FDA Panel Gives Strong Backing to RSV Vaccine for Protecting Infants

An FDA panel on Thursday gave a strong endorsement for what could become the first maternal respiratory syncytial virus (RSV) vaccine approved for protecting infants against the annual scourge.

In a unanimous vote, all 14 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) said that the available data support the efficacy of Pfizer's RSV prefusion F protein vaccine when given to mothers in the second or third trimester of pregnancy for preventing RSV-related lower respiratory tract illness in infants, including severe cases.

And VRBPAC voted 10-4 in support of the vaccine's safety profile, with most of the concern centering around a numerical imbalance in premature births.

Overall, however, the potential of a first-of-its-kind vaccine to protect against severe RSV disease in infants was at the center of conversations.

"If the vaccine actually lives up to the data that we've seen today, I can guarantee that many infants and their parents will breathe easier in the coming years," said Jay Portnoy, MD, of Children's Mercy Hospital in Kansas City, Missouri, who voted in favor of the vaccine's efficacy and safety.

On the question of safety, "we're not worried about the mother having the adverse effects," he said. "We're worried about the child being born a little bit earlier."

"The problem is, if the child is born earlier, that also reduces the efficacy of the treatment because earlier birth means less antibody is transferred," Portnoy continued. "So this is a very complex thing, because the harm actually makes the benefit less -- so there's an interaction between the two."

During discussions leading up to the vote, Amanda Cohn, MD, of the CDC, called the phase III study data supporting the vaccine "incredibly impressive."

"Having done this vaccine trial in pregnant women in and of itself is a huge accomplishment," said Cohn, who also voted 'yes' on both questions. "I just feel like we should be raising the bar higher."

Multiple vaccine trials, including those for COVID-19, have included larger numbers of participants to assess safety, she noted.

"That doesn't mean that I don't think this vaccine is incredible valuable," said Cohn, but "enrolling more people in these clinical trials and having really strong post-licensure evaluations ... will be what we need to reassure the public and to give pregnant women the data that they need to make the decision to get vaccinated."

RSV leads to 58,000 to 80,000 hospitalizations among children younger than 5 years of age each year in the U.S., according to CDC data.

Data supporting Pfizer's vaccine, which has been given a proposed trade name of Abrysvo, derive in large part from a global phase III trial (MATISSE) involving nearly 7,000 infants, with mothers receiving the vaccine at a dose of 120 µg during the third trimester. (The maternal vaccine is identical to the company's candidate for older adults, which garnered the support of VRBPAC earlier this year and is currently under review with the FDA.)

The product showed a vaccine efficacy (VE) of 81.8% (99.5% CI 40.6-96.3) against medically attended severe RSV-associated lower respiratory tract illness in infants within 90 days of birth, and a VE of 69.4% (97.58% CI 44.3-84.1) at 180 days after birth, with cases occurring in 0.5% of the vaccine arm and 1.8% of the placebo arm.

According to safety data presented on Thursday, no meaningful differences between the vaccine and placebo groups were observed among the expectant mothers in terms of the overall rates of unsolicited adverse events (AEs) within a month of vaccination. Common AEs among vaccine recipients included fatigue (46% vs 44% in the placebo group), headache (31% vs 28%), muscle pain (27% vs 17%), and injection site pain (41% vs 10%), though most were mild to moderate, and resolved within a few days.

One maternal death in the vaccine group, due to postpartum hemorrhage and hypovolemic shock, was deemed unrelated to the product both by investigators and the FDA.

AEs and significant AEs in infants were reported at a similar frequency across the two study arms. However, for preterm births, there was a non-statistically significant imbalance observed: 5.7% of infants in the vaccine group were born premature versus 4.7% in the placebo group.

The issue of preterm births was a sticking point for committee members who voted 'no' on the safety question.

Henry Bernstein, DO, of Cohen Children's Medical Center in New Hyde Park, New York, said he was concerned that the imbalance might be a "clinically significant signal."

"Even though it's a small number in a study of several thousand," he added, there are millions of births per year, "and a small percentage of a large number is a large number."

Holly Janes, PhD, of the Fred Hutchinson Cancer Center in Seattle, said she took a literal interpretation of the question, "Are the available data adequate to support the safety of immunization?"

"I felt on balance that there was too much uncertainty," said Janes, given that the vaccine will be rolled out to a broader, more diverse population that "has a higher incidence of low birth weight to begin with."

At data cutoff, the sponsor identified five infant deaths in the vaccine group compared with 12 in the placebo group. One death from prematurity-related complications, involving an infant born extremely premature in the vaccine group 10 days after the mother's vaccination, could not be ruled out by FDA as being possibly related to the vaccine.

Pfizer noted during the meeting that pharmacovigilance studies will continue to monitor outcomes in both maternal and infant populations.

While FDA is not bound to follow the recommendations of its advisory committees, it typically does. The agency is expected to make a decision on the vaccine by August.

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