TORONTO— Pfizer and BioNTechs mRNA vaccine is being administered to people in the UK, Canada and the US after being approved for emergency use in these nations. The rapid approval process and experimental nature of this technology trigger concerns over safety and efficacy claims, only to be eclipsed by the need for a solution to the toll of this pandemic on human and economic health.
As made evident in Neil Fergusons Report 9, the first and most influential public health literature used to inform policy makers, strict lockdown measures were necessary until a vaccine became available. This was so even though a coronavirus vaccine nor the experimental mRNA vaccine technology being developed had never been brought to market.
What does the scientific literature and history of mRNA vaccines reveal about the possibility of a safe and effective SARS-COV2 vaccine?
Citing scientific literature provided by Pfizer and BioNTech, on December 9 2020, Health Canada authorized use of the COVID-19 Pfizer BioNTech vaccine under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for use in Covid-19. This order’s purpose was to expedite the authorization for the drugs relating to COVID-19, with respect to urgent public health needs.
On December 11 2020, the FDA granted an Emergency Use Authorization for this same vaccine. These approvals followed the UKs December 2nd decision to provide emergency regulatory approval and they were the first to administer this vaccine to patients.
mRNA Description and History
According to a 2013 paper published in PLOS, a non profit, open access science and technology publisher, it takes 10.7 years on average to develop a vaccine. The most rapid vaccine approval was for the mumps vaccine, formulated in the 1960s. It took less than 4 years from creation to approval, and was developed using live attenuated viruses within chicken embryos. mRNA vaccines have never been approved for use in any country.
According to the CDC, the new mRNA vaccines triggered an immune response to a certain component of a virus, instead of relying on past technologies which introduce weakened or inactivated germs into our bodies. This immune response generates antibodies which protects a person from getting infected if they come in contact with the real virus.
For the COVID-19 vaccine, BioNTech had created a synthetic mRNA code for the body to generate its own “spike protein” characteristic of the SARS-COV2 virus. Once vaccinated, the mRNA code enters human cells and instructs the body to create a spike protein and displays it on its cell wall. At this point, the immune system recognized the spike protein as foreign and developed an immune response, which is repeated if it encounters the spike protein again, on SARS-COV-2. According to Health Canada, mRNA vaccines were developed at unprecedented speed because they’re made in a lab using accessible materials.
Although relatively easy and quick to produce compared to traditional vaccine-making, no mRNA vaccine or drug has ever won approval since it emerged in the work of Katalin Karikó and Drew Weissmen in the 1990s. Katalin, now a senior vice president at BioNTech, identified the problems with this approach in a discussion with Statnews. She was fighting the fact that synthetic RNA was extremely vulnerable to the body’s natural defenses and would be destroyed before reaching the targeted cells. She also observed that this generated an immune response which rendered the therapy a risk for her animal and human trial participants.
In 2005, the technology seemed to experience a breakthrough. This is summarized in volume 969 of Methods in Molecular Biology. Here Karikó, Weissman and two other researchers demonstrate that by modifying the nucleoside (the hereditary-controlling component of all living cells) of synthetic RNA, they reduce “the potential of RNA to activate RNA sensors”, reducing the likelihood of an immune response.
Studies on rats and primates began emerging which showed promise for this technique. For example, in 2018 the Journal of Experimental Medicine published a study which concluded that Nucleoside-modified mRNA vaccines produced strong antigen-specific T cell responses. T cells are responsible for immune response to foreign invaders in the body.
In that same year however, pioneer in the field Drew Weissmen published a report in Nature Reviews Drug Discovery entitled mRNA vaccines – a new era in vaccinology. He stated that despite the promising future of this technology, trials have shown challenges in advancing this vaccine for widespread use. In studying preclinical and clinical results of mRNA vaccines, the authors evaluated the potential use of these vaccines against influenza, Ebola, Zika and Streptococcus viruses and found that in some trials the ability to provoke a desired immune response was “limited in humans compared to their animal counterparts”. Further, they asserted that “the side effects were not trivial.” They cautioned that further research was needed to determine how different animal species respond to mRNA vaccines and how to stimulate immune signaling without inflammatory response in humans.
Weissmen cited literature on the first ever mRNA vaccine tested on humans, entitled Safety and immunogenicity of mRNA rabies in healthy adults […]. In this study, 10% of participants experienced a grade 3 event seven days post intramuscular vaccination. A Grade 3 adverse event is defined by the U.S. Department of Health and Human Services (HHS) as, a “severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care” such as “bathing, dressing and undressing, feeding self, using the toilet, taking medications”
Another study of note, according to Weissmen, was the 2017 Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses. All researchers in this study were employed by Moderna or Valera, a Moderna venture. They conducted tests in vitro, on live mice, ferrets as well as on humans. According to these scientists, “mRNA vaccines can induce protective immunogenicity with acceptable tolerability profiles.” Adverse effects on the human trial were abundant however, with 100% of subjects reporting adverse effects. 66% of the effects were mild, 32% were moderate and 13% were categorized as severe. Using the Center for Biologics Evaluation and Research (CBER) severity scale, Mild AEs were defined as those having no limitations in normal daily activities, moderate AEs as causing some limitations, and severe AEs were defined as events causing inability to perform normal daily.
In summary, there have been studies of mRNA vaccines in the past both on a variety of viruses, and for respiratory illnesses. The data shows promise in this experimental rapid technology, but there have been concerns over clinical trial data. Was BioNTech able to remedy and overcome these concerns in their Covid-19 vaccine?
Health Canada cited the Phase 1/2/3 placebo-controlled, randomized, observer blind study to evaluate the safety, tolerability, immunogenicity and efficacy of the SARS-COV-2 vaccine in their approval of the vaccine. Pfizer conducted studies, sponsored by BioNTech.
This document revealed the vaccine boasted a 95% effectiveness rate. This was determined by asking participants who develop acute symptoms associated with Covid-19 infection to get tested using a nasal PCR test. 169 Participants in the placebo study tested positive compared to 9 in the vaccinated group, meaning 95 of those within the vaccinated group didn’t develop symptoms that would trigger a test result. This methodology identified only Covid-19 positive participants who exhibited symptoms, which means the number of positive but asymptomatic Covid-19 remains unknown. For this reason, public health officials have called for the continuation of mask wearing and social distancing after vaccination.
The British Medical Journal cites experts’ concern over lack of transparency in the Pfizer trials in their October feature entitled: Covid-19: Vaccine trials need more transparency to enable scrutiny and earn public trust, say experts.
Although the protocols for the Pfizer vaccine have been made public, there has been no independent Data and Safety Monitoring Board (DSMB) to review the data from these clinical trials.
Further, procurement Minister Anita Anand confirmed in a press conference on Monday that Coronavirus vaccine makers are shielded from liability in the event of adverse effects. This means if any adverse effects emerge within the population as a result of this vaccine, Canadians and the Canadian government are paying the bill.
Since the cited study did not include any data on adverse effects, it became necessary to reference the FDAs briefing document, also sponsored by Pfizer and BioNTech. These documents detailed the observed Adverse Reactions throughout the study. The most frequent adverse reactions in a random subset were: injection site pain (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%) and fever (14.2%) and were usually mild or moderate in intensity and resolved within a few days after vaccine administration.
“Severe adverse reactions occurred in 0.0% to 4.6% of participants, were more frequent after Dose 2 than after Dose 1, and were generally less frequent in adults ≥55 years of age (≤2.8%) as compared to younger participants (≤4.6%)” (p.43 FDA briefing document).
The briefing document highlighted reports of imbalanced adverse effects in the vaccine group comparatively to the placebo group. This was the case for lymphadenopathy (swelling of the lymph nodes), which was 10x more likely to occur in the vaccine group. Bell’s palsy (facial paralysis) was reported by four vaccine participants and no placebo participants, with three of four cases remaining unresolved at date of publication. Appendicitis was reported in 8 of the vaccine participants, and 4 placebo participants. Further, suspected Covid-19 cases that were not PCR confirmed were not recorded as adverse effects. Two patients were hospitalized with apparent COVID symptoms shortly after the administration of their second dose, but could not identify the cause of illness given the administration of repeated negative PCR tests.
Is it possible to assert with a reasonable degree of certainty that this vaccine is safe and effective for all Canadians? Or was the approval criteria lessened given the perceived desperate need for vaccines in order to re-open Canada?
As it related to the claims of efficacy, the data was structured in such a way that affirms reduction of Covid-19 symptoms in 95% of vaccinated participants, but it cannot be said to be effective in preventing the spread of Covid-19. Whether that metric is sufficient given the risk profile of the vaccine, is up to each individual to decide.
Vaccine hesitancy has been presented as a serious public health concern by politicians and world leaders. Reluctance to get vaccinated necessarily implies a desire to learn more about one’s health and a general malaise regarding the precedent of damages in this domain. Doubting and researching a vaccine in order to decide for oneself is characteristic of a sovereign empowered being, utilizing their fundamental human rights over the supremacy of their own body. Absolutism and shaming in this regard only serves to undermine our ability to discuss compassionately and support each other’s communities and health.
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