Background
COVID-19 vaccines were developed and given emergency use authorization (EUA) in record time. In late 2020, the Food and Drug Administration (FDA) granted EUA to three COVID-19 vaccines for adults: Pfizer (2 doses), Moderna (2 doses) and Johnson & Johnson (1 dose). Subsequently, the Pfizer and Moderna vaccines also received EUA approval for use in children as young as 6 months of age. Pfizer, Moderna and Johnson & Johnson boosters were also approved. Federal, state, and local governments, as well as many companies, hospitals, restaurants, universities, and a few K-12 school systems, imposed vaccine mandates for work, business, education, travel and cultural events. As of December 2022, only vaccinated visitors can enter the USA.
Vaccination policies were some of the most divisive elements of the pandemic, engendering protests at various times and termination of employment for some professions or government employees over their refusal to get vaccinated. Because mandates were initially based on the assumption that vaccines were capable of halting transmission, it is important to delve into the trials in detail.Testing for SARS-CoV-2 is important for multiple reasons. At the clinical level, when someone has COVID-like symptoms, it is important to find out whether they have COVID-19 or something else, in order to provide effective treatment. To prevent COVID-19 spread, it is important to test hospital and nursing home staff and visitors, so they do not infect frail elderly high-risk individuals. It is also important for disease surveillance and sero-prevalence estimation. This latter topic is covered in Chapter 5 on Public Health Data.
Randomized Vaccine Trials in Adults
The Pfizer randomized trial showed 95% efficacy against symptomatic COVID-19 infection, the trial’s primary endpoint. The Moderna randomized trial showed 94% efficacy against symptomatic COVID-19 infection, that trial’s primary endpoint. The Johnson & Johnson randomized trial showed 67% efficacy against moderate or severe COVID-19 infection, the trial’s primary endpoint, and 67% efficacy against any symptomatic infection, a secondary endpoint.
Despite roughly 37,000, 28,000 and 40,000 participants, respectively, only 5% of patients were in the >75 age group, the group at highest risk for a severe outcome due to age. Thus, none of the Pfizer, Moderna or the Johnson & Johnson trials were sufficiently powered to evaluate efficacy against hospitalization and death, and none could determine efficacy against transmission.
While the trial designs allowed rapid deployment to the public, the limitations in knowledge they produced– particularly about absolute risk reduction for hospitalization and death, vaccine adverse reactions, and about the fact that trials did not study whether vaccines limited transmission – were not clearly conveyed to the public.
Should pharmaceutical companies have designed trials using COVID-19 death and/or COVID-19 hospitalizations as primary end points? Why were more older patients not enrolled in order to achieve that?
Who was responsible for conveying uncertainty about the trials in terms of benefits against hospitalization, death, transmission and long-term effectiveness? The manufacturers, the FDA, the CDC, or all of them?
As of November 2022, the CDC website states that vaccines are “effective at protecting people from getting seriously ill, being hospitalized, and dying”, but does not mention that the presented data about the current benefit was based on observational data rather than randomized clinical trial data, which had not been updated since 2021. Observational data is very likely to be confounded by differences in underlying health between vaccinated and unvaccinated. Why does the CDC’s messaging not contain nuance around these issues and why are they not transparent about the limitations in our knowledge when relying on non-randomized data?
If the follow up period had been longer in the randomized trials, robust risk benefit analysis could have been performed and stratified for different age groups and among those with and without infection-acquired immunity. Why were the trials terminated after a short period of follow up for young and middle-aged adults?
In the Pfizer trial, 567 patients in the placebo group and 526 in the treatment arms had evidence of prior COVID-19 infection. In each arm, there was only 1 reinfection (or <0.2% for both), according to the primary endpoint definition (Table 8 page 27), which was roughly 5 times less than symptomatic infection in the placebo arm (n=164/17720 or 0.9%) for those without evidence of prior infection. Why wasn’t this low rate of reinfection in both the treatment and placebo arms acknowledged in vaccine recommendations? Why did the CDC not make it clear to the public that previously infected people, per Pfizer’s own RCT, demonstrated a much lower risk of reinfection? Would official acknowledgement of these data have decreased the push to require low risk individuals to be vaccinated in work and school settings?
Why was a longer and larger randomized trial not performed to assess the benefits and risks of the booster for young adults, when there was no longer an emergency? One observational study found an unfavorable risk-benefit analysis for use of boosters in adults 18-29. Why were the FDA and CDC not more transparent and concerned about unfavorable risk-benefit analysis in young adults, especially when it became clear vaccines did not stop transmission?
The Moderna trial included prespecified secondary endpoints of asymptomatic infections and seroconversion but did not report any seroconversion results in their initial publication in December of 2020. In November of 2021, results were published demonstrating only 63% efficacy against asymptomatic PCR-confirmed infection by the end of the study period and 59% efficacy against seroconversion (or asymptomatic infection detected) at day 57 (Supplement Table S28). As a prespecified endpoint, the latter information should have been available at the time of publication in December of 2020. Why did the FDA allow Moderna not to disclose these seroconversion data? Why was it not communicated better to the public that vaccine efficacy at the time of initial publication against symptomatic and asymptomatic PCR positive infections together was less than 90%? Whose responsibility is it to communicate these results to the public? Should the FDA have demanded data on seroprevalence in the initial trial results, given that Moderna specified seroprevalence as a primary endpoint?
Why did the FDA remain silent on these results while vaccine mandates and vaccine passports were supported by the government, leading to many Americans losing their jobs and health-care staff shortages during the Delta and Omicron waves of 2021?
Why were Pfizer’s trial protocol criteria for documenting an infection so different from how infections were documented in many Western countries, including the United States? Specifically, “evidence of infection” in the Pfizer trial pooled two different methods for determining SARS-CoV-2 positivity (PCR and anti-nucleocapsid). Doing so could significantly overestimate vaccine efficacy due to the lower rate of anti–nucleocapsid conversion in vaccine recipients when compared to placebo. This is because people who are infected but vaccinated are less likely to develop evidence of seroconversion (by producing anti-nucleocapsid antibodies) than those who are unvaccinated. Specifically NIH and Moderna researchers noted that 93% of placebo recipients generated measurable anti-nucleocapsid antibodies, while only 40% of vaccine recipients did so. Did the use of anti-nucleocapsid conversion for evidence of infection underestimate infections in the vaccine recipient cohort?
In early 2022, Christine Stabell Benn et al. published pooled clinical trial results showing a reduction in all-cause mortality for the adenovirus-based vaccines (J&J, AstraZeneca, and Sputnik) but not for the mRNA vaccines (Pfizer and Moderna). Why did the FDA not do these pooled analyses in 2021? Considering these results, is it possible that some people could have benefited more from receiving a different, non-mRNA, vaccine?
Why did pharmaceutical companies not design trials to evaluate all-cause mortality? If older participants had been enrolled or if the trial had lasted longer, randomized studies could have helped determine if there were all-cause mortality and COVID-19-specific mortality benefits from vaccination with mRNA vaccines. Why did the FDA not insist on having trials with the above-mentioned endpoints? Why did the FDA instead accept symptomatic disease as an endpoint?
Vaccines were developed and approved in record time. What contributed to this remarkable accomplishment?
The Pfizer and Moderna randomized trials ended after less than 6 months when those who had received the placebo were offered vaccination. This meant there was no randomized information on long term efficacy and adverse reactions. An argument can be made for ending the trial for older high-risk participants, but why was this time-frame selected for younger participants with low mortality risk?
Why were only three vaccines available in the United States in 2020 and 2021? Why did other vaccine manufacturers not submit applications and/or receive FDA approval?
Why was the Johnson & Johnson vaccine paused for central venous sinus thrombosis for all ages when the risk-benefit ratio was clearly most unfavorable for women under 50? Why were there no similar pauses or suspension due to Pfizer- and Moderna-associated myocarditis in young males?
In September of 2022, a study used data from the Pfizer and Moderna randomized trials to show an excess serious adverse event rate post Pfizer of 1/990 and post Moderna of 1/662 compared with controls who received placebo. Why was a study such as this performed by independent scientists and not requested by the FDA or from the manufacturers in 2020 or 2021? Why were individual level data, which were requested by the authors not made public by the FDA, Pfizer or Moderna? Why was an age-gradient risk-benefit analysis not performed?
There were early indications that prior infection provided significant protection against reinfection and even more robust protection against future severe disease. Why, in all age groups and demographics, did the FDA and the CDC assume that the benefits of two doses of vaccine in previously infected people would exceed the potential risks of vaccine adverse reactions?
For previously infected people, why were no randomized trials done with sufficient sample size, and thus power, to assess vaccine efficacy against severe disease? Without evidence from such a trial, why were previously infected individuals told to get vaccinated?
Vaccine Prioritization and Distribution
Some states prioritized older highest-risk adults for early vaccination in the winter and spring of 2021, when vaccines were in short supply, together with health care workers. In other states, a large number of young adults got vaccinated through their employers while those over 65 years had difficulty getting vaccinated.
Why were many younger low-risk adults given the vaccine before high-risk older adults? Did this cause unnecessary deaths, and if so, how many?
The United Kingdom and other European countries implemented strict risk-based vaccine prioritization. By contrast, the CDC prioritized young health care workers with or without natural immunity before Americans over the age of 75, who had the same priority as frontline essential non-healthcare workers of all ages, such as store clerks, teachers and transit workers. What led some states, such as Florida and Texas, to reject the CDC guidelines and instead prioritize by age?
In April and May 2021, Michigan had a regional COVID-19 spike while COVID-19 was on the seasonal decline in most other states. The federal government refused to send additional vaccine doses and resources to Michigan during this regional emergency. Why did they not send vaccines where they were most acutely needed? How many people died because of this?
US states have different seasonal patterns for COVID-19 disease, with the north having a large winter peak while the south has both a winter and a summer peak. Should seasonal patterns have been taken into account for timing vaccine dose distribution for different states?
People who have recovered from COVID-19 infection already have excellent immunity. Why were they given the same vaccine priority as those without immunity? How many people died unnecessarily because those with natural immunity got the vaccine before susceptible older Americans with high mortality risk?
With a global vaccine shortage throughout 2021, young adults in first world countries were vaccinated before much higher risk elderly in low- and middle-income nations. Was this public health policy appropriate given disease risk gradient by age, with over a thousand-fold difference in the mortality risk between old and the young? Why did universities in the United States mandate vaccines for students while millions of older high-risk adults in the developing world desperately needed the vaccine? Globally, how many excess deaths were caused by such policies?
Vaccine Safety
When a drug or vaccine is approved, there is often not enough safety data from clinical trials to provide data about potentially rare adverse reactions or even common adverse reactions in specific subpopulations. In the United States, there are several post-market vaccine safety surveillance systems run by the CDC and FDA. The three most important are (i) CDC’s Vaccine Safety Datalink (VSD), which uses electronic health records from integrated health systems such as Kaiser Permanente and Health Partners, (ii) the FDA Biologics Effectiveness and Safety System (BEST), which uses health insurance claim data and Medicare data, and (iii) the Vaccine Adverse Event Reporting System (VAERS), run jointly by CDC and FDA, which uses spontaneous reports from the public and health care providers about potential or suspicious adverse reactions. Pharmaceutical companies are legally obligated to report any adverse reactions to the VAERS system, so pharmaceutical companies should not have data above and beyond the data recorded in VAERS.
The purpose of these vaccine safety systems is not only to detect and report vaccine safety problems but to demonstrate to the public when vaccines are safe. If relevant analyses are withheld, the public does not know if the vaccines are safe or not.
Not all VAERS reports are causal, as there will be some adverse events after vaccination simply due to chance. The raw unanalyzed VAERS data is publicly available, and it has been widely used by vaccine critics to publicize adverse events that may or may not be causal or occurring at a rate which is higher than expected in the absence of the vaccine. Along with the raw data, why did the CDC and FDA not publish the VAERS analyses they routinely conduct to help determine if the observed adverse events are more than one would expect by chance?
Because VSD data are based on electronic health records, have well-defined denominators for total number vaccinated, and contain other relevant health information, VSD data are higher quality than VAERS data. A September 2021 VSD report for mRNA vaccines showed good safety for many outcomes. When specific concerns about COVID-19 vaccine safety arose among the public, why were there not more reports from the VSD system to either refute or confirm those concerns?
Why have there been so few public reports on COVID-19 vaccine safety using the FDA BEST system?
In April 2021, there were reports of blood clots after the J&J vaccine, primarily among women under 50. There were no reports among anyone above 50. Despite this, CDC paused the vaccine for everyone, including the high-risk older people for whom the vaccine is most important. The pause led to a sharp decline in J&J vaccinations at a time when vaccines were still in short supply. How many older people died because of this pause? How did the pause affect hard to reach populations, such as rural residents and the homeless, for which one-dose vaccines may have advantages over two-dose vaccines?
A vaccine scientist with expertise in the early evaluation of safety data objected publicly to pausing the J&J vaccine for older Americans (Dr. Martin Kulldorff, who was on the faculty of Harvard Medical School and is one of the authors of this document). After voicing his concerns, he was fired from the CDC working group on COVID-19 vaccine safety. Who made that decision? Will such terminations affect willingness of other public health scientists to voice their views when those views are contrary to the views of the CDC?
In April/May 2021, Israel reported an increased risk of myocarditis after the Pfizer vaccine, predominantly in young males after dose 2, putting the risk at somewhere between 1/3000 to 1/6000 for males 16-24. The first published study to assess subclinical myocarditis following the second dose of Pfizer in adolescent boys 13-18 found a rate of clinical and subclinical myo/pericarditis of 3.5%. VSD data confirmed excess myocarditis risk, especially after the second dose and boosters. Data from France and Nordic countries found post-vaccination myocarditis rates to be 3-4 times higher post-Moderna than post-Pfizer. Why did it take so long for the CDC and FDA to identify and quantify the myocarditis signal and perform a cost-benefit analysis? On their Biologics License Application (BLA) approval of Moderna, FDA required a US post-market analysis of myo/pericarditis and subclinical myocarditis to be completed in 2025. Why not sooner or before approval for younger ages? The BLA approval also required measuring long term consequences of post-vaccination myocarditis in affected individuals.
In September of 2021, why were non-stratified data published in one of the United States premier medical journals, the New England Journal of Medicine, which gave a false impression of a very low rate of post-vaccination myocarditis in young males by grouping all ages and both sexes together resulting in an overall rate of 1-5/100,000 vaccinations when we knew from CDC and FDA data that the main safety signal was in young males? Why has it not been made well known that the Pfizer-Moderna combination has the highest rate of post-vaccination myocarditis? Why are many young males still mandated to get vaccine doses, including those who already have immunity from a prior COVID-19 infection?
Why were no studies run to look at other co-risk factors for myocarditis, such as previous infection or other risk factors such as exercise following vaccination?
Given the clear relationship in this demographic between myocarditis and the second dose of Pfizer, why was Pfizer not questioned further when they stated they had not seen a higher than expected rate?
In the fall of 2021, much of Northern Europe placed restrictions on use of Moderna in those under age 30. In the US, why were the mRNA vaccines, or at least the two-dose regimen, not paused or suspended in males <30, to perform a thorough risk-benefit analysis and to determine if spacing doses, omitting the second dose, or using lower doses could minimize harm? Why was there no discussion of preferentially giving Johnson & Johnson or other vaccines than Moderna to young males due to increased risk of myocarditis?
In the summer of 2021, the FDA reported that they saw a “signal” of a potential increase in heart problems after the mRNA vaccines. Why was this presented in a press release without any actual data? Why were there no timely follow-up reports to determine whether this was a causal relationship or not?
The FDA BEST system has reported safety signals for acute myocarditis/ pericarditis, myocardial infarction, Bell’s Palsy, pulmonary embolism and immune thrombocytopenia after mRNA vaccines. Have these risks been formally communicated to the public?
Vaccines and COVID-19 Transmission
The randomized controlled vaccine trials did not evaluate the ability of the vaccines to reduce or prevent transmission.
Why did Pfizer, Moderna and Johnson & Johnson not evaluate transmission as part of their vaccine trials?
In 2021, without supporting evidence, the CDC claimed that the COVID-19 vaccines “can keep you from getting and spreading the virus that causes COVID-19.” Was this messaging deliberate or an honest mistake by the CDC?
When the public learns that CDC is making inaccurate claims about COVID-19 vaccines, how does that affect the trust in the benefits of this and other vaccines? How does this affect trust in our public health agencies?
Why did it take so long to correct this information? Were CDC officials with knowledge of the shortcomings of the vaccine afraid to speak against official CDC views?
Vaccine Mandates and Passports
In 2021, universities, hospitals, governments and private employers started requiring proof of vaccination, often firing those who would not or could not comply. The vaccine mandates included people who had infection-acquired immunity, despite substantial evidence of robust immunity in recovered persons, even those who had mild or asymptomatic infections. Furthermore, the vaccine trials did not assess the ability of the vaccine to reduce transmission.
Why were mandates pursued without carve-outs for those with immunity due to prior infection? Why were people fired, destroying careers and reducing healthcare capacity?
Why were there mandates for low risk working age employees and students?
What was the intent of the vaccine mandates? If it was to prevent transmission, why was it not made clear that we did not yet know whether or not the vaccines prevented transmission?
Why did many organizations continue with mandates through summer and fall of 2021, despite data demonstrating both waning efficacy of symptomatic infection and reduced long term ability to curb viral spread?
Was it appropriate to have vaccine mandates in demographics, such as young students, in which it was not certain that the benefits of the vaccine would outweigh the risk?
To what extent have COVID-19 vaccine mandates reduced long term trust and uptake of other vaccines?
In August 2022, the CDC changed its COVID-19 prevention guidelines so that “vaccinated people now have the same guidance as unvaccinated people”. What caused this change? Why did it not happen sooner?
As of November 2022, the United States continues to demand proof of vaccination from international visitors. What is the rationale for this? How does this affect immigrant families in the United States and the tourism industry?
Randomized Vaccine Trials in Children
Pfizer included 16–17-year-old adolescents as part of its adult trial. For both Pfizer and Moderna vaccines, separate randomized trials were subsequently conducted for 12-15- and 12–17-year-olds respectively, for 5-11 year olds and for children between 6 months and 5 years old. The pediatric trials were small and participants were followed for fewer than 4 months. The Pfizer and Moderna trials were not powered to detect vaccine efficacy against severe disease, nor rare but serious adverse events. There was no assessment of the impacts of the vaccine on viral acquisition or transmission. It thus was impossible to perform a reliable risk benefit analysis for this very low risk population.
Pfizer failed to demonstrate significant efficacy against symptomatic infection (page 53 of the FDA submission) after either 2 or 3 doses of vaccine in either the 6-month to 2-year olds or in 2-5 year olds. While not statistically significant, the rate of severe disease was twice as high in vaccinated (0.33%) compared to unvaccinated (0.11%) 2-5 year olds. Moderna found a non-statistically significant vaccine efficacy (table 84) against asymptomatic infection of 4% in children aged six months to two years and 23% in children between two and six years old. Compared to the ~90% efficacy for adults, Moderna has low efficacy against symptomatic infections in children: 50% in children aged six months to two years, and 42% in children between two and six years old. From multiple observational studies in 5-11 year olds, it is clear efficacy against infection wanes quickly, in a matter of weeks to months.
Given that healthy children are at such low risk for severe COVID-19 disease, why did the FDA approve these vaccines with such weak evidence on efficacy and little knowledge about potential adverse reactions?
For the Pfizer vaccine, should the fact that the point estimate of severe disease was higher in the vaccinated arm have been cause for concern or reason for a larger study to look at severe disease as an endpoint?
Why did regulators choose the Emergency Use Authorization (EUA) pathway when a child’s overall risk of serious disease is less than that for influenza during an average year?
Should randomized vaccine trials in children have been powered and lengthened to evaluate severe disease, waning efficacy, and rare but serious adverse events?
Some have argued that the primary purpose of vaccinating children is to protect adults around them. If so, why were the trials not designed to evaluate child-to-adult transmission?
Why were children with prior infection not studied separately?
Should trials have been designed with stratification, to separately evaluate vaccine efficacy and risk among children with comorbidities who may be at higher risk for severe COVID-19 versus children without any comorbidities?
In an FDA meeting on June 28, 2022, Pfizer Vice President for Viral Vaccines Kena Swanson acknowledged that “there is no established correlate of protection” between antibody levels and protection from disease. Was a surrogate endpoint of antibody titres appropriate for a booster vaccine in children when the risk to children of severe disease after 1 dose, let alone two doses, of mRNA vaccination is incredibly low?
There were multiple data points (See Section G points 4 & 5, below) in the trials to suggest a possible signal for increased susceptibility to other infections in vaccine recipients in both the Moderna and Pfizer Pediatric trials. With such low risk from COVID-19 in children, why was this signal ignored as it trended to more overall harm than benefit? Is post-authorization surveillance data currently being collected?
Has the CDC made attempts to calculate risks vs benefits of each dose of the vaccine in children and adolescents? Using observational data, one study estimated benefits and risks of vaccination in adolescents stratified by health status and prior infection. It found 2 doses of vaccination to carry more risks than benefits (considering myocarditis risks only) for every adolescent group except non-immune girls with risk factors. Why was this not addressed by the CDC? Why did they not perform or publish their own similar analyses?
The recommendations for vaccinating and boosting children against COVID-19 currently vary internationally. Multiple European countries, including Sweden, Denmark, Norway and Finland are only recommending fall bivalent booster doses for those over 50-65 years or otherwise considered to belong to a high-risk group. Denmark specifically stated in June of 2022 that children (under 18) cannot get vaccinated against COVID-19 unless they have a medical evaluation from a physician who deems it advisable. Sweden, the UK, and Finland do not routinely recommend vaccination for healthy children under 12. Why is the United States still recommending COVID-19 vaccines, including boosters, for all healthy children 6 months and up?
The EMA\ECDC recommended in a joint statement in September of 2022 that the bivalent booster “be directed as a priority to people who are more at risk of progressing to severe disease” and gave more nuanced guidance than the CDC. Why is the CDC recommending a bivalent booster dose to all children regardless of previous infection or health status? Why does the CDC differ from the EMA\ECDC in this recommendation?
Vaccines recommended by the CDC for “routine administration” are eligible to be covered under the Health Resources & Services Administration, protecting the manufacturers from liability. Did this play a role in the ACIP’s decision to endorse adding the COVID-19 vaccination to the recommended vaccine schedule? Was this appropriate without evidence that benefits of additional COVID-19 vaccinations in children outweigh the risks?
Vaccine Safety in Children
For drugs and vaccines with a large absolute risk reduction in mortality, the benefits outweigh the risks even if there is a small risk of serious adverse reactions. Since children have a very small risk for serious COVID-19 outcomes, the absolute risk reduction is, by default, at most very small, and even a small risk for serious adverse reactions can tip the benefit-risk balance against the vaccine. It is therefore critical to have a precise and thorough understanding of COVID-19 vaccine adverse events in children. For concerns about myocarditis in children, see Section C above. Here we discuss vaccine safety concerns specific to children.
For the Pfizer vaccine, 16-17 years olds were included in the adult clinical trial, with 76 participants in the treatment arm and 77 in the placebo arm. For 12-15 year olds, a new randomized trial was conducted with 49 and 51 participants respectively, for a total of 125 participants in the treatment arm. In April 2021, Pfizer submitted an amendment to their application with an additional 1,131 and 1,129 participants respectively. These numbers are less than for many other childhood vaccine trials, and not sufficient for a thorough evaluation of potential adverse events. Considering their very low risk for hospitalization and mortality, why did the FDA approve the Pfizer vaccine for children based on such small numbers?
In the randomized trial for 5-11 year olds, Pfizer enrolled 1,518 children in the treatment arm and 750 in the placebo arm. Were these numbers of participants sufficient for pre-approval evaluation of vaccine safety?
In the Pfizer trial, 2/3 of the treatment arm population did not remain in the trial through completion. Why did so many participants in the Pfizer under-5-year-old trial fail to complete the trial? For the 6-month to 23-month age group, there were 3,031 treatment participants in the Moderna trial and 1,178 treatment participants in the Pfizer trial. For the 2-year-old to under 5-year-old age group, there were 1,761 treatment participants in the Moderna trial and 1,835 treatment participants in the Pfizer trial. Was this a sufficient sample size to answer important questions?
Although absolute numbers are too small to reach significance, there were more instances of other respiratory tract infections in the vaccine arm in pediatric mRNA trials. In the Pfizer 6-month-old to 23-month-old group, there were 5 episodes of RSV bronchiolitis, 2 episodes of pneumonia and an episode of gastroenteritis in the treatment arm. By comparison, there were 3 episodes of RSV bronchiolitis in the placebo arm. In the Moderna 6-month-old to 23-month-old cohort, there were increased events of croup (1.3% of vaccine recipients and 0.3% of placebo recipients), RSV (0.8% vs 0.5%), and pneumonia (0.2% vs 0%) in trial participants. In the Moderna 6-11 year-old trial, increased rates of respiratory tract infection were noted in the treatment arm. RSV infection was increased (0.3% vs 0%) and other upper respiratory tract infections were increased (3.9% vs 2.5%). Should these events have been investigated as potentially vaccine related?
Why was leukopenia, or low white blood cell count, not studied in the pediatric trials despite its presence (Supplement: figure S3) in adult trials? There was at least one case of moderate leukopenia with mild thrombocytopenia with fever in the 2-year-old-to-under-5-year-old Pfizer treatment arm.
In the Moderna trial for the 2-5-year-old cohort, fever was reported more frequently after each dose among participants with positive SARS-CoV-2 antibodies at baseline compared to those with negative SARS-CoV-2 status: 13% vs 8% after dose 1 and 21% vs 17% after dose 2. In the absence of clear benefit against severe disease or infection with no reduction in severe cases even in the absence of a prior infection in the randomized trials, should this have been considered before recommending the vaccine to children with infection-acquired immunity?
Effects on Confidence in Other Vaccines
During the pandemic, vaccinations against common childhood diseases decreased. The purpose of transparent vaccine safety surveillance systems is not only to find vaccine adverse reactions, when they exist, but also to ensure trust in vaccines when they are efficacious and safe. Since the COVID-19 vaccines were approved, we have seen increasing vaccine skepticism and hesitance in the population.
How much of the reduction in childhood vaccination rates were due to less access to medical care during lockdowns? Did school closures affect vaccine uptake? Was this a temporary effect? What proportion of children were able to catch up with their missed vaccinations after lockdowns lifted and schools reopened?
Since excess risk of myocarditis after mRNA vaccines is well established for young men, why was it considered “anti-vaccine” to discuss this adverse reaction to the vaccine, when such evaluations and discussions have been considered “pro vaccine” for other vaccines, such as intussusception after rotavirus vaccines and febrile seizures after measles containing vaccines?
What are the public health implications of not being thorough and transparent about known but rare vaccine adverse reactions? Is the loss of trust in the FDA and CDC partly related to a lack of transparency about COVID-19 vaccine adverse events? To what extent has this led to potentially deadly decreases in vaccination rates for other childhood vaccinations such as polio and measles? How much of the reduction in childhood vaccination rates is due to increased vaccine hesitancy because of increasing distrust in the medical and public health establishment and lack of full transparency about COVID-19 vaccines? How might this have been prevented or mitigated?
How have COVID-19 vaccine mandates and coercion affected trust in and uptake of other vaccines?
Waning Vaccine Efficacy and Boosters
In the summer of 2021, studies showed that vaccine induced immunity was rapidly decreasing. In a study from Qatar, vaccine effectiveness against infection went to 0% after 20-24 weeks. This led to the introduction of booster shots in late 2021. Rather than using randomized trials, boosters were evaluated using observational data, which are confounded because people who choose to get a booster dose will likely have different health status, behaviors, and/or attitudes towards vaccination than those who do not choose to boost.
Early information about waning vaccine efficacy came from countries such as Israel and Qatar. Why did the United States not collect its own data on this in a timely manner?
Why did the FDA approve boosters without randomized trials to evaluate the efficacy and safety of COVID-19 booster vaccines? In particular, why were there no randomized booster trials in people under 65, for whom there was no longer an emergency?
Using a database of 4.7 million people, an Israeli study failed to identify any benefit of Pfizer booster doses against hospitalization in people <40. Why were boosters recommended for those under 50 without accompanying data showing efficacy?
Why was evidence of quickly waning vaccine effectiveness against hospitalization not widely communicated to the public until after the bivalent booster was available?
Why did the CDC and the FDA not conduct a proper benefit-risk evaluation of boosters in young adults and children? Why was the very low absolute risk reduction against severe disease not considered? An independent analysis anticipated that for every one COVID-19 hospitalization prevented in previously uninfected young adults <30, there would be more than 18 serious adverse events, including 1.7 to 3.0 booster-associated myocarditis cases in males, and 1,373 to 3,234 cases of grade ≥3 reactogenicity (defined as interfering with daily activities). Why did the CDC and the FDA ignore such information? How might risks of myocarditis and other side effects after a booster with an unknown and at most modest benefit erode public trust in vaccines?
A Danish household transmission study [6] found no difference in secondary transmission rates in boosted vs vaccinated vs unvaccinated people. Why are boosters being mandated by universities, hospitals and other employers, without any proof of lasting efficacy against transmission? Are there harms that might arise from suggesting that boosting will make school and college campuses “safe” without reliable evidence that boosters can reliably prevent infection and transmission?
In the absence of transparent COVID-19 data collected and released in the US, Americans have had to repeatedly look to other countries for reliable information. In an Israeli study using a head-to-head comparison between boosted vs. non-boosted people, in people under age 30 the risk of COVID-19 death among non-boosted people was zero, the same as in boosted people. In people <40 there was no detected benefit of the booster against severe COVID-19. Considering known adverse reactions, why did the CDC recommend boosters to this age group?
When the FDA authorized boosters for young people, on three separate occasions, why did they bypass the recommendation of their own Vaccines and Related Biological Products Advisory Committee (VRBPAC), consisting of external advisory experts?
Recommendations for the bivalent COVID-19 vaccine were based on small sample sizes yet made for everyone “12 and up”. Director Walensky cited the reason for the overly broad recommendation as the need to “simplify messaging” to the public. Why did the CDC choose this strategy instead of focusing the messaging on the importance of boosters to those truly at risk of infection?
Some emerging data suggest that the monovalent and bivalent boosters elicit similar neutralizing antibody responses against all viral variants. Data from Qatar also show no difference in severe disease regardless of prior infection and number of vaccine doses, but show increased susceptibility to infection after boosting. Is the CDC tracking this concerning signal for “imprinting”? Is the CDC or NIH conducting or funding any studies on this topic? Why is Qatar but not the United States able to maintain and run robust national data analyses that provide rapid feedback for these types of policy decisions?
Multiple European countries, including Sweden, Denmark, Norway and Finland, now only recommend bivalent booster doses for those over 50 or 65 years old, or those belonging to a high-risk group. The European CDC and European Medicine Agency released a joint statement saying updated boosters should be “directed as a priority” to those 60 years and older or high risk groups. Why did the US deviate ñ from this and recommend a booster for young healthy people who face very low risks from COVID-19, most of whom have already been infected, when the benefits and risks of the new bivalent vaccine were not known, and no risk-benefit calculation had been performed?
While it is the responsibility of the FDA to license a vaccine, recommendations for vaccine use are developed by the ACIP (which advises the CDC). In the ACIP meeting discussing the bivalent booster recommendations, Dr. Sara Oliver stated that, “It is a PREP Act liability if the ACIP recommendations are different than the [FDA’s] EUA recommendations". Rather than providing guidance based on the clinical expertise of its members, did the ACIP recommendations simply mimic the FDA’s EUA recommendations in order to avoid Prep Act Liability [7], as alluded to by Dr. Oliver? Did mentioning the PREP Act during the ACIP meeting by Dr. Oliver or others contribute to bivalent booster recommendations that were not nuanced based on age, health conditions or prior infection? Does it affect trust in public health if the CDC is not, or believes they are not, legally able to provide recommendations that are appropriately individualized and nuanced because they are focused on avoiding liability for the vaccine manufacturer?
Footnotes
[6] See Table S8 in the linked study.
[7] “When the Secretary determines that a threat or condition constitutes a present or credible risk of a future public health emergency, the Secretary may issue a PREP Act declaration. The declaration provides immunity from liability (except for willful misconduct) for claims of loss caused by, arising out of, relating to, or resulting from the administration or use of covered countermeasures to diseases, threats and conditions identified in the declaration.”