Pfizer/BioNTech coronavirus vaccine

Review of the study and results: Safety and

Efficacy of the BNT162b2 mRNA Covid-19
Vaccine
Sources

See https://www.nejm.org/doi/full/10.1056/NEJMoa2034577?query=featured_home

Others sources are mentioned in this link.

Facts and concerns (Ci):

1. The phase 3 trial was not double blinded
a. It is unclear if this could have led to biases (C1)
2. According to the report, the phase 3 trial was not stratified (cohorts were selected purely by
random 1:1)
a. The placebo group had 0.1% more diabetes with chronic complication, 0.1% more
dementia, 0.1% more lymphoma, 0.1% more peptic ulcer disease, and more moderate
or severe liver disease
b. It’s unclear, as the subgroup analysis of the cases does not include information about
underlying issues, whether the negative bias in the placebo group was relevant to
influence the results (C2)
c. Especially as there are many known and yet unknown factors that may influence
susceptibility for the virus that are not accounted for and should be part of the
stratifications. There are studies finding an array of gene expressions that seem to
increase the risk significantly, and thus a good study design should also take this
variability into account.
3. Randomization was done with the use of an interactive Web-based system
a. It was not disclosed what kind of (pseudo) random generator was used for that, and
whether it could have induced significant biases as the study was not patient blinded
(C3)
4. The participants were overwhelmingly “white” (9% were Black or African American, 4.3% Asian,
0.5% Native American or Alaska Native)
a. It appears the study design does not prove that the results are applicable for different
ethnic groups (also see further) (C4)
5. The study was designed to follow participants for safety and efficacy for 2 years after the second
dose (Phase 2/3 was planned to run up to 2 years. The trial started April 29, 2020 but active
recruitment only from 30th of July)
a. Yet the study was concluded earlier and the data through [only] approximately 14
weeks after the second dose are included in the report
b. And thus there should be a general concern about the premature conclusion of the trial /
report. (also see further) (C5)
6. There are no considerations in the study of the potential influence of false positive / false
negative rates in Covid-19 testing (C6)
7. Vaccine Efficacy : A total of 170 cases was reported
a. [Only] 5 where in the age group ≥75 years and according to the Credibility Interval (CI)
of the study the efficacy could be as low as −13.1% in this subgroup, meaning that in this
age group the vaccination could result in 13.1% more cases. It is not even disclosed how
many – if any – where 80 years or older. (C7)
b. [Only] 7 where in the subgroup “Black or African American” with a potential efficacy of
minimum 31.2% (C8)
c. Participants ≥65 and not at risk [only] yielded 7 cases, according to the Credibility
Interval (CI) of the study the efficacy could be as low as 29.0% in this subgroup (C9)
d. Participants ≥65 and at risk [only] yielded 13 cases, according to the Credibility Interval
(CI) of the study the efficacy could be as low as 44.2% in this subgroup (C10)
e. Participants ≥65 and obese [only] yielded 7 cases, according to the Credibility Interval
(CI) of the study the efficacy could be as low as 27.1% in this subgroup (C11)
f. In the subgroup of participants ≥65 the only cases of the vaccinated group was in the
group of people at risk (C12)
g. The above points illustrate that the trial does not give evidence of vaccine efficacy in the
most important subgroups of patients most at risk (C13)
i. In fact the study’s conclusion openly admits that: “the study was not powered
to definitively assess efficacy by subgroup, the point estimates of efficacy for
subgroups based on age, sex, race, ethnicity, body-mass index, or the presence
of an underlying condition associated with a high risk of Covid-19
complications”
ii. In fact the study published on Repurposed Antiviral Drugs for Covid-19 —
Interim WHO Solidarity Trial Results has a very different view on the needed
sample sizes: “several thousand hospitalized patients with relatively mild
disease and a few thousand with severe disease”. And this is not about a
vaccine that is going to be given to 100’s of millions of people but for the
treatment of people at high risk of covid-19 mortality.
h. Also in the age group 12 to 15 years no cases have been reported in this study
i. Therefore vaccine efficacy in that group has also not been proven (C14)
i. Not only that, if there is no vaccine efficacy in this group then efficacy in disease
transmission and any establishment of herd immunity (if at all possible) seems unlikely
(C15)
8. While there are [only] 10 severe cases were reported, those that took place after vaccination
was considered effective (7 Days after Dose 2.) are still limited to 5 only and include one
vaccinated case. While efficacy is reported there as 75%, statistically it could be as low as -
152.6% meaning that vaccination increases the risk of severe covid-19. (C16)
a. And yet, amazingly, the above seems sufficient for the report to conclude that this
alleviates “many of the theoretical concerns over vaccine-mediated disease
enhancement (VAED)”
b. Yet for this a reference is made to another study,
i. Which is not a randomized controlled trial (C17)
 ii. Which assumes that “age-related differences in immune responses are being
evaluated in phase 3 COVID-19 vaccine trials”, while in reality this study is
statistically underpowered to do that (C18)
iii. Which warns that “risk [of VAED that] would be identified in clinical trials
depend on three important factors: (i) the frequency of VAED, (ii) the time
interval after vaccination when VAED might occur, and (iii) whether the
manifestation of VAED is distinct from natural disease of a similar severity.
Currently, it is unknown whether there would be clinical markers to distinguish
VAED from natural COVID-19 disease.” (C19)
iv. Which assumes that “All phase 3 trial participants are expected to be followed
for at least 1 year. Thus, it is critical to implement and complete phase 3 efficacy
studies to ensure that the vaccine is both safe and efficacious.” (C20)
v. Which concludes that “the only way to address the theoretical risk of VAED is in
phase 3 efficacy trials with sufficient numbers of end points to evaluate safety
and efficacy, and by post licensure surveillance” (C21)
vi. And that “the detection of low rates of VAED, associated with a later exposure
to SARS-CoV-2 in people who have been vaccinated, will depend on rigorous
post licensure surveillance” (C22)
vii. In this conclusion the term theoretical risk of VAED is certainly misleading, as
VAED has most likely occurred in several other vaccines, including for
respiratory syncytial virus (RSV), feline coronavirus, and Dengue virus vaccines
(e.g. Dengvaxia vaccine that may have caused many deaths in the Philippines)
(C23)
c. Given the previous point, we must conclude that the study does not exclude the risk of
VAED and the conclusion of the study is misleading (C24)
d. If VAED would be as “low” as 0.1% and/or occurring later than 14 weeks after
vaccination, the trial would not have the statistical power to detect this, and yet it could
entail a huge risk of increased morbidity and mortality in the wider / real population
(C25)
9. In fact many of the concerns raised are recognized by the developer of the vaccine and included
in their legal disclaimer “BioNTech Forward-looking statements"
a. Namely, that are a “number of risks and uncertainties that could cause actual results to
differ materially and adversely from those set forth in or implied”
b. That these “These risks and uncertainties include, but are not limited to: the ability to
meet the pre-defined endpoints in clinical trials”
i. “including [the] stated rate of vaccine effectiveness and safety and tolerability
profile observed to date”
ii. Including the fact that there will be “more diverse populations upon
commercialization”
iii. Including “other potential difficulties.”