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Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 μg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

In a phase 3 trial, adults (≥60 years of age) received one 120-μg dose of RSVpreF vaccine (17,215) or placebo (17,069). Vaccine efficacy against RSV-associated lower respiratory tract illness was 67 to 86%.

Respiratory syncytial virus causes clinically significant illness in children and adults. In a placebo-controlled trial, a prefusion stabilized F protein vaccine led to an 83% lower risk of RSV infection.

In a placebo-controlled, phase 2–3 trial, one dose of mRNA-1345 led to a lower incidence of RSV disease among adults 60 years of age or older. Solicited local and systemic adverse reactions occurred more often with the vaccine.

A combination of adenovirus 26 and protein vaccines was used to deliver a prefusion stabilized RSV protein. RSV-related lower respiratory tract illness developed in fewer vaccine recipients than placebo recipients.

Respiratory syncytial virus is a major cause of illness in infants. In this randomized, double-blind, placebo-controlled trial, the safety and immunogenicity of a bivalent RSV prefusion F protein–based vaccine was assessed in pregnant women and their infants. Anti-RSV antibodies were elicited with efficient transplacental transfer.

Respiratory syncytial virus (RSV) causes a significant disease burden in older adults. The live recombinant vaccine based on a nonreplicating modified vaccinia Ankara (MVA-BN) poxvirus, MVA-BN-RSV, encoding for multiple proteins of RSV subtypes A and B, was assessed for efficacy against respiratory disease caused by RSV. Adults aged ≥60 years, with or without underlying chronic conditions, were enrolled and randomized in a 1:1 ratio to receive a single dose of vaccine or placebo and were followed for disease caused by RSV infection during the 2022–2023 season. The 2 primary endpoints were RSV-associated lower respiratory tract disease (LRTD) with ≥3 and ≥ 2 symptoms; acute respiratory disease (ARD) was a key secondary endpoint. The humoral RSV-specific immune response was assessed at baseline and 14 days post-vaccination. Safety was evaluated by collection of solicited adverse events (AEs) and unsolicited AEs for 7 and 28 days post-vaccination respectively, and SAEs for the entire study period. In total, 18,348 participants were included in the final efficacy and safety analyses. Vaccine efficacy was 42.9 % (95 % CI: −16.1; 71.9) against RSV-associated LRTD with ≥3 symptoms, 59.0 % (95 % CI: 34.7; 74.3) against LRTD with ≥2 symptoms, and 48.8 % (95 % CI: 25.8; 64.7) against ARD. The primary objective was not met for LRTD with ≥3 symptoms since the lower bound of the 95 % CI was below 20 %, the prespecified success criterion. The vaccine-elicited immune response showed mean fold-increases of 1.7 for RSV A and B neutralizing antibodies and 2.9 and 4.3 for RSV-specific IgG and IgA, respectively. The vaccine displayed mild to moderate reactogenicity, and no safety concerns were identified. MVA-BN-RSV induced suboptimal protection against RSV-associated LRTD, likely due to suboptimal neutralizing antibody response. The vaccine had an acceptable safety profile and confirmed immunogenicity, overall showing promise for MVA-BN-vectored constructs targeting other diseases. Trial Registration:Clinicaltrials.gov Identifier NCT05238025 (Registered February 14, 2022).

An RSV prefusion F maternal vaccine was assessed for efficacy against RSV disease in infants. The trial was stopped early owing to a higher incidence of preterm birth in the vaccine group than in the placebo group.

Background. Respiratory syncytial virus (RSV) is a leading cause of childhood bronchiolitis and pneumonia, particularly in early infancy. Immunization of pregnant women could boost preexisting immune responses, providing passive protection to newborns through placental transfer of anti-RSV antibody. Methods. In this first-in-humans clinical trial of a purified recombinant RSV protein F vaccine engineered to preferentially maintain prefusion conformation (RSV-PreF), 128 healthy men 18–44 years old were randomized to one dose of a RSV-PreF vaccine containing 10, 30, or 60 μg of RSV-PreF antigen, with or without alum adjuvant, or control, and followed for one year for safety and immunogenicity outcomes. Results. Injection site pain was the most common adverse event, reported by up to 81.3% of participants. The highest RSV neutralizing antibody responses were in the 30 μg RSV-PreF/alum, 60 μg RSV-PreF/alum, and 60 μg RSV-PreF/nonadjuvant groups. Responses were evident on day 7, and 30 days after vaccination these participants had RSV-A neutralizing antibody titers of ≥1:512, and >70% had titers of 1:1024, with titers increasing by 3.2–4.9 fold. Responses remained high on day 60 but waned on days 180 and 360. Conclusions. The RSV-PreF vaccine elicited rapid RSV neutralizing antibody responses in healthy young men, with an acceptable adverse event profile.

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.