An article entitled “Covid Vaccines for Children Should Not Get Emergency Use Authorization” was recently published in The BMJ by Drs. Wesley Pegden, Vinay Prasad, and Stefan Baral. The central thesis of the argument is that “severe outcomes or death associated with COVID-19 infection is very low for children, undermining the appropriateness of an emergency use authorization for child COVID-19 vaccines”. They express a concern that under an Emergency Use Authorization (EUA), “the risk of rare adverse events remains and, if the benefit achieved by an intervention is insufficient, any serious, yet rare, adverse effects can prove to be the lasting legacy of a regulatory decision”. The article contained several crucial omissions that I believe undermine their conclusion.
Is COVID-19 low risk for children?
First, let’s examine the statement that the risk COVID poses to children is “very low”. While the risk to children is many orders of magnitude lower than the risk to older adults, the risk is not zero. One study of 7,780 pediatric patients recorded 7 deaths (0.09%), though the actual death rate is almost certainly less than this. With millions of children contracting COVID-19, even rare harms add up. According to covkidproject.org, as of March 28, 2021, 582 children have died in the US of COVID-19. I will note that other sources with different methodologies have found a lower death toll. According to the CDC, 482 children have died. Regardless of the exact number, it is fair to say that essentially, a child dies of COVID-19 every day in the US. These were lives cut tragically short and each child leaves behind a grieving family.
Of course, death is the most severe, but not the only adverse outcome of contracting COVID-19. According to the American Academy of Pediatrics, “Children were 1.2%-3.1% of total reported hospitalizations, and between 0.1%-1.9% of all child COVID-19 cases resulted in hospitalization”. A CDC report found that among 69,700 laboratory-confirmed cases of COVID-19 in children younger than 20 years, the hospitalization rate was 2.5-4.1%. Another study of 20,714 children with COVID-19 found that 2,430 (11.7%) were hospitalized.
Unfortunately, finding reliable data for the total number of children hospitalized this pandemic is difficult. Some sources account only for cases who were confirmed positive for COVID-19, while others try to estimate the actual number. Additionally, many states do not provide the age distribution of hospitalizations, and the age cut-off for children is not the same in each state. According to one CDC website, by December 2020, prior to the pandemic’s peak, nearly 192,000 children younger than 17-years had been hospitalized for COVID-19. According to other sources, even the CDC, the number of hospitalized children is substantially lower, perhaps 30,000 children were hospitalized in 2020. Regardless of the actual number, a non-trivial percentage of children who contract COVID-19 will need to be hospitalized.
Importantly, some of these children can be quite sick with multisystem inflammatory syndrome (discussed by Clay Jones). In fact, in one study, 33% of children admitted to the hospital need ICU-level care and 6% required invasive mechanical ventilation. 58% of the hospitalized children had no underlying medical condition. The most common underlying condition was obesity, which is present in 19.3% of American children. Hispanic children were hospitalized eight times more often than White children, and Black children were hospitalized five times more often than White children.
Moreover COVID-19 is a new disease, and we must consider that there may be long-term complications. Although the vast majority of people who contract the disease seem to fully recover, not all do. This is true for children as well. According to one study from Italy, “more than half of children aged between 6 and 16 years old who contract the virus have at least one symptom lasting more than 120 days, with 42.6 percent impaired by these symptoms during daily activities.” Some children haven’t recovered their ability to smell and taste. Time will tell if they ever will. Interestingly, many with “long-COVID” report feeling much better after being vaccinated, an area for further investigation.
Is COVID-19 an emergency for children? (Is it an emergency for teenagers over 16 years, who have already been vaccinated by the millions?) These are obviously subjective questions. However, none of these concrete harms to children were presented in the article by Drs. Pegden et al. They presented the risk to children simply as being “very low”.
Reasonable people may disagree about whether COVID-19 constitutes an emergency for children, however real harms of COVID-19 to children should have been presented to give the reader an informed view. Based on reaction to the article on Twitter, many readers erroneously believe COVID-19 is essentially completely harmless for children or much less dangerous than other vaccine-preventable diseases. In fact, the direct toll that COVID-19 has taken on children, even with much of normal life suspended, exceeds that of several other vaccine-preventable diseases (such as the flu, chickenpox, and even measles), before vaccines for these diseases were available.
Additionally, a recent study estimated that 43,000 American children lost a parent to COVID-19. While it is not clear how many of these adults contracted the disease from their child, it safe to speculate that some did. Parental loss was not mentioned in the article by Drs. Pegden et al.
How about the vaccines?
Second, let’s examine the vaccines, specifically the mRNA vaccines, which are most likely to be approved for children. I don’t think it is an exaggeration to say that these vaccines are the greatest scientific achievement of my lifetime. Drs. Pegden et al. agree, writing “the rapid development of highly effective COVID-19 vaccines is a triumph of science”. Hundreds of millions of doses of these vaccines have been administered so far, including millions of doses to teenagers 16 years and older, without a hitch so far.
Most importantly, the vaccine has been studied in a randomized double-blind placebo-controlled study in children ages 12-15 years. The results were overwhelmingly positive. According to the press release from Pfizer, “The trial enrolled 2,260 adolescents 12 to 15 years of age in the United States. In the trial, 18 cases of COVID-19 were observed in the placebo group (n=1,129) versus none in the vaccinated group (n=1,131).” The press release further notes that the vaccine “was well tolerated, with side effects generally consistent with those observed in participants 16 to 25 years of age.” Children in this trial will continue to be monitored for two years.
This successful trial was not mentioned by Drs. Pegden et al.
It seems reasonable to expect that an article on the pediatric COVID-19 vaccine would at least mention a successful Phase 3 study on the vaccine in children, with the caveats that 1) it’s a press release and 2) that the full results have not yet been published. Notably, this follows the pattern for the vaccine trials in adult populations, where the full results were not published until after the EUA was issued. Of course, as with the EUA for adults, FDA regulators will rely on reams of trial data in deciding whether or not to authorize the vaccine for children, not just a press release.
Though the numbers are small, Israel has also vaccinated at least 600 children ages 12-15 years without problems. Additionally, Moderna also reported success with a randomized trial of 3,235 subjects. According to the company, its vaccine was 96% effective for adolescents ages 12-17 years and there were no serious safety concerns. This data was announced on May 6th, the day before the publication by Drs. Pegden et al., and was certainly too late to be included in their paper. Assuming the formal publications support this data (it would be a major scandal if they didn’t), this should add confidence that the vaccines are rigorously studied in children, and the results are very positive thus far. Canadian health official recently authorized the vaccine writing, “After completing a thorough and independent scientific review of the evidence, the Department has determined that this vaccine is safe and effective at preventing COVID-19 when used in children between 12 and 15 years of age.”
Further studies on younger children just started, and if all goes well, vaccines may be issued under an EUA for children ages 2-11 years by September 2021. The order of the trials and vaccine approval by age were set up this way purposefully. If the vaccine is safe and effective in 16 and 17-year-old children, as has been the case thus far, then there is every expectation this true 14 and 15-year-olds. Similarly, if real-world experience shows the vaccine is safe in 12 and 13-year-olds, it is not unreasonable to assume that it will be safe in children a few years younger than this, though of course independent studies are being done in these age groups. The system seems to be working. Pediatric trials have been halted for viral vector vaccines due to the rare risk of blood clots in young adults. This conscious ordering of vaccine-trials and likely authorization was not mentioned by Drs. Pegden et al.
Instead of discussing the successful trial of the COVID-19 vaccine in children and the logic underlying subsequent trials, the authors devote space to discussing the 1976 swine-flu vaccine fiasco which led to several cases of Guillain-Barré syndrome. Indeed, the only reference in their article was about this vaccine mishap, which they intended to serve as a warning about unintended consequences regarding vaccines. In fact, the vast majority of vaccine side effects, which are rare to begin with, occur less than two-months after vaccination, a crucial time frame as I will discuss. Though there have been tragic mishaps in the past, the overall history of vaccines should inspire great confidence in their safety. That vaccine effects almost never emerge after two-months was not discussed by Drs. Pegden et al.
While it is true that unexpected vaccine side effects might emerge, it is more likely that COVID-19 might do something unexpected. In Brazil, for example, 1,300 babies have died of COVID-19, though the reasons are likely multifactorial. It is not inconceivable that a COVID-19 variant could significantly affect children and spread widely before we could widely vaccinate children. Precaution against the unknown works in both directions.
An Emergency Use Authorization versus a license
Now let’s examine what is perhaps the core of the argument by Drs. Pegden et al. To be clear, they are not against children being vaccinated against COVID-19. Rather, they are against most children being vaccinated under an EUA. They instead feel that “a wide rollout of child COVID-19 vaccines should follow the standard regulatory process as for most children”. They do say, “emergency use authorizations should be considered for children at genuinely high risk of serious complications from infection”. Recall however, that 58% of hospitalized children had no identified risk factor and about 15 million American children have obesity as a risk factor.
So, what is the difference, then between an EUA and the “standard regulatory process”? I honestly wasn’t sure, and the article by Drs. Pegden et al. does not discuss the difference at all. Since the article does not describe these core features of the regulatory program for COVID-19 vaccines, their readers may be left with the misimpression that a vaccine authorized for children under an EUA has not been rigorously tested in children. Based on reaction to the article on Twitter, this was certainly the case for many readers. Surveys already show that parents are reluctant to vaccinate their children, and articles implying that an EUA is significantly inferior to full FDA approval may further vaccine-hesitancy.
Importantly, the criteria for an EUA for a vaccine are appropriately stringent. Firstly, there has to be a determination “that there is an actual or significant potential for a domestic emergency.” On March 13, 2020, there was a Presidential declaration of a national emergency due to COVID-19. After an emergency is declared, the FDA can issue an EUA for a product under these conditions:
- the product may be effective in diagnosing, treating, or preventing such disease or condition, based on the totality of the available scientific evidence;
- the known and potential benefits of the product outweigh its known and potential risks; and
- there is no adequate, approved, and available alternative to the product.
As far as I know, the regulations say nothing about differentiating between emergencies in different populations, such as children and adults. From a regulatory perspective, either there is an emergency or there isn’t.
With regard to the vaccine against COVID-19, the FDA put out a 24-page guideline specifying the manufacturing and testing criteria that must be met for a vaccine to receive an EUA. According to the FDA, “the issuance of an EUA would require a determination by FDA that the vaccine’s benefits outweigh its risks based on data from at least one well-designed Phase 3 clinical trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner”. This guideline is not mentioned by Drs. Pegden et al.
FDA briefing documents are publicly available for each of the three COVID-19 vaccines authorized for adults under an EUA. They are 53-62 pages of dense data. The FDA explains its decision for each vaccine in an equally lengthy decision memorandum. Clearly, these documents are the product of substantial research and effort. These documents are not mentioned by Drs. Pegden et al.
Similarly, there is 24-page guideline specifying the manufacturing and testing criteria that must be met for a vaccine to receive licensure. This guideline is not mentioned by Drs. Pegden et al. The key difference between an EUA and full FDA-approval is the amount of time that has passed after the trials have been completed. Since the vast majority of vaccine side-effects occur shortly after vaccination, an EUA requires waiting two-months after completion of the full vaccination in the clinical trial. According to the FDA guideline:
Data from Phase 3 studies should include a median follow-up duration of at least two months after completion of the full vaccination regimen to help provide adequate information to assess a vaccine’s benefit-risk profile, including: adverse events; cases of severe COVID-19 disease among study subjects; and cases of COVID-19 occurring during the timeframe when adaptive (rather than innate) and memory immune responses to the vaccine would be responsible for a protective effect.
In contrast, when companies apply for full FDA approval</a, “Safety assessments throughout clinical development should include…Serious and other medically attended adverse events in all study participants for at least 6 months after completion of all study vaccinations”.
So, the key difference between an EUA and full FDA approval seems to be waiting two months versus six months after the completion of a Phase 3 trial. No extra testing is required, though assuredly the FDA will consider real-world data from the hundreds of millions of people who have received the vaccine under an EUA. Pfizer just submitted an application for full FDA approval in adults last week, nearly six months after they were granted an EUA. This process is expected to take several months. The full FDA approval is not based any new studies from those that led to the EUA. As a company executive explained, “We are pleased to work with U.S. regulators to seek approval of our COVID-19 vaccine based on our pivotal Phase 3 trial and follow-up data”. In order to get FDA approval, “Pfizer-BioNTech will have to comply with a key requirement: providing follow-up data six months after vaccinations.”
What happens if we wait?
Were we to wait for full FDA approval for children, it is unlikely that any child would be vaccinated before 2022. Despite the reduced risk of hospitalization and death from COVID-19 in children, such a delay poses unacceptable risk to the unvaccinated and under-vaccinated in the wider community, and would assure that the pandemic, and the potential for development of escape variants, stays with us that much longer. Schools may be less likely to open in the fall if fearful teachers resist returning to classrooms full of unvaccinated children.
To repeat, Drs. Pegden et al. argue that most children should be vaccinated only after the vaccine is approved by “standard regulatory process”. Their paper did not call for more or larger studies in children (which nobody would oppose), but rather a regulatory framework whose additional safety measure is waiting four additional months. In order for this delay to be of value, one would have to posit there is a significant vaccine side effect that is both unique to children and that it will only emerge between 2-6 months after vaccination at a high enough frequency that it will be detected under the limited structure of a clinical trial.
It is implausible that a full FDA approval would be substantially more likely to detect “rare adverse events” than the already stringent regulatory framework of an EUA, especially considering about 2 million teenagers older than 16 years have already been safely vaccinated thus far. On Twitter, Dr. Baral effectively conceded this point, writing that it is “unlikely to see major A/E (adverse events) in the trial” and that one “will only see rare outcomes with scale”. So what real advantage does the “standard regulatory process” confer over an EUA? Nothing that I can think of. Perhaps I am unaware of other safety features of the “standard regulatory process” that would make the vaccine meaningfully safer for children over an EUA. If these exist, the article does not say what they might be. Perhaps they find the 24-page FDA guideline for vaccine licensure deficient in some way? If so, they do not say.
A reasonable concern of the authors is that “controversy surrounding mass child vaccination under emergency use authorizations could feed vaccine hesitancy in the United States at a time when public attitudes towards vaccination are critical.” The authors are rightly fearful that adverse events in children would undermine confidence not just in the COVID-19 vaccine, but all vaccines.
Unfortunately, those of us who are familiar with the anti-vaccine movement know what is about to happen. Millions of children ages 12-15 years will soon be vaccinated against COVID-19. Horrible, improbable things will happen to a few of them. The media will write emotionally powerful stories about some these children. Parents of these children will implore others “not to make the same mistake I did”. The anti-vaccine movement will amplify and distort these tragedies to implicate the vaccine, though of course we must always keep an open-mind and consider that the vaccine is responsible. Anti-vaccine activists will claim the COVID-19 vaccines were “rushed” and “not properly studied”. Parents will be frightened. Of course, this has been the pattern with nearly every vaccine for years before COVID-19 emerged.
Drs. Pegden et al. would have us believe that this situation can be mitigated if only trial participants were followed for several additional months and the vaccine granted full FDA approval. Considering that the highly-studied, 50-year-old MMR vaccine is still inappropriately blamed for a wide assortment of maladies, it is implausible that a few more months of safety data and a different regulatory approval label would meaningfully refute anti-vaccine rhetoric and calm anxious parents.
A final point made by Drs. Pegden et al. is that given the high-efficacy of the COVID-19 vaccine, “future trajectories of hospitalizations and deaths will largely be determined by vaccination rates in adults”. In other words, high vaccine-uptake in adults will likely crush COVID-19 and obviate the need to vaccinate children. I certainly hope so, and data from highly-vaccinated countries such as Israel and the UK is very encouraging. Indeed the departing chief of the UK vaccine task force recently predicted that “sometime in August, we will have no circulating virus in the UK”.
However, currently in the US, our vaccine picture for adults is decidedly mixed. Our vaccine curve peaked in mid-April and vaccine-uptake is highly variable from one location to another. Only 33% of the population is fully vaccinated, and no state has over 50% of its citizens fully vaccinated. Maine is leading the way with 44.4%. Fourteen states have fully vaccinated less than 30% of their citizens. Even with these low numbers, states are currently turning down more shipments of vaccines as demand wanes. The low vaccination rates in many parts of the country were not mentioned by Drs. Pegden et al.
I hope this ages poorly, but given the large numbers of unvaccinated adults, COVID-19 is likely to remain a threat to American children for the foreseeable future, especially in regions of low-vaccine uptake. Many scientists doubt that the US will achieve the vaccination numbers needed for herd immunity. Given this, every opportunity to immunize a person against COVID-19 is an opportunity to protect individuals, prevent outbreaks, and exponential spread of the virus.
Perhaps the most valid objection to vaccinating children in the US, one not addressed in the article, is that the pandemic is still raging in other parts of the world where vaccine-supply is highly limited. I am entirely sympathetic to the idea that it is unethical to vaccinate American children, while in most countries of the world, highly vulnerable adults remain unprotected. However, for political reasons, no country is going to be shipping large amounts of vaccine to other countries for the time being. As such, any vaccine unused by American children will sit unused in refrigerators for the foreseeable future.
Conclusion: It’s about what isn’t said
To summarize, the article by Drs. Pegden et al. does not mention that:
- 482-582 children have died of COVID-19 in the US.
- A non-trivial percentage of children who contract COVID-19 will need to be hospitalized.
- One-third of hospitalized children require ICU level, care and 6% require invasive mechanical ventilation.
- Over half of children hospitalized with COVID-19 had no underlying health condition.
- 19% of American children are obese and therefore “high-risk.”
- COVID-19 may cause long-term complications in children.
- Tens of thousands of children have lost a parent due to COVID-19.
- Millions of teenagers older than 16-years have been safely vaccinated so far.
- A highly successful trial of the COVID-19 vaccine has been completed in adolescents. (Another successful trial has also been completed, with preliminary data just released).
- Further vaccine trials (and presumed approvals) are proceeding in a purposeful, stepwise fashion by age.
- An EUA for a COVID-19 vaccine requires a two-month waiting period and data “from at least one well-designed Phase 3 clinical trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner.”
- Vaccine side-effects almost never emerge after two months.
- The core difference between an EUA and full FDA-approval is four additional months of observation after already-completed trials.
- Vaccine rates in the US are unlikely to be high enough to achieve herd immunity, especially in certain regions.
The article by Drs. Pegden et al. does mention that:
- The swine-flu vaccine caused Guillain-Barré syndrome in 1976.
Given these omissions, the authors fail to make that their case that an EUA is inappropriate for children or that waiting for a full FDA approval would add substantial safety benefit. Of course, I concede that unexpected adverse events might occur uniquely in children. Issuing an EUA is a calculated risk and that risk is not zero. That is why the stepwise approach being used and post-marketing surveillance are so crucial. Calls for extra “scrutiny” and “caution” sound nice, but they are just empty Pablum unless paired with concrete safety recommendations.
Fundamentally, the decision to vaccinate children is an all-or-nothing decision. There is no way to gently ease into a vaccination campaign in the middle of a pandemic. Either millions of children will be vaccinated over a short time frame or they won’t be. Given the obesity rates in America, even vaccinating children with a risk factor for severe outcome, as proposed, would potentially mean that millions of children would be vaccinated in a short time frame, the exact scenario the authors wish to avoid.
Millions of children have contracted already COVID-19 in the US. Millions more remain vulnerable. Were the vaccine to be delayed for the purposes of obtaining a different regulatory label the additional safety information would be extremely marginal. Although the overall rate would be low relative to adults, during this delay, many children would get sick, some would die, some would be hospitalized or suffer a long-term complication. Others would lose a parent. A safe and effective vaccine can prevent many of these tragedies. We should use it now for children older than 12 years and later for younger children, if supported by positive results from Phase 3 studies in this population.