That’s an important question. Given mounting concern about vaccine equity on the one hand, and the true risk factor(s) on the other hand for children under the age of 12, not to mention some fear (at least some segments within American society about safety concerns), a University of Pittsburgh professor of Pediatrics makes the case for continued vaccine research in pediatric populations. TrialSite appreciates Professor Judy Martin’s transparency and straight talk. A summary of her recent piece in The Conversation is followed by some considerations for a broader rational discussion across the nation. Some notions are challenged here, meant for meaningful debate, something that’s critically important in this age of COVID-19.
First published in The Conversation, TrialSite breaks down the case made by Professor Judy Martin, a well-known principal investigator who receives funding from the National Institutes of Health to conduct SARS-CoV-2 vaccine research. Currently, both Pfizer and Moderna are sponsoring clinical trials with children participating in ages ranging from 11 years old down to six months old. This surprises many people that babies are included in these vaccine trials. With results not ready for translation into potential public policy modifications for several months, Professor Marin explains why this is occurring.
Prior to commencing a brief overview, we mention Martin’s credentials. She conducts her NIH-funded research out of the University of Pittsburgh’s Pittsburgh Vaccine Trials Unit, which is well-known in the world of vaccine research. In her Op-Ed, she shares that this unit conducts both adult and pediatric studies involving COVID-19 vaccines. The investigator shares that she’s been conducting pediatric vaccine research for over 20 years now.
Ms. Martin emphasized that the Pittsburgh VTU participated in the heavily funded COVID-19 Prevention Network, which was the consolidation and rationalization, not to mention streamlining, of several NIH/NIAID trial site networks in a bid to take on the COVID-19 pandemic.
Now Professor Martin shares with the world that the Pittsburgh-based VTU will conduct the mRNA vaccine investigating the safe dosage regimens for children 6 to 11 years old. This will require fully risk-informed and consented volunteers that have not been coerced or enticed (consented by parents or guardians, performed under ethical review board oversight). TrialSite supports this kind of transparency.
The Clinical Trials
Offering full transparency, Professor Martin shares with the world that their VCU has conducted three (3) adult clinical trials involving both Moderna and Johnson and Johnson vaccines. Moreover, they are a trial site for Moderna’s KidCove study, enrolling cohorts from 6 to 11 years of age down to 6 to 24 months of age in this Phase 2 trial investigating the safety and appropriate dosing regimen. Now the University of Pittsburgh trial site proposes to progress to a Phase 3 pediatric trial commencing in mid-August involving children aged 6 to 11 in both American and Canada.
Information & Education
This top Pittsburgh academic medical investigator shares with the reader how the COVID-19 vaccines were developed, noting that Operation Warp Speed pumped at least $18 billion into the vaccine development. She shares a summary of the vaccine development lifecycle, an overview of the rigorous process, and opines that these amazing products ultimately “work by tricking the body’s immune system into making proteins, called antibodies, that fight disease—but without giving a person the disease.” Further describing the phases of clinical trials and the regulatory process, the historical COVID-19 vaccine development effort in America has led to three authorized vaccines under EUA by the FDA for people 18 years and up while the BNT162b2 (Pfizer-BioNTech) is now available for young people 12-years of age and up. TrialSite suggests that her comments include a broad overstatement, in that the relative importance of antibodies versus T effector cells in providing protective immunity against death and disease is not well understood. Her comments also overlook and simplify the pattern of known and emerging adverse events associated with these vaccines, which presumably could be a key focus of the proposed Phase 3 trial, along with the expected effective rate. In risk assessment for clinical trials, one typically must assume that the experimental product confers no benefit, and therefore the risks must be completely disclosed and those risks must be proportional to the potential significance of the intervention for the intended population.
The Rational for Children’s Trials
Professor Martin argues that while about two-third of all adults in American have received at least one COVID-19 vaccine dose by mid-July, 2021 with a circulating Delta and people throughout the country engaging in seemingly normal, pre-pandemic behavior school’s just around the corner. All of those kids, under 12 who aren’t yet eligible for access to the emergency use authorized investigational products, this combination of A) uncertainty about what kinds of transmissibility will occur at school and B) delta variant transmissibility and potency lead to a growing risk for yet another surge. Unstated is that the total number of COVID-attributed deaths (in USA, per CDC) in this age cohort to date is less than 380. This means that out of approximately 610,000 deaths for an extremely low rate of .0063%. According to a recent entry in Nature deaths asociated with children and COVID-19 are extremely low. https://www.nature.com/articles/d41586-021-01897-w
Importantly, she argues it’s the fact that “children have important differences in physiology and responses to vaccines from those of adults” and thus treating this cohort will be instrumental in finally ending the pandemic. That is, “children are not just little grownups; their bodies differ from adults in important ways.”
While true in general, it does not logically follow that vaccination of children is necessary to “finally end.. the pandemic. “ This statement relies on the hypothesis that the current vaccines are highly effective in preventing infection, viral replication, and transmissibility. To date, this hypothesis is not supported by available data, and in fact, the converse appears to be true. It also relies on the hypothesis that childhood (versus adult) transmission plays an important role in viral transmissibility to high-risk individuals (including the aged, obese, and other high-risk populations). Again, there are no compelling data to support this. In general, the belief that these vaccines can prevent viral infection, replication, and transmission is not well supported, as evidenced by the epidemiology of delta variant infection, disease, and death in previously vaccinated individuals (as well as WHO’s advice regarding mask use to prevent infection and spread of delta in all cohorts).
The University of Pittsburgh researcher goes on to emphasize some of the differences between adults and children, from the feature of a rapidly developing brain to the delta in immune systems, especially in babies and toddlers. Dr. Martin shares:
“For the first few months of life, infants’ immune systems still possess the antibodies they received from their mothers across the placenta during late pregnancy. This changes how newborns respond to pathogens and makes them less able to mount an immune response to some vaccines. Young children’s bodies gradually ramp up their own immune systems as their protection from mom wears off.” While a general truism, in the specific case of the current US SARS-CoV-2 vaccines available under EUA, these maternal-fetal kinetics are not known. Characterization of this time would seem a useful precursor to initiating infant studies and should be performed prior to initiating such studies.
Other factors include the change in dosage from a safe and effective adult vaccine to what’s tolerable safety in a child, as Martin emphasizes “there can be important differences in how their bodies respond to it.” TrialSite agrees, both in terms of immunogenicity and in terms of safety.
The Key Drivers for Clinical Trials
Martin declares for the key pivotal aforementioned reasons: “Vaccines often need to be tailored specifically for young children.” She offers up an example: made from polysaccharides—those sugar molecules that coat the outside of the pneumococcal bacteria—the Pneumococcal vaccine is designed to prevent pneumonia in adults yet this vaccine product doesn’t work in infants due to the fact that they’re not capable of eliciting an immune response to the molecules. Thus a modified vaccine for babies was designed and developed. And, of course, the dosage level in a safe and effective vaccine for adults may need to be modified considerably for children.
Safety becomes of utmost importance, proclaims Martin, and clinical trials, with myriad safety layers and stage gates, can catch safety signals that weren’t produced in adult studies. Of course, much like most trials, the fully informed consent of volunteers is key, which necessitates awareness, trust, and engagement with volunteer communities. In the case of pediatric clinical trials, the “volunteer” is participating in the trial and incurring adverse event risks based on information provided to a parent or guardian. It will be crucial to demonstrate that the parent or guardian is free of external pressures and has not been coerced or enticed in any way to “volunteer” the participation of the child. TrialSite presumes that the relevant ethics review board will ensure that this is the case. Careful monitoring and validation of the absence of coercion will be crucial. Given the current public messaging concerning SARS-Cov-2/COVID-19 vaccines, it will be challenging to identify and verify parents or guardians that have not been pressured in any way to “volunteer” a child for such studies.
First, TrialSite again commends Dr. Martin for the transparency, candor, and outreach to a broader world. She makes the case why pediatric vaccine research is needed to progress vaccines against SARS-CoV-2. Some key factors she didn’t raise include what’s the actual risk of COVID-19 to children, and the practicalities of obtaining non-coerced informed consent. At what numbers are children infected during the first waves across America? What’s the rate of hospitalization and death? We know that, generally, about 90% of total COVID-19 cases end up as asymptomatic to mild-to-moderate in nature. Of the 10% or so that experience disease progression, the vast majority are adults. Despite fear-driven talk in the mainstream media, as noted above, the incidence of death and disease from COVID-19 is extremely low among children. TrialSite supports Dr. Martin, and also supports a more transparent analysis into the true risks associated with COVID-19, particularly when it comes to children, ensuring a more holistic and balanced discussion—and a less emotionally charged, fear-driven hyperbole. Then the proper risk-benefit analysis is possible. TrialSite suggests studies are different than mass vaccination programs, and detailed proper informed consent is necessary for parental or guardian authorization. Of course, the University of Pittsburgh’s VTU is one of the top in the country, if not the world, and understands these important principles.
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