Safety and immunogenicity of a single-dose adenovirus-vectored rabies vaccine over 1 year in adults and children in Tanzania: interim data from an ongoing, partly randomised, controlled, phase 1b/2 trial.

BACKGROUND: Rabies kills approximately 59 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, has the potential to provide low-cost, single-dose pre-exposure rabies prophylaxis. We aimed to assess the safety and immunogenicity of ChAdOx2 RabG, including in comparison to a currently licensed vaccine. METHODS: We performed a single-centre, age de-escalation, dose-escalation, partly randomised, open-label, phase 1b/2 trial. Healthy adults (18-45 years) and children (2-6 years) who were rabies vaccine-naive and from the semi-urban Bagamoyo area in Tanzania were recruited through a series of community meetings. Adults were first enrolled into a group receiving 2·5 × 1010 virus particles of ChAdOx2 RabG (middle dose); after safety review, adults were randomly assigned (3:1) to receive ChAdOx2 RabG (5 × 1010 virus particles; full dose) on day 0 or an inactivated rabies virus (IRV) vaccine on day 0 (single-visit IRV). Children were first enrolled into a group receiving 1 × 1010 virus particles of ChAdOx2 RabG (low dose), and then into a group receiving the middle dose. After safety review, children were randomly assigned (3:2:2) to receive a full dose of ChAdOx2 RabG on day 0, single-visit IRV, or IRV vaccine on day 0 and day 7 (two-visit IRV). ChAdOx2 RabG was administered intramuscularly at a single anatomical site and IRV intradermally at two anatomical sites. Randomisation was done in blocks by clinical staff using lists generated by an independent statistician. The primary outcome was safety, assessed in the intention-to-treat population. The secondary outcome was rabies virus neutralising antibody (VNA), assessed with a validated assay in participants in the single-visit, full-dose ChAdOx2 RabG groups and the single-visit IRV vaccine groups who attended the nominal 1-year visit. Follow-up is planned for up to 5·5 years after vaccination; here we present data up to 1 year. The trial is registered at ClinicalTrials.gov (NCT04270838). FINDINGS: Between March 3, 2022, and March 9, 2023, 63 adults (three in the middle-dose ChAdOx2 RabG group, 45 in the full-dose ChAdOx2 RabG group, and 15 in the single-visit IRV group) and 111 children (three each in the low-dose and middle-dose ChAdOx2 RabG groups, 45 in the full-dose ChAdOx2 RabG group, 30 in the single-visit IRV group, and 30 in the two-visit IRV group) were enrolled. Participants reported predominantly mild-to-moderate reactogenicity, most commonly injection-site pain or feverishness, and no serious adverse reactions. In adults, geometric mean VNA titres on day 365 were 2·0 (95% CI 1·4-2·9) after single-visit, full-dose ChAdOx2 RabG vaccination and 0·4 (0·2-0·7) after single-visit IRV vaccination (geometric mean ratio 5·1 [95% CI 2·5-10·4]; p<0·0001). In children, geometric mean VNA titres on day 365 were 6·1 (4·5-8·2) after single-visit, full-dose ChAdOx2 RabG vaccination and 0·7 (0·5-1·1) after single-visit IRV vaccination (geometric mean ratio 8·6 [5·4-13·9]; p<0·0001). In a post-hoc analysis, day-365 VNA titres in children who received ChAdOx2 RabG exceeded titres in those who received two-visit IRV (geometric mean 3·0 [95% CI 2·2-4·1]; geometric mean ratio 2·0 [1·3-3·1]; p=0·0028). INTERPRETATION: The ChAdOx2 RabG vaccine was safe and well tolerated in Tanzanian adults and children. It achieved robust attainment and maintenance of VNA responses, with titres at day 365 exceeding the correlate of protection (VNA ≥0·5 IU/mL) and titres in licensed vaccine comparator groups. ChAdOx2 RabG might be an option for lower-cost, easier-to-deliver pre-exposure prophylaxis for people in rabies-endemic areas, extending the range of contexts in which pre-exposure prophylaxis is considered a cost-effective option for rabies prevention. FUNDING: UK Medical Research Council. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.