BACKGROUND: Chikungunya disease is a growing global public health concern. Vimkunya (previously chikungunya virus virus-like particle vaccine, previously PXVX0317) is a single-dose, pre-filled syringe for intramuscular injection. Here, we report safety, tolerability, and immunogenicity data for Vimkunya versus placebo in healthy adolescents and adults aged 12-64 years, and evaluate lot-to-lot consistency. METHODS: This pivotal phase 3, randomised, double-blind, placebo-controlled, parallel-group trial was done at 47 clinical trial sites in the USA. Eligible participants were healthy adolescents and adults aged 12-64 years. Participants were divided into three age strata (12-17 years, 18-45 years, and 46-64 years) within each site and randomly assigned (2:2:2:1) to receive one of three consecutively manufactured lots of Vimkunya or placebo (same excipient composition without chikungunya virus virus-like particle or aluminium hydroxide components) on study day 1. Neither participants, nor clinical site personnel, nor the funder knew participants' individual treatment assignments until all participants completed their involvement in the trial and the database was cleaned and locked. Participants attended a screening visit, followed by a day 1 visit that included random assignment, blood sample collection, and administration of a single dose of Vimkunya or placebo by intramuscular injection in the deltoid muscle. The coprimary endpoints were: the difference in chikungunya virus serum neutralising antibody seroreponse rate (vaccine minus placebo) at day 22
chikungunya virus serum neutralising antibody geometric mean titre (GMT) at day 22 for vaccine and placebo
and chikungunya virus serum neutralising GMT ratio at day 22 between all three pairs of vaccine lots (A:B, B:C, and A:C) in adults aged 18-45 years. The trial is registered with ClinicalTrials.gov, NCT05072080 and EudraCT, 2023-002124-42. FINDINGS: Between Sept 29, 2021, and Sept 23, 2022, 4215 participants were screened, of whom 3258 were eligible and enrolled (1667 [51·2%] female and 1591 [48·8%] male), and 3254 (99·9%) received either Vimkunya (n=2790) or placebo (n=464). The immunogenicity evaluable population included 2983 participants, of whom 2559 received Vimkunya and 424 received placebo. At day 22, 2503 (97·8%) of 2559 participants in the Vimkunya group had a seroresponse, compared with five (1·2%) of 424 participants in the placebo group for the immunogenicity evaluable population. The seroreponse rate difference was 96·6% (95% CI 95·0-97·5
p<
0·0002). In the immunogenicity evaluable population, chikungunya virus serum neutralising antibody GMT at day 22 for the vaccine group was 1618 and for the placebo group was 7·9 (p<
0·0002). At day 22, the serum neutralising GMT ratios for the pairs of lots (A:B, B:C, and A:C) were 0·98 (95% CI 0·85-1·14), 0·97 (0·84-1·12), and 0·95 (0·82-1·10), respectively. Vimkunya had a favourable safety profile
most adverse events were self-limiting and grade 1 or 2 in severity. The most common adverse events were injection site pain (656 [23·7%] of 2764 participants in the vaccine group), fatigue (551 [19·9%] of 2764), headache (498 [18·0%] of 2765), and myalgia (486 [17·6%] of 2764). INTERPRETATION: Vimkunya induces a rapid and robust immune response. These findings support the potential for this vaccine to protect individuals aged 12-64 years from disease caused by chikungunya virus. FUNDING: Emergent BioSolutions and Bavarian Nordic.