Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: a double-blind, multicentre, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: VLA1553 is a live-attenuated vaccine candidate for active immunisation and prevention of disease caused by chikungunya virus. We report safety and immunogenicity data up to day 180 after vaccination with VLA1553. METHODS: This double-blind, multicentre, randomised, phase 3 trial was done in 43 professional vaccine trial sites in the USA. Eligible participants were healthy volunteers aged 18 years and older. Patients were excluded if they had history of chikungunya virus infection or immune-mediated or chronic arthritis or arthralgia, known or suspected defect of the immune system, any inactivated vaccine received within 2 weeks before vaccination with VLA1553, or any live vaccine received within 4 weeks before vaccination with VLA1553. Participants were randomised (3:1) to receive VLA1553 or placebo. The primary endpoint was the proportion of baseline negative participants with a seroprotective chikungunya virus antibody level defined as 50% plaque reduction in a micro plaque reduction neutralisation test (µPRNT) with a µPRNT50 titre of at least 150, 28 days after vaccination. The safety analysis included all individuals who received vaccination. Immunogenicity analyses were done in a subset of participants at 12 pre-selected study sites. These participants were required to have no major protocol deviations to be included in the per-protocol population for immunogenicity analyses. This trial is registered at ClinicalTrials.gov, NCT04546724. FINDINGS: Between Sept 17, 2020 and April 10, 2021, 6100 people were screened for eligibility. 1972 people were excluded and 4128 participants were enrolled and randomised (3093 to VLA1553 and 1035 to placebo). 358 participants in the VLA1553 group and 133 participants in the placebo group discontinued before trial end. The per-protocol population for immunogenicity analysis comprised 362 participants (266 in the VLA1553 group and 96 in the placebo group). After a single vaccination, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 263 (98·9%) of 266 participants in the VLA1553 group (95% CI 96·7-99·8; p<0·0001) 28 days post-vaccination, independent of age. VLA1553 was generally safe with an adverse event profile similar to other licensed vaccines and equally well tolerated in younger and older adults. Serious adverse events were reported in 46 (1·5%) of 3082 participants exposed to VLA1553 and eight (0·8%) of 1033 participants in the placebo arm. Only two serious adverse events were considered related to VLA1553 treatment (one mild myalgia and one syndrome of inappropriate antidiuretic hormone secretion). Both participants recovered fully. INTERPRETATION: The strong immune response and the generation of seroprotective titres in almost all vaccinated participants suggests that VLA1553 is an excellent candidate for the prevention of disease caused by chikungunya virus. FUNDING: Valneva, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.

A randomized, double-blinded Phase 3 study to demonstrate lot-to-lot consistency and to confirm immunogenicity and safety of the live-attenuated chikungunya virus vaccine candidate VLA1553 in healthy adults†.

BACKGROUND: The global spread of the chikungunya virus (CHIKV) increases the exposure risk for individuals travelling to or living in endemic areas. This Phase 3 study was designed to demonstrate manufacturing consistency between three lots of the single shot live-attenuated CHIKV vaccine VLA1553, and to confirm the promising immunogenicity and safety data obtained in previous trials. METHODS: This randomized, double-blinded, lot-to-lot consistency, Phase 3 study, assessed immunogenicity and safety of VLA1553 in 408 healthy adults (18-45 years) in 12 sites across the USA. The primary endpoint was a comparison of the geometric mean titre (GMT) ratios of CHIKV-specific neutralizing antibodies between three VLA1553 lots at 28 days post-vaccination. Secondary endpoints included immunogenicity and safety over 6 months post-vaccination. RESULTS: GMTs were comparable between the lots meeting the acceptance criteria for equivalence. The average GMT (measured by 50% CHIKV micro plaque neutralization test; µPRNT50) peaked with 2643 at 28 days post-vaccination and decreased to 709 at 6 months post-vaccination. An excellent seroresponse rate (defined as µPRNT50 titre ≥ 150 considered protective) was achieved in 97.8% of participants at 28 days post-vaccination and still persisted in 96% at 6 months after vaccination. Upon VLA1553 immunization, 72.5% of participants experienced adverse events (AEs), without significant differences between lots (related solicited systemic AE: 53.9% of participants; related solicited local AE: 19.4%). Overall, AEs were mostly mild or moderate and resolved without sequela, usually within 3 days. With 3.9% of participants experiencing severe AEs, 2.7% were classified as related, whereas none of the six reported serious adverse events was related to the administration of VLA1553. CONCLUSIONS: All three lots of VLA1553 recapitulated the safety and immunogenicity profiles of a preceding Phase 3 study, fulfilling pre-defined consistency requirements. These results highlight the manufacturability of VLA1553, a promising vaccine for the prevention of CHIKV disease for those living in or travelling to endemic areas.

Antibody persistence and safety of a live-attenuated chikungunya virus vaccine up to 2 years after single-dose administration in adults in the USA: a single-arm, multicentre, phase 3b study.

BACKGROUND: Chikungunya virus infection can lead to long-term debilitating symptoms. A precursor phase 3 clinical study showed high seroprotection (defined as a 50% plaque reduction of chikungunya virus-specific neutralising antibodies on a micro plaque reduction neutralisation test [µPRNT] titre of ≥150 in baseline seronegative participants) up to 6 months after a single vaccination of the chikungunya virus vaccine VLA1553 (Valneva Austria, Vienna, Austria) and a good safety profile. Here we report antibody persistence and safety up to 2 years. METHODS: In this single-arm, multicentre, phase 3b study, we recruited participants from the precursor phase 3 trial from professional vaccine trial sites in the USA. Participants (aged ≥18 years) were eligible if they had completed the previous study and received VLA1553. Chikungunya virus-specific neutralising antibodies were evaluated at 28 days, 6 months, and 1 year and 2 years after vaccination. The primary outcome was the proportion of seroprotected participants (ie, µPRNT50 titre of ≥150) at 1 and 2 years, assessed in all eligible participants who had at least one post-vaccination immunogenicity sample available, overall and by age group at the time of vaccination (18-64 years and ≥65 years). Adverse events of special interest at the time of transition from the previous study to the current study (ie, at 6 months) and serious adverse events during the current study were recorded (ie, between 6 months and 2 years). All analyses were descriptive. This study is registered with ClinicalTrials.gov, NCT04838444, and immunogenicity follow-up is ongoing. FINDINGS: In the precursor study, participants were screened between Sept 17, 2020, and April 10, 2021; data cutoff for this analysis was March 31, 2023. Of 2724 participants in the precursor study who received one dose of VLA1553, 363 participants were analysed in this study (310 [85%] aged 18-64 years and 53 [15%] aged ≥65 years at enrolment in the precursor study; mean age 47·7 years [SD 14·2], 207 [57%] of 363 participants were female, 156 [43%] were male, 280 [77%] were White, and 314 [87%] were not Hispanic or Latino). Strong seroprotection was observed at 1 year (98·9% [356 of 360 assessable participants; 97·2-99·7]) and 2 years (96·8% [306 of 316; 94·3-98·5]) after vaccination, and was very similar between those aged 18-64 years (at 1 year: 98·7% [303 of 307; 96·7-99·6]; at 2 years: 96·6% [256 of 265; 93·7-98·4]) and those aged 65 years and older (at 1 year: 100% [53 of 53; 93·3-100]; at 2 years: 98·0% [50 of 51; 89·6-100]) at each timepoint. No adverse events of special interest were ongoing at the time of transition. Ten serious adverse events occurred in nine (2%) participants between the 6-month and 2-year timepoints, including one death (due to drug overdose) that was determined to not be related to VLA1553. INTERPRETATION: After a single VLA1553 vaccination, chikungunya virus-neutralising antibodies above the threshold considered to be protective persisted up to 2 years and there were no long-term serious adverse events related to vaccination. VLA1553 is an efficient and safe intervention that offers high seroprotection against chikungunya virus infection, a virus likely to spread globally with an urgent demand for long-lasting prophylaxis. FUNDING: Valneva Austria, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.

Single-shot live-attenuated chikungunya vaccine in healthy adults: a phase 1, randomised controlled trial.

BACKGROUND: Chikungunya disease, which results in incapacitating arthralgia, has been reported worldwide. We developed a live-attenuated chikungunya virus (CHIKV) vaccine candidate designed for active immunisation of the general population living in endemic regions, as well as serving as a prophylactic measure for travellers to endemic areas. METHODS: This single-blind, randomised, dose-escalation, phase 1 study investigated as primary outcome safety of a live-attenuated CHIKV vaccine candidate. At two professional clinical trial centres in Illinois and Alabama, USA, healthy volunteers aged 18-45 years were randomly assigned (1:1:2) to one of three escalating dose groups (low dose 3·2 × 103 per 0·1 mL; medium dose 3·2 × 104 per 1 mL; or high dose 3·2 × 105 50% tissue culture infection dose per 1 mL) and received a single-shot immunisation on day 0. Individuals in all groups were revaccinated with the highest dose on either month 6 or 12, and followed up for 28 days after revaccination. The safety analysis included all individuals who received the single vaccination; the immunogenicity analysis, which was a secondary outcome, included all individuals who completed the study without major protocol deviations (per-protocol population). The study is registered with ClinicalTrials.gov, NCT03382964, and is complete. FINDINGS: The study was done between March 5, 2018, and Jul 23, 2019, with 120 adults recruited and enrolled between March 5 and June 21, 2018, and assigned to receive a low (n=31), medium (n=30), or high (n=59) dose of the vaccine. The vaccine was safe in the high-dose group and well tolerated in the low-dose and medium-dose groups. Four (7%) of 59 vaccinees in the high-dose group reported any local reaction, and 11 (36%), 12 (40%), and 40 (68%) volunteers in the low-dose, medium-dose, and high-dose groups, respectively, reported any solicited systemic reaction. No vaccine-related serious adverse events were reported. Data up to month 12 after a single immunisation of the 120 healthy volunteers showed a good immunogenicity profile with 100% seroconversion rates achieved at day 14 (103 [100%] of 103) and sustained for 1 year across all dose groups. Mean peak antibody titres at day 28 ranged from 592·6 to 686·9 geometric mean titres from the low-dose to high-dose groups, respectively. A single vaccination was sufficient to induce sustaining high-titre neutralising antibodies, as shown by the absence of an anamnestic response after any revaccination ranging from 94% to 100% of participants. Following revaccination, vaccinees were protected from vaccine-induced viraemia. INTERPRETATION: A novel live-attenuated CHIKV vaccine was well tolerated and highly immunogenic in an adult population and could be an effective intervention for prophylaxis of chikungunya disease worldwide. FUNDING: Valneva, Vienna, Austria; Coalition for Epidemic Preparedness Innovation and EU Horizon 2020.