Positive correlation of Covid-19 vaccine data in adults with 12-16 year olds may be sufficient for EUA

GlobalData Healthcare 10 December 2020 (Last Updated December 10th, 2020 09:00)

Immunogenicity and safety Covid-19 vaccine results in adults are likely to correlate with vaccine receivers aged 12–16 years, experts said. And so, if positive, such results may be enough for the vaccine to secure an emergency use authorisation (EUA) from the FDA, they added.

Positive correlation of Covid-19 vaccine data in adults with 12-16 year olds may be sufficient for EUA

by Reynald Castaneda in London

  • Immune systems mature by age 12 allowing extrapolation from adult data
  • Event-driven, transmission trials more challenging to run in younger volunteers
  • Immunogenicity in adults necessary to put younger volunteer data in context

Immunogenicity and safety Covid-19 vaccine results in adults are likely to correlate with vaccine receivers ages 12–16 years, experts said. And so, if positive, such results may be enough for the vaccine to secure an emergency use authorisation (EUA) from the FDA, they added.

In fact, there is the possibility that Covid-19 vaccines may be more immunogenic in children owing to their heightened likelihood of exposure to circulating coronaviruses, some noted. While this theory is hard to test, there are other theories that still support vaccine immunogenicity in the younger age group, they added. With regards to side effects, although there are no immediate red flags, it is hard to gauge if children may react differently. Multisystem inflammatory syndrome and antibody-dependent enhancement (ADE) will need continued monitoring, some experts noted.

While Pfizer/BioNTech’s Phase II/III BNT162b2 trial (NCT04368728) is already recruiting volunteers as young as 12 years old, a BioNTech spokesperson said a separate pediatric trial will be run, as that would most likely be required by regulatory bodies such as the FDA. Moderna, which did not respond to a comment request, has yet to enroll volunteers to its stand-alone Phase II/III mRNA-1273 trial (NCT04649151) focused on 12–18 year olds. Another vaccine development frontrunner, the University of Oxford in collaboration with AstraZeneca, have yet to detail their pediatric testing plans. In October, Johnson & Johnson indicated plans to investigate its vaccine in youths between ages 12 and 18, but such an investigation has yet to commence.

Experts voiced support for Pfizer/BioNTech’s and Moderna’s choice of immunogenicity endpoints in younger vaccine receivers, noting this may on balance be enough for authorisation. Event-driven trials and studies investigating transmission are logistically challenging to perform, and more so in a mostly asymptomatic patient population such as those under 16. While there are still data gaps in adults, such as data connecting immunogenicity and protection, starting trials in younger people is worthwhile based on available positive results, they added.

Strong rationale to extrapolate adult data to ages 12–16

There will likely be some degree of correlation between immunogenicity and safety data between adults and younger vaccine receivers, said Gary Kobinger, PhD, head, Vector Design and Immunotherapy Special Pathogens, Medical Microbiology, University of Manitoba, Canada. In particular, this correspondence is true for those ages 12–16, as by those ages the immune system has matured, explained Dr Matthew Laurens, associate professor, Pediatrics and Medicine, University of Maryland School of Medicine, Baltimore.

In fact, increased sensitivity to vaccines that younger vaccine receivers may have compared with adults could be a positive, said Dr Steven Zeichner, professor, Department of Pediatrics and Microbiology, University of Virginia, Charlottesville. One hypothesis is that because younger people are at higher risk to circulating community coronaviruses, they would have already established some degree of protection against SARS-CoV-2, explained Dr Douglas Diekema, director, Treuman Katz Center for Pediatric Bioethics, and attending physician, Seattle Children’s Hospital, Washington. This could explain why severe disease is not common in younger people, Zeichner added.

While also noting the community coronavirus hypothesis, Zeichner stressed more data is needed. Lauren added that the possibility of requiring just one dose of a two-dose vaccine because of previous community coronavirus infections may be a stretch, as the key element with antibodies is their specificity. Moderna is measuring immunogenicity after both the first and second shot.

There are also other theories on why children are less impacted by severe Covid-19 disease, which could bolster vaccine efficacy in this subpopulation. One is that children don’t have enough ACE2 receptors, which are needed by SARS-CoV-2 to enter the human cell, Laurens said. Another theory is that immune system senescence, which is proportional with age, is the culprit for more severe cases in older adults, Diekema noted.

With regards to safety, two elements need to be investigated, one within two weeks of inoculation as well as longer-term risk at least six months, Diekema said. With limited mRNA vaccine experience, it is hard to gauge if younger people could have more severe manifestations of the milder side effects seen in adults, Laurens noted. However, it is encouraging that those aged 65 years and older do not have increased risk for side effects compared with younger adults, he said. Both Moderna and Pfizer/BioNTech vaccines are reported as well tolerated, though there are severe cases of headache and fatigue. According to the briefing document that support Pfizer’s pitch to the FDA for an EUA in ages over 16, reactogenicity was mostly mild to moderate and short-lived after dosing in participants ages 12 to 15 years old.

While there is early adverse event data, more information is needed due to the scale of Covid-19 vaccination, Kobinger said. ADE is yet to manifest with either mRNA vaccine, and data showing these vaccines protect against severe disease somewhat assuages ADE concerns, Laurens noted. Yet, this potential side effect still needs monitoring, he added.

There are some concerns about children reacting differently or the vaccines having a somewhat different safety profile, particularly because of the quite rare but sometimes serious complication called multisystem inflammatory syndrome, Zeichner said. This syndrome is observed in children one-two weeks after having asymptomatic Covid-19, said Dr Yvonne Maldonado, professor, infectious diseases in pediatrics and health research and policy, Stanford University, California. Symptoms include rash and fever, which is notably different from Covid-19, but blood tests show the patient has SARS-CoV-2 antibodies, and the patient is in the same household as a Covid-19

positive adult, she noted. However, this syndrome’s pathogenesis is still unclear and so is its potential link to vaccines, Zeichner and Maldonado noted.

Trial design investigating immunogenicity for authorisation logical

With no safety red flags, immunogenicity data in vaccine receivers ages 12–16 may be enough to support vaccine efficacy and thus authorization filings, Zeichner said. Event-driven endpoints such as those used in adult trials or transmission risk reduction are challenging to measure in this subpopulation, he explained.

Moderna’s stand-alone trial in 12–18 year olds has coprimary efficacy endpoints of acceptable threshold for antibody levels, and comparison of the geometric means of the serum neutralising antibody level in this study and the 30,000-volunteer Phase III trial (NCT04470427) in adults. In Pfizer/BioNTech trial’s Phase III portion, the primary endpoint relevant to the 12–15 year old subgroup is investigating adverse events, but there is a secondary endpoint investigating geometric mean response of SARS-CoV-2 neutralising titres in the 12–15 and 16–25 year old subgroups.

Since children are mostly asymptomatic, an event-driven trial would need even more volunteers than the Phase III adult trials to find a difference between the vaccine and placebo arms, Zeichner and Diekema explained. The stand-alone Moderna trial in youths is recruiting 3,000 volunteers, whereas 2,000 participants in the almost 44,000-subject Phase III Pfizer/BioNTech trial belong to the 12–15 year old stratum. Laurens said these numbers are likely large enough to identify what immunogenicity levels should be expected.

Pediatric vaccine trial enrollment is inherently challenging, Zeichner said. Among the hurdles, the parent or guardian would need to take time off as well as the child from school for both to travel to the trial site, he added.

As for investigating transmission risk, the endpoint would not only cover the vaccine receiver but also family members, making it even more logistically tough to perform, Zeichner said. In fact, frontrunner vaccine developers have no data in preventing transmission, as this is already challenging in adults since it requires frequent testing of all volunteers to capture asymptomatic infections, added Nikolai Petrovsky, PhD, professor, College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Reasonable to start trials in younger people even with gaps in adult data

However, the correlation between immunogenicity and protection is yet to be established, even in adults, said Dr Shabir Madhi, professor of vaccinology, Wits University, Johannesburg, South Africa. Without such adult data, it would be hard to say if immunogenicity data in trials with younger receivers would lead to protection, Laurens said.

To establish the appropriate benchmarks for neutralising antibody and cellular-driven immunogenicity data, at least six-month immunogenicity and protection data in adults is needed, said Petrovsky. There could be different immunogenicity levels right after injection and six months down the line, he noted. Experts underscored that current data only features protection based on events counted seven days after Pfizer/BioNTech’s second dose and 14 days following Moderna’s.

Based on trial timelines and protocols divulged by Moderna and Pfizer/BioNTech, six-month adult data could become available in 2Q21. News reports show the Phase III Pfizer/BioNTech trial started inoculating volunteers as young as 12 in late October, but the BioNTech spokesperson said it cannot tell exactly when data in this younger cohort would be available. The Pfizer/BioNTech immunogenicity endpoint will be measured a month after the second dose, while Moderna will assess results 57 days after dose 1 and 28 days after dose 2.

While there is no correlative data in adults yet, starting the trials in younger vaccine receivers setting is logical as there is positive protection data in adults, Laurens said. Also, waiting too long may lead to waning interest in running trials in younger volunteers, Diekema noted. In fact, in the highly likely possibility that there is a Covid-19 vaccine shortage for adults in the next six to nine months, protecting mostly asymptomatic children may be less of a priority, added Madhi, the clinical trial lead of Novavax’s Phase IIb NVX-CoV2373 trial (NCT04533399) for Covid-19 in South Africa.

As for vaccine investigations in children younger than 12 years old, those 5–10 years old are less likely to spread the virus versus the 14–16 year old group, Diekema said. Various epidemiological studies show infections do not surge when schools and day-care centers are reopened, but older children are more likely to pass it on to others. There is still value, though, in vaccine investigations in younger children, as they also develop severe disease, Zeichner said.

Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.