Safety, tolerability, and immunogenicity of the ChAdOx1 RVF vaccine against Rift Valley fever among healthy adults in Uganda: a single-centre, single-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial

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Background Rift Valley fever (RVF) is an outbreak-prone viral zoonosis, with no vaccine available for human use. We aimed to assess the safety, tolerability, and immunogenicity of the ChAdOx1 RVF candidate vaccine among healthy adults in an RVF-endemic setting in Uganda. Methods We conducted a single-centre, single-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial in Masaka, southwestern Uganda. Healthy, non-pregnant adults aged 18–50 years who resided in the clinical site's service area, did not have serum antibodies against the RVF virus nucleoprotein, and had not previously received other adenovirus-vectored vaccines were eligible for inclusion. Participants were sequentially enrolled into three dose groups (group 1 [5·0 × 10 9 virus particles]; group 2 [2·5 × 10 10 virus particles]; or group 3 [5·0 × 10 10 virus particles]) and randomly assigned to vaccine or placebo in a 2:1 (group 1) or 5:1 (groups 2 and 3) ratio by use of permuted blocks. Participants received a single intramuscular dose of the ChAdOx1 RVF vaccine or saline placebo in the non-dominant deltoid. Participants were masked to the intervention administered; however, all study staff were unmasked. Coprimary outcomes were the number, proportion, and severity of local and systemic solicited reactogenicity adverse events within the first 7 days and of unsolicited adverse events within 28 days following vaccination in the vaccine and placebo groups, analysed by intention to treat. The secondary outcomes were humoral and cellular immunity to RVF virus glycoproteins. This trial is registered with ClinicalTrials.gov (NCT04672824) and is closed to recruitment. Findings Between May 5, 2022, and Sept 29, 2022, 30 participants were enrolled, of whom 24 (80%) were men and six (20%) were women (median age 25 years [IQR 22–33]). Adverse events were mostly mild or moderate and self-limiting. Local solicited adverse events were reported in 17 (71%) of 24 vaccine recipients and in no placebo recipients. The most frequently reported local solicited adverse events were injection site pain (one [25%] of four in group 1, five [50%] of ten in group 2, and seven [70%] of ten in group 3); warmth (two [50%] in group 1, three [30%] in group 2, and two [20%] in group 3); and itching (none in group 1, three [30%] in group 2, and two [20%] in group 3). Systemic solicited adverse events were reported in 20 (83%) vaccine recipients and in five (83%) of six placebo recipients. The most commonly reported systemic solicited adverse events were chills (three [75%] of four vaccine recipients vs one [50%] of two placebo recipients) in group 1; fever (two [20%] of ten vs none) and myalgia (four [40%] vs none) in group 2; and fever (four [40%] of ten vs none), headache (six [60%] vs one [50%] of two), fatigue (seven [70%] vs one [50%]), and malaise (seven [70%] vs one [50%]) in group 3. No serious adverse events were reported. By day 14, neutralising antibodies were detected in three (75%) of four individuals in group 1, nine (90%) of ten in group 2, and nine (90%) of ten in group 3. Highest antibody responses were sustained at day 28 (ten [100%]) and at day 84 (nine [90%]) in group 3. By day 14, anti-Gn and Gc immunoglobulin G responses in group 3 preceded other doses, whereas interferon-γ T-cell responses peaked for all doses, preceding the antibody peaks. Interpretation A single dose of ChAdOx1 RVF vaccine seemed to be safe, tolerable, and immunogenic in healthy adults in an RVF-endemic setting, eliciting humoral and cellular immunity. Further evaluation of the 5·0 × 10 10 dose in larger and more diverse populations in areas susceptible to outbreaks is warranted. Funding UK Department of Health and Social Care through the UK Vaccines Network.

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