Efficacy, safety, and immunogenicity of the AS01E-adjuvanted respiratory syncytial virus prefusion F protein vaccine (RSVPreF3 OA) in older adults over three respiratory syncytial virus seasons (AReSVi-006): a multicentre, randomised, observer-blinded, placebo-controlled, phase 3 trial

Background

Duration of protection after respiratory syncytial virus (RSV) vaccination is unknown. This study aimed to evaluate efficacy and safety over three RSV seasons of the AS01_E-adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) against RSV-related lower respiratory tract disease (RSV-LRTD) in older adults.

Methods

In this randomised, observer-blind, placebo-controlled, phase 3 trial (AReSVi-006), participants aged 60 years or older in 275 centres (ie, GP practices and clinical research sites) across 17 countries in Africa, Asia, Oceania, Europe, and North America were randomly assigned (1:1) to receive RSVPreF3 OA or placebo before RSV season one. RSVPreF3 OA recipients were re-randomly assigned (1:1) before RSV season two to receive a second RSVPreF3 OA dose (RSV revaccination group) or placebo (RSV single-dose group). Recipients of placebo before RSV season one also received placebo before season two (placebo group). The primary objective (efficacy against first occurrence of RSV-LRTD over one RSV season) was reported previously. Confirmatory secondary objectives were to demonstrate efficacy over three RSV seasons of a single RSVPreF3 OA dose and of a first dose followed by revaccination 1 year later, against RSV-LRTD, overall and by RSV subtype (success criteria: lower limits of two-sided CIs around efficacy estimates >20% [RSV-LRTD] and >0% [RSV-LRTD by RSV subtype]). This study is registered with ClinicalTrials.gov, NCT04886596, and is complete.

Findings

Participants were enrolled between May 25, 2021, and Jan 31, 2022. Efficacy analyses included 12 468 RSVPreF3 OA recipients and 12 498 placebo recipients. Cumulative efficacy over three seasons of one RSVPreF3 OA dose was 62·9% (97·5% CI 46·7–74·8) against RSV-LRTD, 69·8% (42·2–85·7) against RSV A-related LRTD, and 58·6% (35·9–74·1) against RSV B-related LRTD (median follow-up from day 15 post-dose one 30·6 months [IQR 26·2–32·0]). Efficacy was observed over three seasons among participants aged 60–69 years, participants aged 70–79 years, pre-frail participants (ie, those with a walking speed of 0·4–0·99 m/s in a gait speed test), and participants with pre-existing conditions that increase the RSV-LRTD risk. Efficacy against RSV-LRTD decreased over time. A first RSVPreF3 OA dose followed by revaccination 1 year later had an efficacy that was within the same range as that of one dose. RSVPreF3 OA showed a clinically acceptable safety profile. Between dose one and trial end, eight (<1%) participants in the RSV single-dose group, 12 (<1%) in the RSV revaccination group, and 12 (<1%) in the placebo group had a serious adverse event considered to be related to the trial intervention by the investigator. Five deaths were assessed as related to the trial intervention by the investigator: three in the vaccine groups (cardiopulmonary failure, cardiac arrest, and left ventricular failure) and two in the placebo group (death of unknown cause and pulmonary embolism).

Interpretation

A single RSVPreF3 OA dose was efficacious against RSV-LRTD over three RSV seasons in people aged 60 years or older, despite a decrease in efficacy over time. Further research is needed to establish the optimal revaccination strategy. These results support the favourable benefit–risk profile of RSVPreF3 OA to help protect against RSV-LRTD for at least three RSV seasons.

Funding

GSK.