A single dose of ChAdOx1 Chik vaccine induces neutralizing antibodies against four chikungunya virus lineages in a phase 1 clinical trial

Abstract

Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18-50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and T-cell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT50 seroconversion after a single dose.

Conflict of interest statement

Pedro M. Folegatti is a consultant to Vaccitech, which is developing adenoviral vectored vaccines. Adrian Hill is a cofounder of and consultant to Vaccitech Ltd and is named as an inventor on a patent covering the design and use of Ch.

© 2021. The Author(s).

Figures

Fig. 1. Trial profile.

Study profile showing the allocation of participants to three dosage groups: Group 1, low dose at 5 × 109 vp, Group 2 intermediate dose at 2.5 × 1010 vp, and Group 3 high dose at 5 × 1010 vp. None of the 24 recruited participants were lost in follow-up.

Fig. 2. PRNT50 values over time.

PRNT50 reciprocal titers are shown for each participant. Arrows indicate when ChAdOx1 Chik was administered. Lower limit of detection (LLOD) is 5. a Overall responses by timepoint in all trial volunteers (n = 24). Geometric means and 95% CI; Kruskal–Wallis test with Dunn’s correction. b Same data as (a) but analyzed by dosage groups: low dose was 5 × 109 vp (n = 6), intermediate (mid) dose was 2.5 × 1010 vp (n = 9), and high dose was 5 × 1010 vp (n = 9). Geometric means and 95% CI; Kruskal–Wallis test with Dunn’s correction. One day 56, the sample from the low-dose group was excluded from analysis due to QC failure.

Fig. 3. ELISA titers over time.

CHIKV IgG response by standardized ELISA to E2 protein in 120 serum samples of trial participants. a Individual IgG titers over time (n = 24). The dashed line represents the cut-off value for seropositivity. Geometric means and 95% CI; Friedman test with Dunn’s correction. b Same data as (a) but represented as fold change from baseline (day 0) and analyzed by dosage group: low dose was 5 × 109 vp (n = 6), intermediate (mid) dose was 2.5 × 1010 vp (n = 9), and high dose was 5 × 1010 vp (n = 9). Geometric means and 95% CI; Friedman test with Dunn’s correction. c Correlation of PRNT50 and IgG ELISA by dosage group at 5 time points. Low dose, six participants, n = 29 (on day 56, samples were excluded due to QC failure); intermediate (mid) dose, nine participants (n = 45); high dose, nine participants (n = 45). Spearman correlation, two-tailed. d Same data as (c) but correlation is only shown for the nine participants vaccinated at the intermediate (mid) dose (n = 9 per timepoint). Spearman correlation, two-tailed.

Fig. 4. T-cell responses over time.

a Ex vivo enzyme-linked immunospot (ELISpot) for IFN-γ to CHIKV structural antigens measured as total responses to CHIKV peptides (sum of 13 pools spanning C, E3, E2, 6 K, and E1). SFC per million PBMC during a 6-month follow-up period (n = 24). Median and IQR; Kruskal–Wallis test with Dunn’s correction. b Proportion of spots contributed by C, E3, E2, 6 K and E1 over time. c Intracellular cytokine staining (ICS) by flow cytometry to assess CD4+ and CD8+ T-cell functionality. Percentage of cytokine-producing CD4+ and CD8+ T cells (n = 24). Median and IQR; Mann–Whitney test, two-tailed.