Estimated efficacy of the adjuvanted RSVPreF3 vaccine against diverse and worldwide predominant RSV strains, irrespective of RSV F protein variation: results of a post-hoc analysis from the AReSVi-006 trial

<h2>Summary</h2><h3>Background</h3> All currently approved RSV vaccines/monoclonal antibodies target the prefusion conformation of the F protein (preF). Amino acid (aa) variations in RSV F are increasingly observed, though their impact on vaccine efficacy (VE) remains unknown. We characterised F sequences of isolates from the phase 3 efficacy trial (AReSVi-006; NCT04886596) of the AS01_E-adjuvanted RSV preF-based vaccine (adjuvanted RSVPreF3), evaluated their worldwide representativity, and assessed VE against predominant sequences. <h3>Methods</h3> RSV F aa sequences associated with PCR-confirmed RSV-lower respiratory tract disease (LRTD)/acute respiratory illnesses (ARIs) in AReSVi-006 (in adults aged ≥ 60 years, over three RSV seasons) were characterised and compared to the RSVPreF3 sequence and F sequences reported in public databases during the same period. VE against predominant RSV F sequences was estimated (post-hoc analyses). <h3>Findings</h3> We identified 19 RSV-A and 27 RSV-B F sequences, differing with 6–25 aa from RSVPreF3; these were representative of worldwide circulating strains during the trial. Two RSV-A and three RSV-B sequences were associated with most RSV-LRTD/ARI cases. The distribution of cases between vaccinated and placebo groups and VE estimates were within similar ranges in each RSV season across the predominant sequences. The aa sequences with the smallest and largest numbers of mutations compared to RSVPreF3 were not consistently associated with the highest and lowest VE estimates against RSV-LRTD/ARI. <h3>Interpretation</h3> Our findings support the efficacy of adjuvanted RSVPreF3 across a broad set of RSV strains, representative of globally circulating strains. VE was maintained irrespective of distance to RSVPreF3 in terms of the number of aa variations. <h3>Funding</h3> GSK.