Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial

Background Multiple active vaccination approaches have proven ineffective in reducing the substantial morbidity and mortality caused by respiratory syncytial virus (RSV) in infants and older adults (aged >= 65 years). A vaccine conferring a substantial and sustainable boost in neutralising activity is required to protect against severe RSV disease. To that end, we evaluated the safety and immunogenicity of DS-Cav1, a prefusion F subunit vaccine. Methods In this randomised, open-label, phase 1 clinical trial, the stabilised prefusion F vaccine DS-Cav1 was evaluated for dose, safety, tolerability, and immunogenicity in healthy adults aged 18-50 years at a single US site. Participants were assigned to receive escalating doses of either 50 mu g, 150 mu g, or 500 mu g DS-Cav1 at weeks 0 and 12, and were randomly allocated in a 1:1 ratio within each dose group to receive the vaccine with or without aluminium hydroxide (AlOH) adjuvant. After 71 participants had been randomised, the protocol was amended to allow some participants to receive a single vaccination at week 0. The primary objectives evaluated the safety and tolerability at every dose within 28 days following each injection. Neutralising activity and RSV F-binding antibodies were evaluated from week 0 to week 44 as secondary and exploratory objectives. Safety was assessed in all participants who received at least one vaccine dose; secondary and exploratory immunogenicity analysis included all participants with available data at a given visit. The trial is registered with ClinicalTrials.gov, NCT03049488, and is complete and no longer recruiting. Findings Between Feb 21, 2017, and Nov 29, 2018, 244 participants were screened for eligibility and 95 were enrolled to receive DS-Cav1 at the 50 mu g (n=30, of which n=15 with AlOH), 150 mu g (n=35, of which n=15 with AlOH), or 500 mu g (n=30, of which n=15 with AlOH) doses. DS-Cav1 was safe and well tolerated and no serious vaccine-associated adverse events deemed related to the vaccine were identified. DS-Cav1 vaccination elicited robust neutralising activity and binding antibodies by 4 weeks after a single vaccination (p<0middot0001 for F-binding and neutralising antibodies). In analyses of exploratory endpoints at week 44, pre-F-binding IgG and neutralising activity were significantly increased compared with baseline in all groups. At week 44, RSV A neutralising activity was 3middot1 fold above baseline in the 50 mu g group, 3middot8 fold in the 150 mu g group, and 4middot5 fold in the 500 mu g group (p<0middot0001). RSV B neutralising activity was 2middot8 fold above baseline in the 50 mu g group, 3middot4 fold in the 150 mu g group, and 3middot7 fold in the 500 mu g group (p<0middot0001). Pre-F-binding IgG remained significantly 3middot2 fold above baseline in the 50 mu g group, 3middot4 fold in the 150 mu g group, and 4middot0 fold in the 500 mu g group (p<0middot0001). Pre-F-binding serum IgA remained 4middot1 fold above baseline in the 50 mu g group, 4middot3 fold in the 150 mu g group, and 4middot8 fold in the 500 mu g group (p<0middot0001). Although a higher vaccine dose or second immunisation elicited a transient advantage compared with lower doses or a single immunisation, neither significantly impacted long-term neutralisation. There was no long-term effect of dose, number of vaccinations, or adjuvant on neutralising activity. Interpretation In this phase 1 study, DS-Cav1 vaccination was safe and well tolerated. DS-Cav1 vaccination elicited a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks. A single low-dose of pre-F immunisation of antigen-experienced individuals might confer protection that extends throughout an entire RSV season. Funding The National Institutes of Allergy and Infectious Diseases. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Automated summary

The study evaluated the safety and immunogenicity of the DS-Cav1 prefusion F subunit vaccine in healthy adults aged 18-50 years. Results showed that DS-Cav1 vaccination was safe, well tolerated, and induced robust and sustained neutralising activity and binding antibodies. Higher vaccine doses or a second immunisation provided a transient advantage, but did not significantly impact long-term neutralisation, indicating that a single low-dose of pre-F immunisation may confer protection throughout an entire RSV season.