A maternal respiratory syncytial virus (RSV) vaccine candidate prevents infections in infants and comes with "generally favorable" safety data, said FDA staff in briefing documents released ahead of an advisory committee meeting this week, but the reviewers "noted potential uncertainty based on the numerical imbalance in premature deliveries."
On Thursday, members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) will weigh in on whether the available data support the safety and 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.
The FDA recently approved the first-ever RSV vaccine for older adults, but no vaccine exists for protecting infants, a particularly vulnerable group. A prior effort at developing a formalin-inactivated RSV vaccine in the late 1960s failed when vaccinated infants developed enhanced respiratory disease following their first infection.
RSV infections make up the bulk of lower respiratory tract infections in infants, with hospitalization rates ranging from 1% to 3%, and peaking in early infancy, according to the briefing documents. Mortality rates for hospitalized infants range from 1% to 3% as well.
"Risk factors for severe disease include prematurity, underlying chronic lung or heart disease, and immunodeficiency; however, healthy infants 0 to 6 months of age are also at significant risk for morbidity and mortality," wrote agency staff.
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 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 placebo-controlled trial 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 by this point.
However, the study's second primary endpoint -- any medically attended RSV-associated lower respiratory tract illness -- did not meet statistical criteria for success through 90 days, with cases occurring in 0.7% and 1.6% of the infants in the two groups, respectively. VE against RSV-associated hospitalization -- a secondary endpoint -- was 56.8% (99.17% CI 10.1-80.7) within 180 days of birth.
As for overall safety, FDA staff said there were no meaningful differences between the vaccine and placebo groups in the overall rates of unsolicited adverse events (AEs) within 1 month after vaccination. AEs and significant adverse events in infants were reported at a similar frequency across the two groups.
But for preterm births, "a numerical imbalance, though not statistically significant, was observed," FDA staff wrote, with 5.7% of infants in the vaccine group being born premature compared with 4.7% in the placebo group.
At data cutoff, five infant deaths were reported in the vaccine group compared with twelve in the placebo group.
"FDA agrees with the investigator's conclusions for 4 out of 5 of the infant deaths," wrote agency reviewers. "However, for 1 case of extreme prematurity in an infant born to an 18-year-old mother at 10 days after vaccination who died from prematurity-related complications, FDA is unable to exclude the possibility of the extreme prematurity and subsequent death being related to receipt of the investigational product."
For the expectant mothers, the most commonly reported solicited adverse reactions among vaccine recipients were fatigue (46% vs 44% in the placebo group), headache (31% vs 28%), muscle pain (27% vs 17%), and injection site pain (41% vs 10%). Agency reviewers noted that these were mostly mild and moderate, and resolved within 3 to 4 days after vaccination.
There was one maternal death in the vaccine group due to postpartum hemorrhage and hypovolemic shock. "FDA agreed with the investigator's assessment as not related to vaccine administration," the briefing document noted.
While FDA is not bound to follow the recommendations of its advisory committees, it typically does.