A briefing document from the Food and Drug Administration (FDA) says that enrollment for all clinical studies of vaccines for respiratory syncytial virus (RSV) in infants is on hold over concerns about potential safety findings from a clinical trial involving two vaccine candidates.
The document, released ahead of a meeting tomorrow of the FDA's Vaccine and Related Biologic Products Advisory Committee (VRBPAC), revealed that a phase 1 trial evaluating the safety, tolerability, and immunogenicity of two Moderna RSV vaccine candidates (mRNA-1365 and mRNA-1345) in infants aged 5 months to 8 months was paused in July after five cases of severe to very severe lower RSV respiratory tract infection (LRTI) were reported in infants who received a 15-microgram (μg) dose of mRNA-1345 (3 cases) or a 15-μg dose of mRNA-1365 (2 cases), compared with 1 case in the placebo group. Five of the 6 infants required hospitalization, with 1 needing mechanical ventilation.
"The observed imbalance in severe/very severe cases of RSV LRTI in the mRNA-1345 and mRNA-1365 vaccine development program among 5-month to <8-month-old recipients of mRNA-1345 (15 μg) and mRNA-1365 (15 μg) has uncertain implications for the ongoing and future pediatric development of other non-live attenuated RSV vaccines," the FDA said.
Moderna was made aware of the safety signal and paused further enrollment on July 17 and notified the FDA of the study-wide pause on July 19, according to the document. The FDA then put a clinical hold on the trial. On September 12, Moderna announced that the RSV program for seronegative children -- those without detectable RSV antibodies -- younger than 2 years old was listed under discontinued programs.
The trial also found that vaccine immune responses in infants who received mRNA-1345 and had previously been exposed to the monoclonal antibody nirsevimab were blunted compared with those who had not received nirsevimab, suggesting a possible interaction.
Marketed under the brand name mRESVIA, mRNA-1345 was approved by the FDA in May for use in adults aged 60 and older. It's one of three RSV vaccines that have been licensed for adults and pregnant women within the past 2 years. Moderna is conducting a phase 1 trial of mRNA-1365 as combination vaccine for RSV and human metapneumovirus.
The observed imbalance in severe/very severe cases of RSV LRTI in the mRNA-1345 and mRNA-1365 vaccine development program among 5-month to <8-month-old recipients of mRNA-1345 (15 μg) and mRNA-1365 (15 μg) has uncertain implications for the ongoing and future pediatric development of other non-live attenuated RSV vaccines.
The need for a pediatric vaccine for RSV, which is the leading cause of infant hospitalization in the United States, is clear. But the briefing document notes that this isn't the first time pediatric RSV vaccine development has been stalled over safety concerns. In the 1960s, administration of a formalin-inactivated RSV vaccine resulted in two infant deaths from vaccine-associated enhanced respiratory disease (VAERD). Since then, pediatric studies of RSV vaccines have proceeded cautiously owing to concerns over the risk of VAERD.
The FDA says it's convening VRBPAC to discuss considerations for RSV vaccine safety in children. While the committee will not vote tomorrow, it will address the interpretation of the safety data from the mRNA-1345 and mRNA-1365 pediatric clinical development program and the implications of the findings for future development of pediatric non-live attenuated RSV vaccines, as well as interactions between RSV monoclonal antibodies and RSV vaccines.