BACKGROUND: Immune responses to alphavirus vaccines might be impaired when heterologous alphavirus vaccines are administered sequentially. We aimed to compare immunogenicity and safety of a chikungunya virus virus-like particle (CHIKV VLP) vaccine in previous recipients of heterologous alphavirus vaccines with alphavirus-naive controls in the USA. METHODS: In this open-label, parallel-group, age-matched, sex-matched, phase 2 randomised controlled trial, which was conducted at two clinical study sites in the USA, adults (aged 18-65 years) who had previously received an investigational Venezuelan equine encephalitis virus vaccine (previous alphavirus vaccine recipients
n=30) and sex-matched and age-matched alphavirus vaccine-naive controls (n=30) were intramuscularly administered one 40 μg dose of CHIKV VLP vaccine on day 1. Immunogenicity was based on serum neutralising antibodies assessed by an in-vitro luciferase-based anti-CHIKV NT FINDINGS: Between Nov 20, 2019, and Jan 19, 2021, 60 participants (20 [33%] female and 40 [67%] male
40 (67%) White
median age 47·0 years [IQR 13·5]), 30 previous alphavirus vaccine recipients and 30 alphavirus vaccine-naive controls, were enrolled, vaccinated with CHIKV VLP, and completed the trial. The anti-CHIKV neutralising antibody seroconversion rate at day 22 was 100% (95% CI 88·6-100) in both groups. GMTs peaked in previous alphavirus vaccine recipients and alphavirus vaccine-naive controls at day 22 (2032·5 [95% CI 1413·0-2923·6] and 2299·2 [1598·1-3307·8], respectively) and were similar between the groups on day 22 and all subsequent visits. A higher proportion of previous alphavirus vaccine recipients (93·3% [95% CI 78·7-98·2]) had a four-fold neutralising antibody increase at day 8 than did alphavirus vaccine-naive controls (66·7% [48·8-80·8]
p=0·021). There was no statistically significant difference in the incidence of solicited adverse events between the previous alphavirus vaccine recipients and alphavirus vaccine-naive controls (53·3% vs 40·0%, respectively), although the relatively small sample size of the trial limited the power to detect a significant difference, and there were no reported vaccine-related serious adverse events. INTERPRETATION: CHIKV VLP vaccine was well tolerated and similarly immunogenic in both alphavirus vaccine-naive participants and previous recipients of a heterologous alphavirus vaccine. There were no significant differences in adverse events between the groups. The results of this study support the use of CHIKV VLP vaccine in individuals with previous alphavirus vaccine exposure. FUNDING: Defense Health Program, Emergent Travel Health, and Bavarian Nordic A/S.