Safety and immunogenicity of a live-attenuated chikungunya virus vaccine in endemic areas of Brazil: interim results of a double-blind, randomised, placebo-controlled phase 3 trial in adolescents.

Abstract

Background: Chikungunya outbreaks have been reported in Brazil since 2014. Adolescents are a sensitive population who would benefit from a prophylactic vaccine. This study assessed the immunogenicity and safety of the vaccine VLA1553 in adolescents in Brazil. With an overall trial duration of 12 months, we now report data on safety and immunogenicity over a period of 28 days after vaccination.

Methods: In this double-blind, randomised, placebo-controlled phase 3 trial, adolescents aged 12 to <18 years were recruited. The trial was performed at ten trial sites across Brazil. Eligible participants were generally healthy. The main exclusion criteria comprised immune-mediated or chronic arthritis or arthralgia, a known or suspected defect of the immune system, or any live vaccine received within the 4 weeks before trial vaccination. Randomisation was stratified by baseline serostatus in a 2:1 ratio to receive VLA1553 (at a dose of 1 × 10⁴ TCID₅₀ per 0·5 mL [ie, 50% tissue culture infectious dose]) or placebo. VLA1553 or placebo was administered intramuscularly as a single-dose immunisation on day 1. The primary endpoint was the proportion of baseline seronegative participants with chikungunya virus neutralising antibody levels of 150 or more in μPRNT₅₀ (a micro plaque reduction neutralisation test), which was considered a surrogate of protection. The safety analysis included all participants receiving a trial vaccination. Immunogenicity analyses were performed in a subset. The trial is registered with ClinicalTrials.gov, NCT04650399.

Findings: Between Feb 14, 2022, and March 14, 2023, 754 participants received a trial vaccination (502 received VLA1553 and 252 received placebo) with a per-protocol population of 351 participants for immunogenicity analyses (303 in the VLA1553 group and 48 in the placebo group). In participants who were seronegative at baseline, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 247 of 250 (98·8%, 95% CI 96·5-99·8) participants 28 days after vaccination. In seropositive participants, the baseline seroprotection rate of 96·2% increased to 100% after vaccination with VLA1553. Most (365 [93%] of 393) adverse events were of mild or moderate intensity, VLA1553 was generally well tolerated. When compared with placebo, participants exposed to VLA1553 had a significantly higher frequency of related adverse events (351 [69·9%] of 502 vs 121 [48·0%] of 252; p<0·0001), mostly headache, myalgia, fatigue, and fever. Among four reported serious adverse events (three in the VLA1553 group and one in the placebo group), one was classified as possibly related to VLA1553: a high-grade fever. Among 20 adverse events of special interest (ie, symptoms suggesting chikungunya-like disease), 16 were classified as related to trial vaccination (15 in the VLA1553 group and one in the placebo group), with severe symptoms reported in four participants (fever, headache, or arthralgia). 17 adverse events of special interest resolved within 1 week. Among 85 participants with arthralgia (68 in the VLA1553 group and 17 in the placebo group), eight adolescents had short-lived (range 1-5 days), mostly mild recurring episodes (seven in the VLA1553 group and one in the placebo group). The median duration of arthralgia was 1 day (range 1-5 days). The frequency of injection site adverse events for VLA1553 was higher than in the placebo group (161 [32%] vs 62 [25%]), but rarely severe (two [<1%] in the VLA1553 group and one [<1%] in the placebo group). After administration of VLA1553, there was a significantly lower frequency of solicited adverse events in participants who were seropositive at baseline compared with those who were seronegative (53% vs 74%; p<0·0001) including headache, fatigue, fever, and arthralgia.

Interpretation: VLA1553 was generally safe and induced seroprotective titres in almost all vaccinated adolescents with favourable safety data in adolescents who were seropositive at baseline. The data support the use of VLA1553 for the prevention of disease caused by the chikungunya virus among adolescents and in endemic areas.

Funding: Coalition for Epidemic Preparedness Innovation and EU Horizon 2020.

Translation: For the Portuguese translation of the abstract see Supplementary Materials section.