Safety and immunogenicity of bivalent RSVpreF vaccine formulated in a multidose vial in healthy female participants in the USA: a multicentre, randomised, open-label, noninferiority phase 3 study.

Background: Bivalent respiratory syncytial virus (RSV) prefusion F protein vaccine (RSVpreF) is currently available as a preservative-free, single-dose vial (SDV) presentation. RSVpreF offered in a multidose vial (MDV) may help reduce vaccination costs in lower-middle-income countries (LMICs). We aimed to evaluate the immunogenicity, safety, and tolerability of the RSVpreF MDV presentation compared with those of the SDV presentation. Methods: This phase 3, randomised, open-label, noninferiority study was conducted at six sites in the United States. Study recruitment occurred in June-August 2024, with follow-up to September 20, 2024. Healthy, nonpregnant, nonbreastfeeding female participants (aged 18-49 years) were randomly allocated (1:1), via an interactive response technology system, to receive intramuscular injection of either single-dose RSVpreF with preservative 2-phenoxyethanol (2-PE; MDV presentation [RSVpreF MDV]) or RSVpreF without 2-PE (SDV presentation [RSVpreF SDV]). The primary outcomes were demonstration of noninferior immunogenicity of RSVpreF MDV compared with RSVpreF SDV at 1 month after vaccination and safety profile comparisons. Noninferiority was declared if the lower 95% CI bound for the geometric mean ratio (GMR) of neutralising geometric mean titres (GMTs) of RSVpreF MDV to those for RSVpreF SDV was >0·67 (1·5-fold noninferiority margin) for both RSV A and RSV B. This study was registered at ClinicalTrials.gov (NCT06473519) and is complete. Findings: Between June 24, 2024, and August 2, 2024, 488 participants were enrolled, of whom 453 were randomly allocated to study groups, and 450 were vaccinated (RSVpreF MDV, n = 223; RSVpreF SDV, n = 227). The evaluable immunogenicity population was 434 participants (RSVpreF MDV, n = 218; RSVpreF SDV, n = 216). Participant demographic and baseline characteristics were similar across vaccination groups. Vaccination with RSVpreF MDV met prespecified criteria for immunologic noninferiority compared with RSVpreF SDV. GMRs comparing neutralising GMTs of RSVpreF MDV versus RSVpreF SDV 1 month after vaccination were 0·96 (95% CI, 0·84-1·10) for RSV A and 0·91 (0·79-1·06) for RSV B. Solicited local reactions and systemic events within 7 days after vaccination were similar across groups (RSVpreF MDV: 50%, 69%; RSVpreF SDV: 55%, 67%, respectively). Unsolicited adverse events, most of which were mild or moderate in severity, were also reported by similar percentages of participants across groups. Interpretation: Immunogenicity, safety, and tolerability outcomes with RSVpreF MDV are similar to those for the currently licensed RSVpreF SDV presentation. Although this study had a short follow-up, excluded pregnant individuals, and was conducted outside of LMICs (where the MDV presentation is likely to have the greatest utility), our findings are encouraging and contribute to the broader body of evidence, including previous trials in pregnant individuals in varied global regions. In the event of future licensure, which is currently under evaluation, further safety monitoring of the RSVpreF MDV presentation would continue through established pharmacovigilance activities. Funding: Pfizer.