Report 4: “Review of ‘Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine’
Team Five: Review of Polack with comments and questions.
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
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 Perez Marc, M.D., Edson D. Moreira, M.D., Cristiano Zerbini, M.D., Ruth Bailey, B.Sc., Kena A. Swanson, Ph.D., Satrajit Roychoudhury, Ph.D., Kenneth Koury, Ph.D., Ping Li, Ph.D., Warren V. Kalina, Ph.D., David Cooper, Ph.D., Robert W. Frenck, Jr., M.D., Laura L. Hammitt, M.D., Ozlem Türeci, M.D., Haylene Nell, M.D., Axel Schaefer, M.D., Serhat Unal, M.D., Dina B. Tresnan, D.V.M., Ph.D., Susan Mather, M.D., Philip R. Dormitzer, M.D., Ph.D., Uğur Şahin, M.D., Kathrin U. Jansen, Ph.D., and William C. Gruber, M.D., for the C4591001 Clinical Trial Group*
NEJM 383:27 12/31/2020.
Abstract:
BNT162b2: full length spike protein, nucleoside modified
21,720 BNT162b2 21728 Placebo
Severe covid after first dose:
● 9 in Placebo group
● 1 in BNT162b2
Cases of covid onset after at least 7 days after second dose:
• 8 cases in BNT162b2 • 162 cases in Placebo:
“The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of adverse events was low and was similar in the vaccine and placebo groups.” P2603 p3.
Main Body of Paper:
“A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728)”, P2603 p4.
“Safe and effective prophylactic vaccines are urgently needed to contain the pandemic, which has had devastating medical, economic, and social consequences.” P2604 p 1.
“Findings from studies conducted in the United States and Germany among healthy men and women showed that two 30 mg doses of BNT162b2 elicited high SARS-CoV-2 neutralizing antibody titers and robust antigen-specific CD8+ and Th1-type CD4+ cell responses.”
“Here we report safety and efficacy findings from the phase 2/3 part of a global phase 1/2/3 trial evaluating the safety, immunogenicity, and efficacy of 30 mg of BNT162b2 in preventing Covid-19 in persons 16 years of age or older.” P2604 p3.
“Collection of phase data on vaccine immunogenicity of phase 2/3 data on vaccine immunogenicity and the durability of the immune response to immunization is ongoing, and those data are not reported here.” P 2604 p 3.
Study group included HIV, hep B or C patients.
Exclusion: Prior history of covid-19, immunosuppression. P. 2604 p 5.
Pfizer conducted trials, collected the data, performed the data analysis, data interpretation, and the writing of the manuscript. “This data set and these trial results are the basis for an application for emergency use authorization.9” P2604 p 3.
Study Design:
Table S1, Online Supplementary Appendix: Explanation of the various denominator values for use in assessing the results (available NEJM.org)
- 44,820 subjects screened & 43,448 participants injected:
- BNT162b2
- 18,860 received Dose 1; 28 withdrew after an adverse reaction.
- 18,556 received Doses 1 and 2; 48 discontinued after the second dose.
- 18,508 received Doses 1 and 2 and completed the two-month follow-up.- Placebo
- 18,846 received Dose 1; 18 withdrew after an adverse reaction.
- 18,530 received Doses 1 and 2; 95 discontinued after the second dose.
- 18,435 received Doses 1 and 2 and completed the two-month follow-up.
- 43,355 subjects Modified intention-to-treat (mITT) efficacy population.
- All age groups 12 years of age or older.
- 100 participants who were 12 to 15 years of age “...contributed to person time years but included no cases.” P2605 p5.
- 40,137 subjects evaluated 7 days after the second dose “with or without evidence of prior infection”.
- 37,706 subjects “Safety population” (defined by the FDA):
- Persons 16 years of age or older.
- Median of 2 months of follow-up as of October 9, 2020.
- 36,523 subjects evaluated for efficacy 7 days after the second dose and “who had no evidence of prior infection”.
- 8183 subjects = Reactogenicity Subset========================================================================
METHODS
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“Participants received two injections, 21 days apart, of either BNT162b2 or placebo, delivered in the deltoid muscle.” P2604 p6. Aspiration not mentioned.
Adults 16 years of age or older who were:
- Healthy, or
- Had stable chronic medical conditions, including but not limited to:
- Human immunodeficiency virus (HIV)
- Hepatitis B virus
- Hepatitis C virus infection
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DIVISION OF WORK
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- Pfizer:
1. Design and conduct of the trial,
2. Data collection,
3. Data analysis and interpretation
4. Writing of the manuscript.
- BioNTech:
- Trial sponsor
- Manufactured BNT162b2
- Contributed: interpretation of the data and the writing of the manuscript.
- All the trial data were available to all the authors, who vouch for its accuracy and completeness and for adherence of the trial to the protocol, which is available with the full text of this article at NEJM.org. This data was not on the web site 4/13/2022.
- An independent data and safety monitoring board reviewed efficacy and unblinded safety data.
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SAFETY
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- Observation for 30 minutes after injection.
- Solicited data:
1. End points. 2. Specific local or systemic adverse events. 3. Use of antipyretic or pain medication within 7 days after the receipt of each dose of vaccine or placebo, as prompted by and recorded in an electronic diary in a subset of participants (the reactogenicity subset)
- Unsolicited: Unsolicited serious adverse events through 6 months after the second dose.
- Adverse event data through approximately 14 weeks after the second dose are included.
- Safety data are reported for all participants who provided informed consent and received at least one dose of vaccine or placebo.
- Per protocol, safety results for participants infected with HIV (196 patients) will be analyzed separately and are not included here.
- A stopping rule for the theoretical concern of vaccine-enhanced disease was to be triggered if the one-sided probability of observing the same or a more unfavorable adverse severe case split (a split with a greater proportion of severe cases in vaccine recipients) was 5% or less, given the same true incidence for vaccine and placebo recipients. Alert criteria were to be triggered if this probability was less than 11%.
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EFFICACY
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Efficacy of BNT162b2 against confirmed COVID-19:
- First Primary Endpoint: Onset of confirmed COVID-19 at least 7 days after the second dose in participants who had been without serologic or virologic evidence of SARS-CoV-2 infection up to 7 days after the second dose. P. 2604
Restated: Confirmed COVID-19 after 28 days following the initial dose. COVID-19 positives prior to 28 days were considered unvaccinated. P2605 p 3.
- Confirmed Covid Diagnosis: FDA criteria. (No reference provided).
- One of the following symptoms:
- Fever
- Chills
- Diarrhea
- Vomiting
- Loss of taste
- Loss of smell
- New or increased cough, shortness of breath, or muscle pain
- Plus: a respiratory specimen in suspected SARS-CoV-2 positive by NAAT obtained during symptomatic period +/- four days before.
- Second Primary Endpoint: was “efficacy in participants with and without evidence of prior infection.” P2605 p 3.
- Major secondary endpoints: Efficacy against severe covid. “Details are provided in the protocol.” P2605 p4.
- Confirmed covid.
- One of the following:
- Respiratory failure
- Acute neurologic event
- Renal dysfunction
- Hepatic dysfunction
- ICU admission
- Death
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RESULTS
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Reactogenicity: n = 8183.
Local reactions: Younger recipients reported symptoms more often than recipients age 55 and older.
LOCAL PAIN BY AGE
Dose Under 55 55 and older
First dose 83% 71%
Second dose 78% 66%
Systemic reactions: More were reported after the second dose than after the first:
- Fatigue: 59% under age 55, 51% age 55 or older, placebo 23%
- Headache: 51% < 55, 39% age 55 or older, placebo 24%
- Temperature above 38°C after the second dose: 16% under age 55 and 11% age 55 or older.
- Temperature of 38.9-40°C: 0.2% after Dose 1 and 0.8% after Dose 2; placebo was 0.1% after both doses.
- Temperature above 40°C: two participants, one in the vaccine group and one in the placebo group.
- Antipyretic/analgesic use:
- Under age 55: 28% after Dose 1 and 45% after Dose 2.
- Age 55 or older: 20% after Dose 1 and 38% after Dose 2.
- Placebo: 10% after Dose 1 and 14% after Dose 2.
Adverse Events: Table S3 (available online):
n= 43,252 according to the published article. P2608 p 3. n = 43,252 according to online Table S1 P 7. “Vaccinated N=43,448 minus 196 HIV+.” n = 43,252 according to online Table S3 P 9. “All enrolled.” At least 1 dose. Any Event, Any Event Related and Any Event Severe are statistically significant, Appendix 1.
ADVERSE-EVENT COMPARISON
Measure BNT162b2 Placebo
Participants 21,621 21,631
All events 5,770 2,638
Related events 4,484 1,095
Share of reported AEs 69% 31%
All AEs as share of group 27% 12%
Related AEs as share of group 21% 5%
Rel = Related adverse event; P = Placebo
LYMPHADENOPATHY
BNT162b2: 64 cases
Placebo: 6 cases
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EFFICACY
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BNT162b2 Placebo Vaccine efficacy
Participants 18,198 18,325
Surveillance time 2.214 2.222
COVID-19 at least 28 days after Dose 2 8 80
COVID-19 before 28 days after Dose 2 39 82 52%
All COVID-19 cases 47 162
Study comparison 8 162 95%
*VE = Vaccine efficacy
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DISCUSSION
========================================================================“A two-dose regimen of BNT162b2 (30 μg per dose, given 21 days apart) was found to be safe and 95% effective against Covid-19.”
“The vaccine met both primary efficacy endpoints, with more than a 99.99% probability of a true vaccine efficacy greater than 30%.”
“These results met our prespecified success criteria, which were to establish a probability above 98.6% of true vaccine efficacy being greater than 30%, and greatly exceeded the minimum FDA criteria for authorization.9”
“…in the interval between the first and second doses, the observed vaccine efficacy against Covid-19 was 52%, and in the first 7 days after dose 2, it was 91%, reaching full efficacy against disease with onset at least 7 days after dose 2.”
“Of the 10 cases of severe Covid-19 that were observed after the first dose, only 1 occurred in the vaccine group. This finding is consistent with overall high efficacy against all Covid-19 cases.”
“The severe case split provides preliminary evidence of vaccine mediated protection against severe disease, alleviating many of the theoretical concerns over vaccine-mediated disease enhancement.11”
“Although the study was designed to follow participants for safety and efficacy for 2 years after the second dose, given the high vaccine efficacy, ethical and practical barriers prevent following placebo recipients for 2 years without offering active immunization, once the vaccine is approved by regulators and recommended by public health authorities.”
Comments/Questions:
1. Diagnosis of covid-19 required only one symptom and a positive NAAT test. Why was only one symptom + a positive NAAT rather than an actual clinical diagnosis based upon symptoms, signs, and supportive laboratory data?
2. NAAT have proven unreliable leaving only one symptom as the basis to diagnose covid-19. Are there any other studies of experimental gene therapy that are dependent upon a single symptom to diagnose a disease? How can this be adequate?
3. What NAAT was used and what are the statistics for false negatives and positives? Was the same test used throughout the study?
4. Aspiration was not reported as the technique for injection of the BNT162b2.
5. “All the trial data”, reported to have been available to all the authors, is no longer available with the full text of the article at NEJM.org as reported in the text. Why not?
6. Participants received “informed consent”. Where can the consent documenting risks, benefits and alternatives be found?
7. Were participants with prior infection with SC2 included or not?
8. Where is the raw data for reactogenicity?
9. Complete reporting of symptoms, signs, laboratory and diagnostic studies is not provided.
10. Table S2 lists 14 disease categories after consolidating All Malignancies, Diabetes, and Liver Disease. The CDC identifies 21 disease categories.1
a. There were 18 subjects with dementia. What legal process was required for each of these individuals? How were they able to communicate their symptoms?
b. What was the distribution of comorbidities the control versus experimental groups given that a major risk factor is clustering of comorbidities in subjects? Data presented in Table S2 provides no information about clustering of comorbidities in the study subjects. Some studies have indicated that covid-19 fatalities were associated with multiple comorbidities average 3.8 per fatality.
c. Hypertension is a major risk factor that was not reported.
d. Coronary artery disease and arrhythmia are risk factors for covid-19 and Prevalence Data was not reported.
e. The number of smokers and drug users was not given.
f. Age is a continuous variable. It is also a risk factor. Table 1 gives age data for 16-55 and >55 years. These categories are overly broad. More granular data is required.
11. “The incidence of serious adverse events was similar in the vaccine and placebo groups (0.6% and 0.5%, respectively).” This data needs to be carefully examined. P2610 p2.
12. “Lymphadenopathy, which generally resolved within 10 days, is likely to have resulted from a robust vaccine-elicited immune response.” Given that lymphocytopenia is associated with BNT162b2, are there other explanations for lymphadenopathy? Was splenomegaly found in these cases? What were the lymphocyte counts for study subjects?
13. “…the occurrence of adverse events more than 2 to 3.5 months after the second dose and more comprehensive information on the duration of protection remain (sic) to be determined.” Shouldn’t a longer follow-up period be required given the experimental nature of this gene therapy?
14. Physicians look to the NEJM as a trusted source for guiding their recommendations to patients. This publication is quite superficial given the gravity of the pandemic and the implications of administering this drug to a significant portion of the human race.
15. The medical files of all covid-19 patients should be carefully reviewed as well as random sampling of the study population.
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APPENDIX 1
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TEST AND CONFIDENCE INTERVALS FOR TWO PROPORTIONS
1. ANY ADVERSE EVENT
Group Events (X) Participants (N) Proportion
Vaccine 5,770 21,621 0.266870
Placebo 2,638 21,631 0.121955
Estimated difference: 0.144916
95% confidence interval: 0.137582 to 0.152249
Z statistic: 38.73
P-value: 0.000
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2. RELATED ADVERSE EVENTS
Group Events (X) Participants (N) Proportion
Vaccine 4,484 21,621 0.207391
Placebo 1,095 21,631 0.050622
Estimated difference: 0.156769
95% confidence interval: 0.150626 to 0.162913
Z statistic: 50.02
P-value: 0.000
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3. SEVERE ADVERSE EVENTS
Group Events (X) Participants (N) Proportion
Vaccine 240 21,621 0.011100
Placebo 139 21,631 0.006426
Estimated difference: 0.00467436
95% confidence interval: 0.00291817 to 0.00643054
Z statistic: 5.22
P-value: 0.000
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4. ANY SERIOUS ADVERSE EVENT
Group Events (X) Participants (N) Proportion
Vaccine 126 21,621 0.005828
Placebo 111 21,631 0.005132
Estimated difference: 0.000696143
95% confidence interval: -0.000695265 to 0.00208755
Note: The supplied source excerpt does not provide a Z statistic or P-value
for this final comparison.
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APPENDIX 2
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CO-MORBIDITY CATEGORY COMPARISON
The source lists 14 Pfizer categories and 21 CDC categories. They are
presented separately below so merged PDF columns do not imply false pairings.
PFIZER CATEGORIES (14)
1. AIDS/HIV
2. Any malignancy
3. Cerebrovascular disease
4. Chronic pulmonary disease
5. Congestive heart failure
6. Dementia report
7. Diabetes with chronic complication
- Diabetes without chronic complication
8. Hemiplegia or paraplegia
- Leukemia
- Lymphoma
- Metastatic solid tumor
9. Mild liver disease
- Moderate or severe liver disease
10. Myocardial infarction
11. Peptic ulcer disease
12. Peripheral vascular disease
13. Renal disease
14. Rheumatic disease
CDC CATEGORIES (21)
1. Cancer
2. Chronic kidney disease
3. Chronic liver disease
4. Chronic lung disease
5. Cystic fibrosis
6. Dementia
7. Diabetes
8. Disabilities
9. Heart conditions
10. HIV/AIDS
11. Immunocompromised
12. Mental health
13. Obesity
14. Inactivity
15. Pregnancy
16. Sickle cell disease
17. Smoking
18. Solid organ/stem cell transplant
19. Stroke or CVA
20. Substance use
21. Tuberculosis