RSV Vaccine Research in Infants May Proceed With Caution

Research and development of a respiratory syncytial virus (RSV) vaccine for infants should continue, but with awareness of documented safety concerns, according to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the US Food and Drug Administration (FDA). 

The VRBPAC met on December 12 to review and discuss safety findings for mRNA-1365 and mRNA-1365, which have been in development for infant immunization against RSV.

No vaccines for RSV are currently approved in the United States for individuals aged ≤ 17 years, but RSV disease is associated with approximately 100-300 deaths, 58,000-80,000 hospitalizations, approximately 520,000 emergency department visits, and approximately 2,100,000 outpatient visits each year, according to the FDA briefing document for the meeting. 

The monoclonal antibody nirsevimab, though not a vaccine, is approved by the FDA for the prevention of RSV lower respiratory tract disease in newborns and infants born during or entering their first RSV season and in children aged ≤ 24 months who are at risk for severe RSV disease in their second RSV season, according to the document. 

Safety and immunogenicity data from ongoing studies in adults and RSV-seropositive children aged 12 months through 59 months supported vaccine studies in younger children. 

However, in July 2024, manufacturer Moderna halted its study because of concerns about severe side effects in a subset of infants aged 5-8 months. In this population, 12.5% of infants who received an mRNA vaccine developed clinically significant/severe RSV compared with 5% of placebo patients. 

Matthew Snape, MBBS, MD, a pediatrician and vice-president of pediatric and maternal vaccines for Moderna, presented clinical data from the study. 

As of October 2024, a total of five cases of severe RSV had been reported in the subset of infants aged 5-7 months vs one case in the placebo group. 

Although the company has no current plan to continue an RSV vaccine program in children aged ≤ 2 years, “safety and immunogenicity surveillance will continue in this study,” Snape said in his presentation. The company’s understanding of the clinical and immunological picture will evolve with the collection of more data, he said. 

In addition, researchers observed some blockage in RSV vaccine effectiveness for young children who had received nirsevimab at least 6 months prior to vaccination.

The mechanism behind increased disease severity in vaccinated children remains unclear, said Pedro A. Piedra, MD, professor of molecular virology and microbiology, and pediatrics at Baylor College of Medicine, Houston, Texas, in a presentation to the committee.

In previous research, vaccine-enhanced disease has not been observed with a live RSV vaccine administered subcutaneously or intranasally, noted Piedra, who was not involved in the current study. Recent research suggests that an imbalance in T-cell priming may be a factor in enhanced disease, he said.

No vote was taken, but the committee agreed that pediatric RSV vaccine research should continue. The consensus among the committee members was that more data are needed. Nirsevimab may have blunted the immune response, but the numbers are too small to draw significant conclusions, and the vaccine should be studied further, they agreed.

“We need to protect these infants because the morbidity [associated with RSV] is huge and the possible benefit is huge, so it is time to move forward,” said Jay M. Portnoy, MD, professor of pediatrics at the University of Missouri, Kansas City, during the committee discussion.

Clinical Perspective

Previous research shows that the majority of RSV infections in infants occur during the first 6 months of life, said David J. Cennimo, MD, associate professor of medicine & pediatrics in the Division of Infectious Disease at Rutgers New Jersey Medical School, Newark, New Jersey, in an interview.

“RSV infection can in infancy can result in significant morbidity including hospitalization for severe respiratory illness,” said Cennimo, who is not involved in the VRBPAC. Although clinicians have some ability to intervene through vaccinating pregnant individuals, a successful infant vaccine “would further expand the modes of protection and help ameliorate the risk of infection and disease burden,” he said. 

When asked about possible drivers of the more severe reactions observed in young children in the Moderna study, Cennimo emphasized that the Data and Safety Monitoring Board was diligent in its review and the study was stopped according to protocol.

“The cases were higher in the vaccinated groups compared to placebo, but these are small numbers,” Cennimo said. “RSV infection is more severe at younger ages, so we could expect more hospitalizations when the study moved to a younger cohort, but not necessarily the discrepancy between vaccine and placebo,” he said. “It is important to note that the hospitalized children were young and RSV-naïve. Looking at the older children’s data, those who were RSV-naïve also had more symptomatic infection, although not requiring hospitalization,” he added.

Older and different vaccine studies have shown a concern for enhanced respiratory disease (ERD) when RSV-naïve and vaccinated infants become more severely ill than those who were not vaccinated, Cennimo told Medscape Medical News. “This may be due to a modification of the immune response and was monitored in this study, and we will need to see further evaluation of the data, which is the reason for the pause,” he said.

Once the data are known, and if they are strong enough to merit vaccine approval, a public education campaign will be needed to explain why RSV is a dangerous infection that should be targeted for vaccination, Cennimo said. “The recent RSV vaccine approval for higher risk adults and in pregnancy should help, because the topic is already known to the public,” he noted.

As for additional research, understanding whether ERD is happening and why is the first order of business, Cennimo said. “In my mind, if the vaccine is to be most effective, it should be given ASAP after birth. The research to show safety and efficacy to that young age will be needed,” he added. 

The vaccine research was funded by Moderna. Piedra disclosed receiving grants from GlaxoSmithKline, Icosavax, and Merck and serving as a consultant for Merck, Moderna, Pfizer, and Sanofi. Cennimo had no financial conflicts to disclose.