FDA committee asks for more data on RSV vaccine safety in infants
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Key takeaways:
- The FDA halted enrollment of young children in RSV vaccine trials after five infants in one study developed severe RSV infections.
- An FDA panel asked for additional data to better understand what happened.
An FDA advisory committee said it wants to see more data to understand the implications of what the FDA called an “imbalance” in cases of severe respiratory syncytial virus among infants participating in an early-stage RSV vaccine trial.
In a briefing document published ahead of Thursday’s meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC), the FDA announced that it was putting a hold on enrolling children aged younger than 2 years in any clinical studies of RSV vaccines being developed in the United States.
The pause was in response to five cases of severe RSV that occurred among infants aged 5 to 8 months who received one of Moderna’s messenger RNA vaccines for RSV during a phase 1 trial.
According to the FDA, Moderna notified the agency in July that it had paused the phase 1 trial of the two vaccines, mRNA-1345 and mRNA-1365, in children aged 5 to less than 24 months after identifying a potential safety signal — there were more cases of severe lower respiratory tract infection (LRTI) among infants in the vaccine arms compared with the placebo arm. The study also showed that participants who received the monoclonal antibody (mAb) nirsevimab at least 6 months before vaccination had blunted immune responses to the vaccines, according to the FDA document.
The cases of severe LRTI raised concern about vaccine-associated enhanced respiratory disease (VAERD), the FDA said. VAERD was implicated in the deaths of two toddlers who received formalin-inactivated RSV vaccines in the 1960s, the FDA noted. The deaths set RSV vaccine research back decades.
The FDA asked the VRBPAC to weigh in on pediatric RSV vaccine trial safety and whether the agency will allow vaccine trials for infants to continue in the future.
“I think we are confronted by a very complicated situation,” VRBPAC member Arnold S. Monto, MD, professor emeritus of public health and epidemiology at the University of Michigan School of Public Health, said during Thursday’s meeting.
Monto said, “it is very clear there is a safety signal and the trials cannot continue, at least in the youngest age group.”
He and other members of the committee did not suggest that all RSV vaccine development for toddlers be halted, but rather that individual vaccine platforms — including mRNA — should be evaluated separately for potential safety issues.
RSV disease is one of the leading causes of hospitalization among young children in the U.S. Although there is a maternal RSV vaccine that can protect infants for up to 6 months after birth — and two mAbs, nirsevimab and palivizumab, that can be given directly to infants — there are no vaccines that can be given directly to people aged younger than 18 years.
Moderna’s mRNA-1345 vaccine is one of several RSV vaccines approved for adults in the U.S. The CDC universally recommends RSV vaccination for everyone aged 75 years or older, and adults aged 60 to 74 years with risk factors for severe disease.
In 2017, the VRBPAC established risk mitigation guidelines to begin testing RSV vaccine candidates among infants and young children, which included safety monitoring and study stopping criteria, according to the FDA’s briefing document. There are an estimated 42 RSV vaccine candidates in development in the U.S., of which 26 have plans for pediatric testing, according to the document.
A data safety and monitoring board did not identify any safety concerns among children aged 8 to 24 months who received one of Moderna’s vaccines in an earlier part of the trial. The safety review was required before enrolling younger infants, the FDA noted.
In the second part of the trial, five infants who received 15 g doses of the vaccines — two out of 20 (10%) who got mRNA-1345 and three out of 20 (15%) who received mRNA-1365 — developed severe or very severe RSV-associated LRTIs compared with one infant out of 20 (5%) in the 15 g placebo group. (Infants in other groups received 30 g doses of the vaccines or placebo. There was one case of severe LRTI in the 30 infants who received a 30 g dose of mRNA-1365, according to the FDA.)
Moderna announced in September that the phase 1 trial of mRNA-1345 for RSV-naive infants would be discontinued based on emerging clinical data.
References:
- FDA. Considerations for respiratory syncytial virus (RSV) vaccine safety in pediatric populations. https://www.fda.gov/media/184301/download. Published Dec. 10, 2024.
- Moderna. Moderna R&D Day highlights progress and strategic priorities. https://investors.modernatx.com/news/news-details/2024/Moderna-RD-Day-Highlights-Progress-and-Strategic-Priorities/default.aspx. Published Sept. 12, 2024. Accessed Dec. 11, 2024.
Perspective
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The VRBPAC meeting focused on pediatric RSV vaccines that should be watched closely as an example of the rigorous process for vaccine approvals and safety monitoring.
The committee discussed RSV vaccine safety in pediatric populations with scrutiny of the current mRNA vaccines in clinical trials. Vaccine design now integrates key scientific principles from VAERD research. Study requirements for any pediatric RSV vaccine included risk mitigation and management strategies, such as assessing immune responses in age de-escalation study designs, stringent eligibility criteria and study-pausing rules.
Two mRNA RSV vaccines progressed to clinical studies in young children, adhering to study requirements. During the studies, an imbalance in severe RSV disease was identified in the vaccine groups compared with placebo, including children who had received one or two doses of a proposed three-dose vaccine series. The studies are currently paused while safety data are under review.
The trials also studied the impact of receipt of the monoclonal antibody nirsevimab during infancy. Children who had received nirsevimab had a lower measured antibody response to vaccine compared with those who had not received nirsevimab. These data are still preliminary because they did not reflect a full vaccine series. As infant and toddler RSV vaccines are studied, it is critical to understand the implications of sequential administration of antibody followed by vaccine. These data will influence guidance on when vaccines should be administered in childhood and which children will benefit from vaccination.
In convening VRBPAC and asking for guidance, the FDA is demonstrating its priorities in vaccine development: safety and efficacy. The committee will be able to review data and provide additional recommendations on how to make RSV vaccines as safe as possible, as well as how to consider administration of vaccine after receipt of monoclonal antibody. Because there are more than 10 other candidate vaccines for the pediatric population, lessons learned from these trials are certain to inform ongoing RSV vaccine research.
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