Background: Older individuals and adults with certain chronic or immunocompromising health conditions are at increased risk of severe respiratory syncytial virus (RSV) disease. Methods: In this phase 3 randomized trial of RSVpreF safety and immunogenicity in 18–59-year-olds at high risk of severe RSV disease, participants were randomized 2:1 to 1 RSVpreF (120 µg) or placebo dose. Primary safety endpoints included reactogenicity events and adverse events (AEs) through 7 days and 1 month after vaccination, respectively, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) throughout the study. In primary analyses, immunogenicity elicited 1 month after RSVpreF was bridged to a randomly selected subset of ≥60-year-olds receiving RSVpreF from the immunogenicity subset in the pivotal phase 3 RENOIR trial, which demonstrated RSVpreF efficacy. Noninferiority was declared if 95% confidence interval (CI) lower bounds were >.667 (neutralizing titer adjusted geometric mean ratios) and >−10% (seroresponse rate differences) for RSV-A and RSV-B. Results: Overall, 678 participants received RSVpreF (n = 453) or placebo (n = 225). Most reactogenicity events were mild/moderate; severe events occurred in ≤2.0% of participants overall. AE frequencies were similar in RSVpreF (7.1%) and placebo recipients (7.6%). No vaccine-related SAEs or NDCMCs were reported. One month after RSVpreF administration, noninferiority criteria were met in 18–59-year-olds versus ≥60-year-olds for RSV-A and RSV-B neutralizing titers and seroresponse rates. Conclusions: RSVpreF was well tolerated with no safety concerns and demonstrated immunobridging to efficacy in 18–59-year-olds at high risk of severe RSV disease versus ≥60-year-olds in whom efficacy was previously demonstrated, supporting use of RSVpreF to prevent RSV-associated disease in this population. NCT05842967.

Background/Objectives: Individuals with immunocompromising conditions are at high risk of developing severe respiratory syncytial virus (RSV) illness. This phase 3, single-arm study assessed the safety and immunogenicity of the bivalent RSV prefusion F protein−based (RSVpreF) 120-µg vaccine in immunocompromised and renally impaired adults. Methods: Participants were stratified by age group (18−<60-year-olds; ≥60-year-olds) and received two RSVpreF doses 1 month apart (i.e., Dose 1 and Dose 2, respectively). Reactogenicity events were collected for 7 days after each dose; adverse events through 1 month after the last dose; and serious adverse events, adverse events of special interest, and newly diagnosed chronic medical conditions throughout the study. Results: One month after Dose 1, RSVpreF elicited robust immune responses overall and across age and immunocompromised subgroups. Overall, geometric mean fold rises from before to 1 month after Dose 1 were high for RSV A and RSV B (8.3 and 9.0, respectively); no additional increases 1 month after Dose 2 (7.5 and 7.8) were observed. The most frequent local reaction was pain at the injection site, which was more common after Dose 2 than after Dose 1. The most frequent systemic event after any dose was fatigue. Most local reactions and systemic events were mild or moderate in severity. Adverse event and serious adverse event rates were 13.5% and 7.3% among 18−<60-year-olds and 22.4% and 14.0% among ≥60-year-olds, respectively. Conclusions: A single dose of the RSVpreF vaccine conferred robust immune responses in immunocompromised and renally impaired adults with no safety concerns. (ClinicalTrials.gov Identifier: NCT05842967).