Maternal RSV Vaccination, Nirsevimab in Infants, and Sequential Administration

Key Takeaways

• A prospective randomized phase 4 comparison examined maternal vaccination, infant nirsevimab, and sequential administration in enrolled mother-infant pairs.
• No related serious adverse events were seen in mothers or infants, and infant nirsevimab reactogenicity was described as mild to moderate.
• Maternal vaccination was associated with high neutralizing antibody levels, cord-to-maternal transfer above 1.3, and sustained infant titers, with modest waning after maternal vaccination and increases after infant dosing.

In a randomized phase 4 trial at eight U.S. sites, maternal RSVpreF vaccination was associated with 17.35-fold and 23.98-fold increases in maternal RSV-A and RSV-B neutralizing antibodies at delivery. Among 181 enrolled mothers, with 180 mothers and 179 infants included in the safety population, no related serious adverse events occurred in mothers or infants during early follow-up.

The prospective, randomized, open-label phase 4 study enrolled mother-infant pairs from uncomplicated singleton pregnancies at 32 0/7 to 36 6/7 weeks’ gestation at eight U.S. sites. Pairs were assigned 1:1:1:1 to maternal vaccine alone, maternal vaccine plus infant nirsevimab at birth, maternal vaccine plus infant nirsevimab at 3 months, or infant nirsevimab alone at birth. In the Pediatrics interim analysis, follow-up ran from September 19, 2024, to May 15, 2025, with infant follow-up through 4 months. Birth-dose groups received nirsevimab within 7 days of delivery, whereas the delayed group received it on day 91 ±7 days. In maternal-vaccine groups, 129 of 135 infants were born at least 14 days after maternal vaccination.

The safety population included 180 mothers and 179 infants, and no related serious adverse events occurred in either group. Among infants, there were no related unsolicited grade 3 or higher adverse events and no related medically attended adverse events. After nirsevimab, local reactions occurred in 17% of infants, mainly pain or tenderness in 13% and erythema in 5%. Systemic reactions occurred in 60%, most often sleepiness or fatigue in 43% and irritability or crying in 43%. Symptoms peaked on days 1 to 2, with local events resolved by day 6 and moderate systemic symptoms by day 7. Overall, reactogenicity was mild to moderate.

Maternal RSVpreF vaccination raised maternal neutralizing titers at delivery by 17.35-fold for RSV-A and 23.98-fold for RSV-B. Delivery titers reached 8547.0 IU/mL for RSV-A and 12 185.6 IU/mL for RSV-B, and they remained durable through 3 months. Cord-to-maternal transfer ratios stayed above 1.3 and were similar across groups, measuring 1.36 and 1.37 in vaccinated mothers and 1.45 and 1.48 in unvaccinated mothers. These findings showed marked maternal boosting at delivery and cord-to-maternal transfer ratios above 1.3 across groups.

Infants in maternal-vaccine groups had higher antibodies at birth than those assigned to infant nirsevimab alone before dosing. In group 1B, delivery titers were 11 597.6 IU/mL for RSV-A and 17 507.7 IU/mL for RSV-B, versus 1109.0 and 1116.1 IU/mL in group 2. In group 2, titers peaked by day 43 after nirsevimab at birth, with RSV-A GMFR 25.12 to 28 980.6 IU/mL and RSV-B GMFR 7.43 to 7533.6 IU/mL. Across groups, infant neutralizing antibodies remained high at 6 weeks and 3 months, with higher birth titers after maternal vaccination, modest waning after maternal vaccination, and increases after infant dosing.