The following is a summary of the primary literature written by Fernando P. Polack, M.D., Stephen J. Thomas, M.D., Nicholas Kitchin, M.D., Judith Absalon, M.D., Alejandra Gurtman, M.D., Stephen Lockhart, D.M., John L. Perez, M.D., Gonzalo Pérez Marc, M.D., Edson D. Moreira, M.D., Cristiano Zerbini, M.D., Ruth Bailey, B.Sc., Kena A. Swanson, Ph.D., et al., for the C4591001 Clinical Trial Group. all figures represented here are directly from the paper ‘Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine’ published Dec. 10, 2020.
I hope this summary could be of use to those who have a background in science and are curious to the safety and efficacy studies of the Pfizer vaccine, but don’t care to sift through the primary literature itself to gather the main points.
A video brief will follow this shortly for those who prefer, as opposed to reading this lengthy write-up.
Background:
BNT162b2 is an mRNA vaccine coupled with a lipid nanoparticle vector. The mRNA sequence represented in this vaccine codes for the spike protein on the surface of the SARS-CoV-2 virus. The spike protein is responsible for cell entry of the virus, as it contacts the ACE2 receptor on the cell surface, causing coupling and cell infection. mRNA for this protein enters the cell (but not the cell nucleus), and cell ribosomes translate the sequence into spike proteins. This allows the immune system to produce specific antibodies that will recognize SARS-CoV-2 in the future, preventing infection and illness.
Methods:
This study was a placebo-controlled, double blind study on the efficacy of a two-injection sequence of vaccine targeting the SARS-CoV-2 virus. Participants were randomly assigned to receive either a saline placebo or the vaccine, in a 1:1 ratio.
- Administration: two injections, 21 days apart, administered intramuscularly into the deltoid muscle of either 30µg of BNT162b2 or saline placebo.
Total final group counts: 18,860 participants received the BNT162b2 vaccine. 18,846 received the placebo.
Safety Findings:
Side effects, both systemic (up to 14 weeks after injection) and acute (up to 30 minutes after injection), appear to be marginally higher than that of the yearly flu vaccine (an attenuated virus vaccine). Safety effects for the 196 HIV patients were evaluated separately and are not included in these figures.
- Systemic side effects: Reported systemic side effects varied by age group and by injection number in the series. The most common side effect across all age groups was
fatigue, as shown below. Fatigue occurred more frequently in younger participants (16-55 years of age). The next two most reported systemic side effects were headache and muscle pain.
- Local side effects: By far the most reported immediate side effect was pain at the injection site. Younger patients (16-55 years old) reported pain at the injection site more frequently than in the older group (55+). Participants in the first injection sequence (83 participants in the younger group and 71 in the older group) and reported more pain at the injection site than in the second injection sequence.
- Adverse effects: More BNT162b2 recipients reported any adverse effects than placebo recipients (27% and 12%, respectively) as well as related adverse effects (21% and 5%, respectively). These adverse effects included most commonly lymphadenopathy (inflammation of the lymph nodes) reported by 64 vaccine recipients, as opposed to 6 placebo recipients.
Four other related adverse side effects were reported: 1 shoulder injury related to vaccine administration, 1 right axillary lymphadenopathy, 1 paroxysmal ventricular arrythmia, and 1 right leg paresthesia.
Four placebo recipients and two BNT162b2 recipients died during the course of the study. Among the four placebo recipients who died, two died from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction. Among the two BNT162b2 recipients who died, one died from arteriosclerosis, and one from cardiac arrest. All deaths were found to be unrelated to either vaccine or placebo.
Safety monitoring will continue for 2 years after the administration of the second injection.
Efficacy findings:
- Efficacy among participants receiving both injections in the series: Among 36,523 participants in the study who had no evidence of prior SARS-CoV-2 infection, 8 cases of SARS-CoV-2 infection were reported with onset at least 7 days after the second injection in the BNT162b2 group as opposed to 162 in the placebo group. This finding indicates 95% efficacy.
mong participants with and those without evidence of prior SARS-CoV-2 infection, 9 participants in the BNT162b2 group and 169 in the placebo group developed SARS-CoV-2 with onset at least 7 days after the second injection. This corresponds to 94.6% vaccine efficacy.
Some subgroups had too few cases of confirmed SARS-CoV-2 infection to prove efficacy within that subgroup with statistical certainty.
Efficacy among those with hypertension were analyzed separately but showed similar efficacy (94.6%).
- Efficacy among participants receiving only the first injection in the series: Between the first and second injections, 39 cases of SARS-CoV-2 infection occurred in the BNT162b2 group and 82 cases occurred in the placebo group, resulting in an efficacy finding of 52%.
This finding indicates early protection by the BNT162b2 vaccine, starting as early at 12 days after the first injection.
Discussion:
A two-dose regiment of BNT162b2, given 21 days apart, is shown to be 95% effective and safe to combat SARS-CoV-2 infection.
Both primary efficacy endpoints were met in this study, with more than a 99.999% certainty of at least 30% efficacy. Although this study did not intend to determine efficacy among different race, sex, age, BMI, nationality, or coexisting condition subgroups, point estimates for each subgroup indicated the vaccine was effective in each category.
Although this study was not intended to investigate the effects of a single BNT162b2 injection, it was shown that partial protection against SARS-CoV-2 infection occurs early after the first injection, with a 52% efficacy before administration of the second injection.
Adverse side effects were shown to be less common and milder in older participants rather than younger. Although local reactions were equally common across the first and second doses, systemic reactions were more common and more severe after the second injection.
Severe fatigue was the most common systemic side effect, with 4% of BNT162b2 participants reporting it. This is higher than the occurrence reported with the yearly influenza vaccine, but lower than the shingles vaccine—both of which are viral vaccines.
Reactions overall were transient and resolved within a few days of onset. Lymphadenopathy resolved after 10 days at the latest, likely the result of a robust immune response.
Serious adverse events had similar occurrence in the vaccine and placebo groups (0.6% and 0.5%, respectively).
The results of this study have medical implications beyond the scope of SARS-CoV-2. This gives proof of concept to the efficacy and safety of mRNA vaccines against human pathogens. mRNA-vaccines are especially promising with this supporting evidence, which shows how swiftly mRNA-based vaccines can be developed as opposed to traditional viral vaccines. The increasing promise of mRNA-based vaccines have a significant implication for the fight against future pandemics and infectious disease outbreaks.
This vaccine was developed in under 11 months.
What are the limitations of this study?
- Immunocompromised individuals, pregnant women, and children under 12 years of age will need to be assessed separately to determine safety and efficacy of the BNT162b2 vaccine.
- The large study group and long period of time over which the study was conducted gives an 83% chance of a serious adverse reaction being reported if the true incidence is 0.01%, but it is not large enough to catch less common serious adverse side effects reliably.
- Long-term reliability will have to be continuously assessed. Leaving placebo group members unvaccinated for 2 years with continued study and at risk has ethical and practical barriers.
- This data does not indicate whether the BNT162b2 vaccine prevents asymptomatic infection.
- The vaccine must be stored at extremely low temperatures for transport. Ongoing stability studies and optimization will hopefully lead to increased temperature tolerance in the future.
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