Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants

Abstract

Background: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants.

Methods: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%).

Results: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups.

Conclusions: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Copyright © 2020 Massachusetts Medical Society.

Figures

Figure 1

Consort diagram on screening, enrolment and disposition of subjects. The maternal safety population included all maternal subjects who received any test article. Infant safety population was all infants born live to maternal subjects who received any test article. The per-protocol efficacy population for maternal subjects was all maternal subjects who received the test article and regimen to which they were randomized and had at least one post-treatment encounter documented during which active and/or passive surveillance activities for RSV-suspect illness could occur, and had no major protocol deviations affecting the primary efficacy outcomes as determined and documented by Novavax prior to database lock and unblinding. The per-protocol efficacy population for infant subjects included all infant subjects who: a) were ≥ 37 weeks gestational age at birth, b) were born to maternal subjects who received a study injection as randomized and ≥ 2 weeks prior to delivery, c) had not received prophylactic treatment with palivizumab between birth and Day 180 after delivery, d) had at least one post-partum contact during which active and/or passive surveillance activities for RSV-suspect illness could occur, and e) had no major protocol deviations affecting the primary efficacy outcomes as determined and documented by Novavax prior to database lock and unblinding. The intent-to-treat efficacy population included all maternal subjects and their infants in the Safety Population for whom at least one post-treatment and post-partum, respectively, efficacy measurement was available for both the mother and the infant as evidenced by collection of surveillance observations.

Figure 2 a-c

Kaplan-Meier Plots for the Primary and Secondary Efficacy Endpoints in the Per-Protocol Population Panel 2a: Time to RSV Medically-significant Lower Respiratory Tract Infection Panel 2b: Time to RSV Lower Respiratory Tract Infection with Severe Hypoxemia Panel 2c: Time to RSV Lower Respiratory Tract Infection with Hospitalization