Pfizer Docs Part 4: Clinical Overview
It's 334 pages long and full of charts, data and other goodies. Get comfortable because this will take some time to digest.
Welcome to Part 4 of this series on the first set of FOIA documents from the Pfizer Biologics License Application (BLA) for Comirnaty. We’ve already covered all the boring stuff, so it’s time to look at something interesting. If you want to start this series at the beginning, click here:
For anyone just starting, Comirnaty is the new name for the vaccine we have been calling BNT162b2 and which Pfizer has been distributing under EUA. There will be more details on that later, when we get to the Clinical Overview.
Module 2 in the BLA contains summaries of the information in the remaining modules. This is probably the only part of the BLA someone at the FDA actually reads, and at over 900 pages it’s longer than Moby Dick1 and just as much of a chore on a summer reading list (that’s just me being cynical - I don’t even know if the staff at the FDA can read).
The introduction: short and simple
Before looking at the Clinical Overview we’re going to read the Introduction. It’s very short and provides some basic information that might come in handy later. What is BNT162b2? From 125742_S1_M2_22_introduction.pdf:
BNT162b2 is a highly purified single-stranded, 5’-capped messenger RNA produced using a cell-free in vitro transcription from the corresponding DNA templates, encoding the viral spike (S) protein of SARS-CoV-2. (Introduction, page 1)
The spike protein is the antigen - the thing that stimulates the immune response. What is transcription?
Transcription is the process by which the information in a strand of DNA is copied into a new molecule of messenger RNA (mRNA). DNA safely and stably stores genetic material in the nuclei of cells as a reference, or template. Meanwhile, mRNA is comparable to a copy from a reference book because it carries the same information as DNA but is not used for long-term storage and can freely exit the nucleus. (nature.com2)
The vaccine is supplied as a concentrate, with six 30 microgram doses in each vial (totaling 180 micrograms per vial) and must be diluted before administration:
Dosage form: BNT162b2 is formulated as concentrate for dispersion for injection. Each vial contains 6 doses of 30 micrograms of COVID-19 mRNA Vaccine, embedded in lipid nanoparticles (total volume: 0.45 mL).
BNT162b2 is administered intramuscularly after dilution as a course of 2 doses (0.3 mL each). It is recommended to administer the second dose 3 weeks after the first dose.
Nothing exciting here, but a few things we might keep in mind when we get to the part of the testing where they trialed different dosages. And just in case we weren’t clear on the purpose of the vaccine:
The proposed indication is active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 16 years of age and older.
Remember that Comirnaty is the first COVID-19 vaccine with FDA approval, and they didn’t request approval for anyone under 16. As we saw in Module 1, they actually requested a deferral on the pediatric studies for the under 16 age group.
Clinical vs. nonclinical testing
Module 2 contains both a Clinical Overview and a Nonclinical Overview. Going into PubMed for a reference, Singh (2016)3 explains that clinical trials are the tests in humans, while the nonclinical (sometimes called preclinical) tests are done either in test tubes (in vitro, meaning in glass) or in animals (in vivo, roughly meaning in life).
A novel vaccine candidate (defined either as the first of its kind based on the mechanism of protection or as the first vaccine for a disease) undergoes an elaborate development process after discovery. Regulatory agencies worldwide divide this development process into preclinical (in vitro and in vivo testing in animals) and clinical (clinical trials in human subjects) stages. (Singh 2016)
We have another reference, Andrade (2016)4, for details about the nonclinical studies:
During the early preclinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. (Andrade 2016)
And we can find these studies in the Pfizer documents. For example, we find the first group of these in 125742_S1_M2_26_pharmkin-written-summary.pdf, such as absorption (section 2.6.4.3), distribution (section 2.6.4.4), metabolism (2.6.4.5), and elimination (section 2.6.4.6, titled Excretion).
Then in 125742_S1_M2_24_nonclinical-overview.pdf we find sections on safety pharmacology (section 2.4.2.3), genotoxicity (section 2.4.4.4), and general toxicology (section 2.4.4).
So the different elements of the nonclinical testing appear to be present, but we’re not going to spend any time with those tests right now. Instead we’re going to focus on the clinical testing.
The Clinical Overview
The Clinical Overview document includes a bit more than just the clinical testing. First we’ll take a look at the claims and the regulatory status.
What are they claiming?
All prescription drugs are submitted with an indication for use and the intended dosage for that indication. These are both listed on page 15 of the Clinical Overview:
The proposed indication and dosing administration for BNT162b2 (30 µg) are:
Proposed indication: Active immunization to prevent COVID-19 disease caused by SARS-CoV-2 virus, in individuals ≥16 years of age
Dosing administration: single 0.3-mL intramuscular (IM) dose followed by a second 0.3-mL dose 3 weeks later
Simple enough - the vaccine is intended to prevent COVID-19, is administered in two doses three weeks apart, and each of those 0.3-mL doses contains 30 µg of BNT162b2.
[µg means micrograms - a microgram is 1/1,000,000 of a gram]
Regulatory status
The section on regulatory status gives us the official names of the vaccine under EUA and the new name once it receives approval.
BNT162b2 has received temporary authorizations for emergency supply in 28 countries and conditional marketing authorizations in 39 countries globally. The name of the product supplied under emergency/temporary use authorization for all applicable regions is Pfizer-BioNTech COVID-19 Vaccine. The name of the product supplied under conditional marketing authorization for all applicable regions is COMIRNATY [COVID-19 mRNA Vaccine (nucleoside modified)]. (Clinical Overview, page 25)
The official name for BNT162b2 is different depending on whether it’s the EUA authorized version or the FDA approved version.
Pfizer-BioNTech COVID-19 Vaccine is the EUA authorized version.
COMIRNATY [COVID-19 mRNA Vaccine (nucleoside modified)] is the BLA approved version.
This may seem like a small detail, but for anyone looking at the difference in liability between an EUA authorized vs. a BLA approved vaccine this is how to tell which was being administered.
Time for the fun stuff - the actual testing
Now we can start to get an outline of the testing. There’s a lot to discuss - the Clinical Overview is just a summary and it’s 334 pages. For now we’re going to try and understand the general outline of the studies, and get into more detail later.
There are two separate clinical studies going on (Clinical Overview, page 18).
BioNTech phase 1/2 study BNT162-01, a FIH (first in humans) study being conducted in Germany
Pfizer phase 1/2/3 study C4591001, started in the U.S. but expanded to several other countries.
The Clinical Overview gives us a little more detail on the vaccine itself:
The vaccine is based on SARS-CoV-2 spike glycoprotein (S) antigens encoded in RNA formulated in lipid nanoparticles (LNPs) and is referred to as BNT162b2 (BioNTech code number BNT162, Pfizer code number PF-07302048). (Clinical Overview, page 18)
Pfizer actually has a different internal code for the vaccine, PF-07302048. This is just something to keep in mind in case they use this number in some of the documents.
There are actually two vaccine candidates being tested, b1 and b2 (Clinical Overview, page 19).
BNT162 vaccine candidates tested in German Study BNT162-01 and pivotal Study C4591001 are:
BNT162b1 (RBP020.3) modRNA encoding RBD (V5)
BNT162b2 (RBP020.2) modRNA encoding P2 S (V9)
Study C4591001 is the “pivotal” study. What is a pivotal study? According to Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012 (Downing et al. 2014):
FDA guidance suggests that drug manufacturers submit at least two trials, each providing independent evidence of efficacy – such studies are known as “pivotal” efficacy trials – but also implies flexibility, describing circumstances in which a single efficacy trial might be sufficient to support approval. (Downing 2014)
Before we continue, what do the phases mean?
For this, we’re going to quote one of our earlier references, The clinical development process for a novel preventive vaccine: An overview (Singh & Mehta 2016).
Phase 1 studies are small, and are intended to find the dosage that’s large enough to stimulate the desired immune response but not create an inflammatory reaction.
Phase I, first-in-man studies refer to the first administration of a vaccine candidate to humans. The primary objective is to evaluate the safety and reactogenicity, while the secondary objective is collection of immune response. Often times, the dose, immunization schedule and mode of vaccine administration are also assessed. (Singh 2016)
Phase 2 studies determine the ideal dose and how to prepare it, as well as providing some data on effectiveness.
The objective is to identify the vaccine preparation, optimal dose, and schedule to be taken up for confirmatory Phase III trials. These studies have the desired statistical power and a defined sample size, and hence are expected to provide a clinically meaningful outcome on the safety, immunogenicity, and efficacy end points. (Singh 2016)
Phase 3 is the big, randomized controlled trial that demonstrates efficacy of the vaccine.
Pivotal Phase III trials, essential for registration and approval to market of a vaccine, assess the effect of the final formulation. These trials are typically designed to evaluate efficacy and safety. Vaccine Efficacy (VE) is defined as the percent reduction in incidence (of disease or infection) among the vaccinated. (Singh 2016)
Now let’s move on to the actual studies.
BioNTech study (BNT162-01)
BNT162-01 is described as a phase 1/2 study, but they are only reporting phase 1 in the Clinical Overview.
BNT162-01 Phase 1
The purpose of phase 1 is to determine the dosage level that’s safe but still causes an immune response.
Study BNT162-01 is the ongoing, FIH, Phase 1 dose level-finding study, in which healthy younger adults (18 to 55 years of age) and older adults (56 to 85 years of age) all receive active vaccine. This study is evaluating the safety and immunogenicity of several different candidate vaccines at various dose levels. (Clinical Overview, page 20)
They started testing two dosage levels above the 30 µg, but didn’t administer the second 60 µg dose because of the reaction to the first 60 µg dose.
In Study BNT162-01, vaccine candidates from the modRNA platform, administered IM in the upper arm in a two-dose regimen separated by approximately 21 days, were:
BNT162b1 (dose levels: 1, 3, 10, 20, 30, 50, 60 µg)
BNT162b2 (dose levels: 1, 3, 10, 20, 30, 50, 60 µg)
For each vaccine candidate, participants received escalating dose levels (N=12 per dose level) with progression to subsequent dose levels based on recommendation from a Sponsor Safety Review Committee (SRC). Note: the SRC recommended that a second dose of BNT162b1 at 60 µg not be administered due to reactogenicity after the first dose. (Clinical Overview, page 21)
The second 60 µg dose was not administered due to reactogenicity. What’s reactogenicity? From The how’s and what’s of vaccine reactogenicity (Hervé et al. 2019)5:
Reactogenicity refers to a subset of reactions that occur soon after vaccination, and are a physical manifestation of the inflammatory response to vaccination. In clinical trials, information on expected signs and symptoms after vaccination is actively sought (or ‘solicited’). These symptoms may include pain, redness, swelling or induration for injected vaccines, and systemic symptoms, such as fever, myalgia, headache, or rash. (Hervé 2019)
The reaction (inflammatory response) to the first 60 µg dose was strong enough that they opted not to administer the second dose.
Pfizer study (C4591001)
This is the study everyone will be focusing on since it includes the randomized controlled trial that is the key evidence for efficacy and safety of the vaccine.
Study C4591001 is the ongoing, randomized, placebo-controlled, Phase 1/2/3 registration study. It was started as a Phase 1/2 study in adults in the US, was then amended to expand the study to a global Phase 2/3 study planning to enroll enough participants to accrue sufficient COVID-19 cases to conduct a timely efficacy assessment; amended to include older adolescents 16 to 17 years of age, then later amended to include younger adolescents 12 to 15 years of age. (Clinical Overview, page 21)
The Pfizer study includes phases 1, 2, and 3. In this study, phase 1 is like the BioNTech study phase 1 and tests difference dosages.
C4591001 Phase 1
Although similar to the BioNTech study (BNT162-01), this study used 100 µg as the highest dose, rather than the 50 µg and 60 µg doses. IM means intramuscular (into the muscle), as opposed to intravenous (into the vein).
The Phase 1 part of the study, randomized participants 4:1 to receive active vaccine or placebo. The vaccines candidates, administered IM in the upper arm in a two-dose regimen separated by approximately 21 days, were:
BNT162b1 (dose levels: 10, 20, 30, 100 µg)
BNT162b2 (dose levels: 10, 20, 30 µg)
Once again there were escalating dose levels, and as in the other study the higher dose was discontinued.
Note: the IRC recommended that a second dose of BNT162b1 at 100 µg not be administered and discontinued due to reactogenicity after the first dose in the younger age group. (Clinical Overview, page 22)
Final dose selection
Based on the phase 1 results, they selected the final dose for the phase 2 and phase 3 studies.
Based upon review of safety and immunogenicity from the Phase 1 part of the study, the final candidate and dose level was selected as BNT162b2 at 30 µg given twice 21 days apart. (Clinical Overview, page 22)
Boosters for phase 1 participants
They are offering booster shots to phase 1 participants, starting six months after their last dose. The phase 1 participants aren’t part of the phase 3 trial, but they may provide some early data on a potential third dose. For now, the results from the booster aren’t being reported.
Phase 1 participants who were randomized to either BNT162b1 or BNT162b2 at dose levels of 10, 20, or 30 µg are being offered booster vaccination with BNT162b2 at 30 µg, approximately 6 to 12 months after their second dose of BNT162b1 or BNT162b2. This provides an early assessment of the safety and immunogenicity associated with a third vaccine dose. Data from Phase 1 participants who receive a booster are not included in this submission and will be reported at a later time. (Clinical Overview, page 23)
Next are phases 2 and 3. The phase 2 participants will also be included in the phase 3 data, so Pfizer is reporting this as a phase 2/3 group.
C4591001 Phase 2/3
In phase 2, a group of subjects are administered the selected vaccine dose and monitored for both adverse reactions and immune response.
Phase 2/3 of Study C4591001 commenced with the selected vaccine candidate and dose level administered to participants who were randomized 1:1 to receive vaccine or placebo. Phase 2 was conducted in the US. The Phase 2 portion of the study evaluated reactogenicity and immunogenicity for 360 participants 18 to 85 years of age enrolled into the study when the Phase 2/3 part commenced, balancing younger (≤55 years of age) and older (>55 years of age) strata within each group. (Clinical Overview, page 23)
This testing is fairly involved, so they do it on a small group (360 people) and for an extended period of time. Phase 1 immunogenicity is tested up to 6 months after dose 2.
In Phase 1, immunogenicity was assessed at Day 1 (before Dose 1) and 7 days after Dose 1; and at Day 21 (before Dose 2) and 7 days, 14 days, 1 month, and 6 months after Dose 2. Data were summarized for each dose level and age group. (Clinical Overview, page 33)
Phase 2 immunogenicity is tested up to one month after dose 2, but six month data was not available when they submitted the BLA.
In Phase 2, immunogenicity was assessed at Day 1 (before Dose 1) and 1 month after Dose 2. Data were summarized by age group and by evidence of prior SARS-CoV-2 infection at baseline per NAAT (PCR) or N-binding IgG assay. Data from the 6-month post Dose 2 time point were not available at the time of the submission data cutoff date (13 March 2021). (Clinical Overview, page 33)
Phase 1 and 2 immunogenicity results
For phase 1, they are reporting a persistent immune response through the six months of planned testing. They tell us the antibody levels at six months are below the level at one month after vaccination, but are still above the pre-vaccination level.
For the groups that received BNT162b2 at 30 µg, persistence of the immune response was observed through 6 months after Dose 2. SARS-CoV-2 serum neutralizing titers and serum S1-binding IgG concentrations at 6 months after Dose 2 had decreased relative to those observed at 1 month after Dose 2 but remained above pre-vaccination and placebo levels. (Clinical Overview, page 139)
Phase 2 is similar, but we only get data at one month.
Based on immunogenicity results from 360 participants in Phase 2 of Study C4591001, BNT162b2 at 30 µg elicited robust SARS-CoV-2 neutralization and S1-binding IgG antibody responses at 1 month after Dose 2 similar to those previously observed in Phase 1 of the study. (Clinical Overview, page 139)
These are details to keep in mind as we have since learned that boosters are now recommended after only a few months. Although for some types of vaccines protection lasts many years, this is not one of those vaccines.
C4591001 Phase 3
This is the big study with close to 44,000 people enrolled (not all of them finished), and will be the subject of most of the discussion by people reviewing these studies.
Phase 3 endpoints
First we need to learn the end points - what they are trying to measure. (Clinical Overview, page 28)
Study C4591001 is the pivotal (and only) efficacy study. The primary efficacy endpoints in the Phase 3 part of the study were:
First primary endpoint: COVID-19 incidence per 1000 person-years of follow-up in participants without serological or virological evidence of past SARS-CoV-2 infection before and during the vaccination regimen – cases confirmed ≥7 days after Dose 2
Second primary endpoint: COVID-19 incidence per 1000 person-years of follow-up in participants with or without evidence of SARS-CoV-2 infection before and during the vaccination regimen – cases confirmed ≥7 days after Dose 2.
The first endpoint is based on confirmed cases a week or more after the second dose, of people who were not previously infected.
The second endpoint is also based on confirmed cases a week or more after the second dose, but also includes people who were previously infected.
Before beginning the study, they have calculated how many subjects they think they need to show at least a 60% efficacy.
For Phase 2/3: the sample size assumed a true VE of 60% after the second dose of study intervention, for which a total of approximately 164 first confirmed COVID-19 illness cases would provide approximately 90% power. This would be achieved with 17,600 evaluable participants per group (or 21,999 vaccine recipients randomized in a 1:1 ratio with placebo) for a total sample size of 43,998. (Clinical Overview, page 30)
They will need to recruit about 44,000 people, and after at least 164 confirmed cases they will have demonstrated their VE (vaccine efficacy).
Phase 3 interim results
They calculated interim results and were apparently happy with how things were going. This looked good enough that they didn’t conduct any additional interim analyses, but instead waited for the end of the study for final efficacy.
Overwhelming efficacy success criteria on the first primary efficacy endpoint were met at the first planned interim analysis of 94 accrued COVID-19 cases as of 04 November 2020, after which additional formal interim analyses were not conducted. (Clinical Overview, page 31)
They calculated vaccine efficacy (VE) at this point:
VE of BNT162b2 was 95.5% with a >99.99% posterior probability for the true VE being >30% conditioning on available data, to overwhelmingly meet the prespecified interim analysis success criterion (>99.5%). (Clincal Overview, page 39)
Of course, there’s uncertainty in the answer. So they give us their confidence interval, which is 88.8% to 98.4%. The confidence interval means they think there’s a 95% chance that the actual VE is between these two numbers.
The 95% credible interval for the vaccine efficacy was 88.8% to 98.4%, indicating that given these observed data there was a 95% probability that the true VE lies in this interval. Also, note that the posterior probability that true VE >86.0% is 99.5% and VE >88.8% is 97.5%. (Clincal Overview, page 39)
And they tell us how many cases this is based on - 4 in the vaccine group and 93 in the placebo (control) group.
VE of BNT162b2 for the same primary efficacy endpoint based on the all-available efficacy population was 95.7%, with 4 cases in the BNT162b2 group and 93 cases in the placebo group. (Clincal Overview, page 39)
Phase 3 exclusions
Before moving on to the final efficacy, let’s take a quick look at subjects who were excluded from the final data. There are always subjects who must be excluded, for a variety of reasons.
Most participants who were excluded from the evaluable efficacy population had not received all vaccinations as randomized or did not receive Dose 2 within the predefined window (ie, 19 to 42 days after Dose 1). (Clinical Overview, page 45)
There were 1,550 subjects excluded from the vaccine group and 1,561 excluded from the placebo group because they didn’t receive both vaccinations, or didn’t receive them within the required time window. Keep in mind that study participants can drop out of the study - the study is completely voluntary.
There were also participants excluded for “important protocol violations.” The vaccine group had many more of these than the placebo group, and we don’t really get a good explanation why (at this point) but they apparently thought the difference was large enough to warrant an extra evaluation.
There were 311 participants (1.4%) in the BNT162b2 group and 60 participants (0.3%) in the placebo group excluded for having important protocol deviations on or prior to 7 days after Dose 2. A post hoc evaluation was performed to assess the imbalance of these important protocol deviations in the BNT162b2 and placebo groups for the final analysis of efficacy. This showed that the majority of exclusions from the evaluable efficacy (7 days) population in the BNT162b2 group were due to dosing/administration errors or administration of study intervention that was deemed not suitable for use. This is detailed in the C4591001 Final Analysis Interim CSR and in Module 2.7.3. (Clinical Overview, page 45)
They note there is a large imbalance between the vaccine and placebo groups but are not clear about why. We’ll keep this in mind and see if we can figure out later what they mean by “administration of study intervention that was deemed not suitable for use.” That might be complicated, and may end up being the subject of another post.
Phase 3 final efficacy
At the end of their study, they had 173 total cases (from all available populations) and calculated a VE of about 95%. There were 8 cases in the vaccine group and 165 in the placebo group.
Among participants without evidence of SARS-CoV-2 infection before and during the vaccination regimen, VE against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0%, with 8 COVID-19 cases in the BNT162b2 group compared to 162 COVID-19 cases in the placebo group (Table 8). The 95% credible interval for the vaccine efficacy was 90.3% to 97.6%, indicating that the true VE is at least 90.3% with a 97.5% probability given the observed data. (Clinical Overview, page 48)
The vaccine efficacy of BNT162b2 for the same primary efficacy endpoint based on the Dose 2 all-available efficacy population was 95.2%, with 8 and 165 cases in the BNT162b2 and placebo group (Table 9). (Clinical Overview, page 48)
That’s the significant part of the study - they recruited about 44,000 people, about 20,000 finished the study in each group, and the vaccine group saw 8 cases and the placebo group 165 cases.
With about 157 fewer cases in the vaccine group of 20,000 people, there was one less case per every 127 people vaccinated. Other researchers (not people at Pfizer) have summarized the NNV (Number Needed to Vaccinate) for the different vaccines, and this is similar to the numbers presented by those papers. This is the subject of another, earlier article6 on my Substack.
That article discusses a statement by the head of the CDC that we would need to vaccinate 1,000,000 kids aged 12-17 to prevent 8,000 cases - which is 125 vaccinations per case prevented, consistent with this data.
Calculating NNV is a little more complicated than just dividing those two numbers so check out the other article - it references a published paper on NNV for the various vaccines and that paper discusses how NNV is calculated.
And please don’t forget that this is cases, not deaths. The total number of all-cause deaths (something we’ll get into another time) was the same for both the vaccine and placebo groups.
Benefits and Risks Conclusions
First, they admit right up front that they don’t know how long the protection will last.
COVID-19 is a serious and potentially fatal or life-threatening human infection. Based on clinical data to date, it is expected that BNT162b2 (30 µg) will elicit an immune response that is likely to protect against COVID-19. The total duration of any such protection is currently unknown. (Clinical Overview, page 325)
The efficacy numbers looked very good at both the interim and final analyses.
Efficacy of BNT162b2 (30 µg) to prevent COVID-19 was overwhelmingly demonstrated at the first interim analysis of 94 cases (data cutoff date: 04 November 2020), with a VE of 95.5% (with a 2-sided 95% credible interval of 88.8% to 98.4%) in pivotal Study C4591001 Phase 3 participants who had no prior evidence of SARS-CoV-2 infection, which met the protocol prespecified success criteria for the first primary endpoint. This was confirmed in the final analyses of 170 cases reported in participants without evidence of past SARS-CoV-2 infection before or during the vaccination regimen, with VE of 95.0% (data cutoff date: 14 November 2020). (Clinical Overview, page 325-326)
But there’s a “but” and it’s a big one:
In the final analysis, among participants without evidence of past SARS-CoV-2 infection before and during the vaccination regimen, observed VE of 66.3% against severe COVID-19 occurring at least 7 days after Dose 2 did not meet the prespecified success criterion of the posterior probability >98.6%, due to the small number of severe cases (1 in the BNT162b2 group, 3 in the placebo group) observed after Dose 2 in the study. (Clinical Overview, page 326)
Did you catch that? There were only 4 severe cases of COVID-19 among all the participants in the study. So few people in the study contracted a severe case that they didn’t meet their own target for success on severe COVID-19 due to lack of data.
Only four people out of over 40,000, or one in 10,000 people, contracted severe COVID-19 during this study - that’s 0.01%.
Time for a break
That’s a lot to digest in one Substack post so we’ll stop here for now.
We’ve looked over the efficacy data but still need to look into reactogenicity in detail. Pfizer and the FDA thought the efficacy data was sufficient for approval, although we now know that whatever protection the vaccine offers, it doesn’t last long.
Recall the proposed indication from the very beginning:
Proposed indication: Active immunization to prevent COVID-19 disease caused by SARS-CoV-2 virus, in individuals ≥16 years of age
They made no claims for how long the immunization would last. This isn’t a part of the study and they aren’t required to make a claim about the duration of immunity.
Before we finish for today, here’s one more thing from the section titled Benefit-Risk Conclusions on vaccine associated enhanced disease (VAED):
The confinement of severe cases of COVID-19 predominantly to the placebo group versus the BNT162b2 group suggests no evidence of VAED. (Clinical Overview, page 329)
With more and more adverse events being reported, it’s looking like this was a very premature assessment.
In the next part, we look at the Protocol for the study:
752 pages for the paperback version from Barnes & Noble:
https://www.barnesandnoble.com/w/moby-dick-melville-herman/1110282307
Archived copy:
https://web.archive.org/web/20220120142657/https://www.barnesandnoble.com/w/moby-dick-melville-herman/1110282307
Nature article on transcription:
https://www.nature.com/scitable/definition/transcription-dna-transcription-87/
Archived copy:
https://web.archive.org/web/20220202055606/https://www.nature.com/scitable/definition/transcription-dna-transcription-87/
Singh K, Mehta S. The clinical development process for a novel preventive vaccine: An overview. J Postgrad Med. 2016 Jan-Mar;62(1):4-11. doi: 10.4103/0022-3859.173187. PMID: 26732191; PMCID: PMC4944327.
https://pubmed.ncbi.nlm.nih.gov/26732191/
Andrade EL, Bento AF, Cavalli J, Oliveira SK, Schwanke RC, Siqueira JM, Freitas CS, Marcon R, Calixto JB. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies. Braz J Med Biol Res. 2016 Dec 12;49(12):e5646. doi: 10.1590/1414-431X20165646. PMID: 27982281; PMCID: PMC5188860.
https://pubmed.ncbi.nlm.nih.gov/27982281/
Hervé, C., Laupèze, B., Del Giudice, G. et al. The how’s and what’s of vaccine reactogenicity. npj Vaccines 4, 39 (2019). https://doi.org/10.1038/s41541-019-0132-6
https://www.nature.com/articles/s41541-019-0132-6
