an extended period of time, where a significant percentage would be likely to be exposed and infected with the wild virus. In this way, any EIR/ADE adverse reactions should be exposed.
While PCS is certain you can seek further advice about these clear, well known risks, from highly reputable immunologists and virologists, we wanted to point out that any vaccine considered for Australia must at the very least address the following key testing regimes and risks:
1. Preclinical testing: all candidate vaccines for Covid-19 must initially include in vivo techniques using animals, including primates, that have been demonstrated to present with lung and liver tissue that reacts in a similar manner to human tissues. Test animals must be subjected to the trial vaccine to demonstrates both adverse reactions and complete seroconversion rate data accurately recorded and provided on antigen-specific T cell responses including cluster of differentiation (CD)4+ and CD8+cytotoxic T lymphocytes (CTLs) and relevant cytokines. Once satisfactory seroconversion has occurred, all test animal subjects must be exposed to the live virus and carefully monitored for an extended period of time (not simply a couple of days). While many researchers argue that animal testing not be utilised for SARS-CoV-2 due to difficulties in identifying suitable subjects that may react to the disease in a similar manner to humans, this step should be required to both test and to provide a level of confidence in safety for the Phase I trial human subjects.
2. Phase I trials on a limited number (~50) of healthy, low-risk humans, in an approximate age range of 18 to 50, who have not been exposed to SARS-CoV-2, must be undertaken with great caution and in close proximity to advanced medical facilities experienced in both virology trials and COVID-19 treatment. Once suitable seroconversion rates have been identified and relevant data collected over a period of weeks. Each subject, where antibody responses are confirmed, must then be exposed to the wild virus and monitored for an extended period (3-4 weeks) to observe for adverse reactions and confirm appropriate response and immunity to the infection.
3. Phase II trials should only commence if acceptable antibody production and response was observed in the vast majority of Phase I subjects and there is no evidence of pathogenic priming or EIR/ADE. This will involve a larger group (>200) of human subjects not exposed to SARS-CoV-2 over a broader range of age groups, including children, pregnant women and older adults to the age of 70 years. Half the subjects receive a saline placebo at the identical frequency of the trial vaccine administration required by the developer. Once suitable seroconversion rates have been confirmed and relevant data collected over a period of weeks, every subject must then be exposed to the wild virus and closely monitored for an extended period (4-6 weeks, not a few days as is common), to compare adverse reactions and the efficacy of the vaccine to the actual viral infection compared to the control group who received a saline placebo. The test subjects should also reside in close proximity to advanced medical facilities.
4. Phase III trials should also only commence if acceptable antibody production and immune responses to the wild virus were observed in the vast majority of Phase II subjects and there is no evidence of pathogenic priming or EIR/ADE. This will involve a significantly larger group (>20,000) of human subjects not exposed to SARS-CoV-2, conducted in “field” conditions that are similar to future routine use over a broader range of age groups (much like the proposed Moderna Phase III trial), and given the risk profile of COVID-19, should include older adults to the age of 90 years. While the likelihood of adverse reactions such as pathogenic priming or EIR/ADE should now be unlikely after the Phase II and III trial data, given the history of SARS and MERS vaccine trials, PCS believes Phase III should utilise a randomised controlled trial (RCT) methodology to incorporate a control saline placebo, to estimate the percentage reduction in the incidence rates of disease due to vaccine against the placebo comparator. While many researchers object to the RCT approach, often citing cost and time (10), the seriousness of possible adverse reactions supports a more conservative approach with this coronavirus. The much larger trial group, circulating amongst the general European or USA pubic would be expected to naturally come in contact with the wild virus, thereby confirm efficacy and absence of the key adverse reactions.
5. Approval can only be considered if the three phases of human trials confirm an acceptable level of immune responses or adverse reactions, that are not permanent in nature, no evidence of pathogenic priming or EIR/ADE and appropriate immunity to the infection. In vaccines where an adjuvant is utilised, additional steps to compare just the adjuvant to the saline placebo will be necessary to assess related adverse reactions. The comparison threshold must both consider the immune responses of test subjects that had received a placebo and the existing infection and disease severity data of the general non-vaccinated population to date, as any vaccine must clearly demonstrate notable improvements and efficacy in acquired immunity and/or disease severity compared to the non-vaccinated group. The Phase III data would be assessed against the standard vaccine approval protocols considering (11):
a. Estimates of the vaccine efficacy for susceptibility, colonization, progression, pathogenicity and infectiousness;
b. Total vaccine efficacy for COVID-19 disease;
c. Indirect effects of those not vaccinated;
d. Total effects of vaccination in those vaccinated;
e. Overall population-level effects.
While there is obviously a sense of urgency to develop and approve a vaccine for COVID-19, this should not be at the expense of safety and efficacy. A rushed, poorly tested vaccine in this case is a dangerous act. COVID-19 disease is clearly not as serious as first postulated by epidemiologists and their models. Global data is now emerging demonstrating the overall net mortality is not excessively higher than previous years for pulmonary disease, and the extreme lockdowns are likely to result in far greater human cost than the actual COVID-19 disease. This means with sensible, balanced and careful public health management, we actually have time to get a vaccine right, if this is possible.
PCS is not promoting the Moderna mRNA vaccine, only their announced Phase III trial regime. The fact remains that even the World Health Organisation notes many aspects of the immune responses caused by DNA/RNA vaccines are not yet fully understood (12). Researchers also point out DNA/RNA vaccines usually only encode one protein from the pathogen, and may not be so effective if an immune response against multiple proteins is required to ensure adequate protection. Viral mutations also add to the complexity.
Lessons must be learned and accommodated from all past attempts to develop coronavirus vaccines, and while these previous efforts may not have generated positive outcomes, PCS is certain their findings could provide some guidance for the most effective vaccine structure and optimal testing regimes to address the possibility of the short-term immunogenicity derived from neutralizing antibodies, previously observed for SARS and MERS-CoV after natural infection (13).
We strongly encourage you to implement and insist upon such conservative vaccine approval measures to ensure the health and safety of all Australians.