Immunogenicity and Safety of the AS01E-adjuvanted Respiratory Syncytial Virus (RSV) Prefusion F Protein Vaccine in Adults Aged 18–49 Years at Increased Risk of RSV Disease Compared with Adults Aged ≥60 Years

BACKGROUND: The AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine (adjuvanted RSVPreF3) is approved for ≥60-year-olds and 50-59-year-olds at increased risk of RSV disease. We evaluated the vaccine's immunogenicity and safety in 18-49-year-olds at increased risk of RSV disease due to certain chronic conditions. METHODS: This open-label, multicountry phase 3b trial included 18-49-year-olds at increased risk (at-risk 18-49 group) and a control group of ≥60-year-olds with or without chronic conditions (≥60 group). Primary objective was to demonstrate immunological noninferiority to adjuvanted RSVPreF3 in the at-risk 18-49 versus ≥60 group, based on group RSV-A/RSV-B geometric mean titer ratios and seroresponse rate differences 1 month postvaccination. Humoral, cell-mediated immunogenicity, and safety were assessed until 6 months postvaccination. RESULTS: Overall, 1458 adults were vaccinated. Immunological noninferiority was demonstrated in the at-risk 18-49 versus ≥60 group at 1 month postvaccination. Both groups showed increased RSV-A/RSV-B neutralizing titers and RSVPreF3-specific CD4+ T-cell frequencies at 1 month postvaccination that declined but remained above baseline at 6 months. Solicited events were more frequent in the at-risk 18-49 (84.3%) than in the ≥60 group (69.4%); most were mild-to-moderate and transient. Rates and intensity of unsolicited adverse events (AEs) were comparable across groups, with low reporting of serious AEs and AEs of special interest. CONCLUSIONS: Adjuvanted RSVPreF3 was immunologically noninferior in 18-49-year-olds with underlying conditions compared with ≥60-year-olds in whom efficacy was previously demonstrated, supporting efficacy inference in this younger population. Up to 6 months postvaccination, the vaccine elicited robust immune responses, and the safety profile was acceptable. Clinical Trial Registration: NCT06389487.