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

Abstract

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 μg, 150 μg, or 500 μg 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 μg (n=30, of which n=15 with AlOH), 150 μg (n=35, of which n=15 with AlOH), or 500 μg (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<0·0001 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 3·1 fold above baseline in the 50 μg group, 3·8 fold in the 150 μg group, and 4·5 fold in the 500 μg group (p<0·0001). RSV B neutralising activity was 2·8 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 3·7 fold in the 500 μg group (p<0·0001). Pre-F-binding IgG remained significantly 3·2 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 4·0 fold in the 500 μg group (p<0·0001). Pre-F-binding serum IgA remained 4·1 fold above baseline in the 50 μg group, 4·3 fold in the 150 μg group, and 4·8 fold in the 500 μg group (p<0·0001). 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.

Figure 1.

Consort Diagram

Figure 2.

DS-Cav1 elicits potent and durable neutralizing activity through 44 weeks post-vaccination. Panels A and B show neutralizing activity in the serum against a reporter RSV A2 virus (RSV A) and RSV B18537 virus (RSV B), respectively at weeks 0, 2, 4, 12, 14, 16, 24 and 44 for subjects immunized with 50, 150, or 500 mcg of DS-Cav1. Significance determined by Student’s t-test (at specific timepoints) without adjustment for multiple comparisons. Panels C and D show neutralizing activity in the serum against RSV A and RSV B, respectively, for each subject vaccinated with 50, 150, or 500 mcg of DS-Cav1 at baseline (W0) and weeks 4 and 44. Significance between dose groups determined by linear regression. Panel E and F show the fold-change in neutralizing activity against RSV A and B, respectively, between W12 and W16 in subjects that received 2 or 1 vaccinations and between W12 and W44 in these groups. Dotted line represents a fold-change of 1. Significance determined by linear regression without adjustment for multiple comparisons. Significance indicated as ***p<0·001, **p<0·01, *p<0·05.

Figure 3.

DS-Cav1 elicits robust and durable pre-F-binding antibodies that recognize the apex and side of the F protein. Pre-F-binding IgG (Panel A) and IgA (Panel C) measured by ELISA and pre-F binding IgG in the presence of excess post-F (Panel B) which competes for post-F exclusive and dual-binding antibodies, demonstrating that binding antibodies are directed to the pre-F-exclusive and shared surfaces of pre-F and post-F. Panel E shows the level of pre-F-binding antibodies that compete with binding of the D25 antibody (apex-binding) and Panel F shows the level post-F-binding antibodies that competed with palivizumab antibody (side-binding). Panels G and H show levels of pre-F-binding IgG (Panel G) and IgA (Panel H) in mucosal samples. Statistical differences comparing weeks 0, 4, and 44 are determined by linear regression with no adjustment for multiple comparisons. Significance indicated as ***p<0·001.