Development of a Single-Shot Live-Attenuated Chikungunya Vaccine: A Phase 1 Randomized Clinical Trial in Healthy Adults

Background: Chikungunya disease has been reported worldwide resulting in incapacitating arthralgia. We developed a live-attenuated Chikungunya virus vaccine candidate designed for active immunization of the general population living in endemic regions, as well as serving as a prophylactic measure for travelers to endemic areas. Methods: An observer-blinded, randomized, dose-escalation phase 1 clinical study investigated safety, immunogenicity and antibody persistence. Healthy volunteers aged 18 to 45 years were randomly assigned 1:1:2 to one of three escalating dose groups (low 3·2×103/0·1mL, medium 3·2×104 /1mL or high dose 3·2×105 TCID50/1mL) and received a single-shot immunization on Day 0. Half of individuals in Group H were challenged with the highest dose on Month 6 and followed up for 28 days post-challenge. Findings: Data up to Month 6 after a single immunization of 120 healthy volunteers showed an excellent immunogenicity profile with 100% seroconversion rates already achieved at Day 14 in all dose groups. Mean peak antibody titers at Day 28 range from 592·6 to 686·9 GMT from Groups L to H, respectively, with maximum titers reaching 2560. A single vaccination is sufficient to induce sustaining high titer neutralizing antibodies, as demonstrated by the absence of an anamnestic response following challenge and the development of sterilizing immunity (96·2% of participants). The vaccine was generally safe and well tolerated in the low and medium dose group, with both doses demonstrating a superior reactogenicity profile compared to the high dose group. Following challenge, vaccinees were protected from vaccine induced viremia. No adverse events of special interest and no vaccine related serious adverse events were reported. 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 supporting further development. Trial Registration: https://clinicaltrials.gov NCT03382964. Funding Statement: Valneva Austria GmbH, Vienna, Austria. Declaration of Interests: NW, RH, OZ, AF, NB, KL, MS, UL, AM, AP, SEL, KD and WB are Valneva employees and own stock and share options in Valneva. All other authors declare that they have no competing interests. Ethics Approval Statement: Ethics committee approval has been obtained prior any study related assessments occurred. The study was compliant with the current International Council on Harmonisation/Good Clinical Practice guidelines and in accordance with the principles set forth in the Declaration of Helsinki. Throughout the study an independent data safety monitoring board consisting of four external medical experts performed periodic reviews of accruing safety information. All enrolled individuals provided their written informed consent prior to any study-related procedure.