A multivalent RSV vaccine based on the modified vaccinia Ankara vector shows moderate protection against disease caused by RSV in older adults in a phase 3 clinical study.

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).