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FDA advisors said that more data are needed to fully understand if there are broader safety concerns related to use of respiratory syncytial virus (RSV) vaccines in young children after an mRNA vaccine trial was halted earlier this year.

Moderna, which had been developing an mRNA vaccine candidate for RSV in infants and toddlers, notified the FDA in July that it had paused a phase I trial due to an imbalance of severe/hospitalized RSV cases in RSV-naive infants ages 5 to 7 months who had received the vaccine versus placebo, raising concern for possible vaccine-associated enhanced respiratory disease (VAERD), according to .

"I think we are confronted by a very complicated situation," said Arnold Monto, MD, of the University of Michigan in Ann Arbor, during the Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting on Thursday.

"We know that passive acquisition of antibody is protective -- highly protective -- and does not produce severe disease in any way," he added. "We now have a platform which should be only inducing antibody formation, which I think it's the right antibody, [but] I think it's very clear that there is a safety signal, and the trials cannot continue, at least in the youngest age group."

In Moderna's trial, there were five cases -- representing 12.5% of participants -- of clinically significant severe or very severe RSV identified in the vaccine groups (all of whom had received one or two doses of a three-dose schedule), compared to one case -- representing 5% of participants -- in the placebo group.

There is no subsequent enrollment or dosing planned; however, surveillance is continuing, according to Moderna. Notably, there is no current plan to continue the company's RSV vaccine program in children younger than 2 years.

"I don't see this, based on our understanding and our ability to develop any kind of new markers for severity, that we can stop or should stop development of potential vaccines using other platforms, because we really don't understand the relationship of the platform to the severity, nor different antigenic confirmations," Monto noted.

"This needs to be done on a vaccine platform-by-vaccine platform basis," he added, and by continuing "with the very careful age de-escalation and previous infection approach, but ... with great caution, and to make sure that if there is a signal, it is caught and appropriately handled."

Karen Kotloff, MD, of the University of Maryland in Baltimore, said that she believes "the safest path is knowing that maternal antibody and monoclonal antibody [through the maternal RSV vaccine and monoclonal antibody nirsevimab (Beyfortus) for infants] are protective."

"The approach that we heard of giving that to protect kids in the first year, trying to get cheaper antibodies made, and then use vaccination for kids after the first year of life, to me, seems the safest way forward to avoid the safety signals that we don't really understand," Kotloff added.

Guest speaker Pedro Piedra, MD, of Baylor College of Medicine in Houston, noted that "RSV vaccines are going to be extremely beneficial once we understand well the issue of safety and risk in younger infants."

"Right now, we have nirsevimab, which is an outstanding monoclonal antibody that is providing high levels of protection against severe disease, but I want to call your attention that it's a monoclonal antibody [and] when you use a monoclonal antibody in such a universal format, you need to expect that mutations will occur and that you may develop either resistant virus or community-resistant-emergent virus that will be resistant to that monoclonal antibody," he said. "And so to rely on the monoclonal antibody to provide protection during the first year of life would raise that caveat that infants are an excellent vector, in a way that, if mutations are to arise, it would be in infants or immunocompromised hosts."

"I want to bring that to the attention because I don't think we can only rely on monoclonal antibodies forever ... and that we need to think downstream, that vaccines will provide broader levels of responses that may be applicable and hopefully safe in the young population," Piedra added.

For Thursday's meeting, VRBPAC was tasked with discussing two topics. In addition to vaccine safety in pediatric populations, including whether currently available evidence indicates a potential safety concern with RSV vaccine candidates in infants and toddlers, the committee also focused on sequential administration of RSV monoclonal antibodies followed by RSV vaccines, and whether currently available evidence suggests potential interactions that may affect active immunization.

Along with the safety signal in Moderna's trial, immune responses to vaccination in participants who had previously received the monoclonal antibody nirsevimab appeared blunted when compared with responses in participants who had not received nirsevimab.

"Nirsevimab may have blunted the immune response, but really in a very small number of patients, and there really are not enough data, as others have said, to draw significant conclusions about RSV vaccination of infants who receive nirsevimab," Henry Bernstein, DO, of the Zucker School of Medicine at Hofstra/Northwell and Cohen Children's Medical Center in New Hyde Park, New York, said. "I think that and agree that this should be studied by vaccine platform and also the number of doses received by the children."

More than two dozen RSV vaccines are in clinical development for children, and there are several vaccines -- including Moderna's mRNA vaccine -- approved for use in older adults, adults with comorbidities, and pregnant women to confer protection to infants at birth.

The development of RSV vaccines for children has been challenging. In the 1960s, pediatric RSV vaccine development was previously stalled due to VAERD.

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