Two days after the FDA revealed that it had halted enrollment in trials of respiratory syncytial virus (RSV) vaccines that involve young children, experts from an FDA advisory panel expressed their frustration at being unable to draw conclusions about the safety and effectiveness of the shots and said more testing is needed.
“This all seems like an incredible conundrum with lots of unanswered questions remaining—lots to still learn,” Henry Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell, said Thursday.
The meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) came after the agency said in a briefing document (PDF) Tuesday that it had halted pediatric RSV vaccine trials in the United States that were enrolling children under 2, as well as those that were enrolling children ages 2 through 5 who are RSV-naïve.
The halt was triggered by an “imbalance,” the FDA said, in cases of severe lower respiratory tract infections (LRTIs) in children in a phase 1 trial of two Moderna RSV vaccines. One of the shots, mRNA-1345, was approved by the FDA in May of this year and is dubbed mRESVIA.
In that phase 1 trial—which was conducted in Panama and included infants as young as 5 months—five children developed severe LRTIs, with four going to the hospital. The trial had been opened up to younger children after there were no safety issues involving kids ages 8 to 23 months who had received one of the vaccines.
There is some concern that the shots can cause or worsen the disease in the younger age group. No vote was taken during Thursday’s meeting to recommend regulatory action. The goal of the VRBPAC discussion was to inform future testing.
After hearing presentations from Moderna on its trial findings and from the FDA, the advisory committee members generally agreed that RSV shots for infants should be examined on a “vaccine platform-by-vaccine platform basis,” according to Arnold Monto, M.D., an epidemiology professor at the University of Michigan.
Other RSV immunizations cleared by the FDA and on the market for infants include Sanofi and AstraZeneca’s preventative antibody Beyfortus and Pfizer’s vaccine Abrysvo, which is approved for use by women in weeks 32 through 36 of their pregnancies. Both have already gone through an RSV season and there have not been concerns raised about their safety.
In a September pipeline update (PDF), Moderna revealed that its RSV program for seronegative infants younger than 2 had been discontinued. At the time, Moderna said it "does not expect program to advance beyond the ongoing Phase 1 based on emerging clinical data."
Thursday, members of the committee were asked to weigh in on whether additional safeguards should be installed when testing vaccine candidates on infants. In the case of Moderna, the company became aware of at least two trial participants testing positive for RSV on July 17 of this year and two days later notified the FDA, which installed the clinical hold.
“The system worked. The safety signal was reached. A proper pause was put in place,” Michael Nelson, M.D., Ph.D., the chief of the asthma, allergy and immunology division at the University of Virginia’s School of Medicine, said during the meeting.
“I’m not totally convinced that the finding of the safety signal means that the safety signal is real,” Nelson added. “In particular, I don’t think we’ve learned enough from those who experience the severe adverse events. More attention to investigating what happens to them in real time, I think could be incorporated into future clinical trials.”
Monto, for one, said that he believes the safety signal is legitimate and it deserves more study. The answers, he said, will not emerge if companies and regulators “shut down programs.”
“Either we go forward very carefully with clinical trials where we may be able to get an answer or we continue to observe natural infection in which over 50 odd years we haven’t really been able to identify anything that would helps us in answering the questions that are currently being raised.”