After a small clinical trial for a respiratory syncytial virus (RSV) vaccine was paused because five infants developed severe illness, members of a Food and Drug Administration (FDA) committee said more data are needed to determine what factors contributed to the results.
On Thursday, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) reviewed data provided by Moderna on its pediatric RSV vaccine trials, which included children ages 5 months to 23 months. A phase 1 trial that included 80 infants ages 5 months to 7 months was paused in July after five infants who received vaccine developed severe to very severe RSV lower respiratory tract infections. One child in the placebo group also developed RSV.
“This is obviously an issue of efficacy, not safety. Let’s keep our eyes open, continue to do studies, gather more data and then I think we’ll be able to speak on this in a more informed manner,” said VRBPAC member Paul A. Offit, M.D., FAAP, director of the Vaccine Education Center and professor of pediatrics at Children’s Hospital of Philadelphia.
The trial began with children ages 8-23 months; 85 received three doses of either RSV vaccine or RSV/human metapneumovirus (hMPV) vaccine. With no safety concerns identified during the 2023-’24 RSV season and no severe/hospitalized RSV cases up to March 2024, the trial was de-escalated to include children ages 5-7 months.
Participants included 80 infants from Panama and one from the United Kingdom who were born at term at the end of the 2023 RSV season and enrolled before the 2024 RSV season. Twenty infants received two doses of an RSV vaccine, 20 received two doses of a combined RSV/hMPV vaccine and 20 a placebo. Remaining participants received one dose of RSV vaccine, the combination vaccine or placebo.
Two infants who received the RSV vaccine and three infants who received the combined RSV/hMPV vaccine were later hospitalized. One hospitalized infant who received the RSV/hMPV vaccine required mechanical ventilation for 48 hours.
On July 17, Moderna stopped vaccination and trial enrollment and notified the FDA and the Data and Safety Monitoring Board.
Trial participants are still being monitored, and Moderna representatives said additional data will be gathered. There are no plans, however, to restart the trial in children younger than 2 years.
"We haven't achieved enough understanding of the exact immune response of study participants, and in particular, I don't think we've learned enough from those who experienced the severe adverse events, and some more attention to be investigating what happens to them in real time, I think, could be incorporated in future clinical trials as well,” said Michael R. Nelson, M.D., Ph.D., chief of the Asthma, Allergy and Immunology Division at the University of Virginia School of Medicine.
VRBPAC members said the additional data and further investigation of the trial’s small sample size should be reviewed given the participants did not receive all three planned doses of vaccine prior to the trial being stopped and all hospitalized children were living in the same country.
RSV causes about 50,000 to 80,000 hospitalizations and 100 to 300 deaths per year in children under 5 years, according to the Centers for Disease Control and Prevention.
Some VRBPAC members remain hopeful an RSV vaccine will be developed for infants, and touted the effectiveness of the monoclonal antibody nirsevimab, which was approved in 2023 for infants younger than 8 months born during or entering their first RSV season and high-risk babies entering their second RSV season.
“I think RSV vaccines are going to be extremely beneficial once we understand well the issue of safety and risk in younger infants,” said Pedro A. Piedra, M.D., FAAP, director of the Respiratory Virus Diagnostic Laboratory at Baylor College of Medicine. “Right now, we have nirsevimab, which is an outstanding monoclonal antibody that is providing high levels of protection against severe disease. If history has taught us well, when you use a monoclonal antibody in such a universal format, you need to expect mutations will occur. I don’t think we can rely on monoclonal antibodies forever. We need to think downstream that vaccines will provide broader levels of responses that may be applicable and hopefully safe in the young population.”
VRBPAC members praised the safety monitoring system.
“The system worked, the safety signal was reached, the proper pause was put in place,” Dr. Nelson said.
