Safety and immunogenicity of a simian-adenovirus-vectored rabies vaccine: an open-label, non-randomised, dose-escalation, first-in-human, single-centre, phase 1 clinical trial

Abstract

Background: Rabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults.

Methods: We did a single-centre phase 1 study of ChAdOx2 RabG, administered as a single intramuscular dose, with non-randomised open-label dose escalation at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adults were sequentially allocated to groups receiving low (5 × 10⁹ viral particles), middle (2·5 × 10¹⁰ viral particles), and high doses (5 x 10¹⁰ viral particles) of ChAdOx2 RabG and were followed up to day 56 after vaccination. The primary objective was to assess safety. The secondary objective was to assess immunogenicity with the internationally standardised rabies virus neutralising antibody assay. In an optional follow-up phase 1 year after enrolment, we measured antibody maintenance then administered a licensed rabies vaccine (to simulate post-exposure prophylaxis) and measured recall responses. The trial is registered with ClinicalTrials.gov, NCT04162600, and is now closed to new participants.

Findings: Between Jan 2 and Oct 28, 2020, 12 adults received low (n=3), middle (n=3), and high doses (n=6) of ChAdOx2 RabG. Participants reported predominantly mild-to-moderate reactogenicity. There were no serious adverse events. Virus neutralising antibody concentrations exceeded the recognised correlate of protection (0·5 IU/mL) in three middle-dose recipients and six high-dose recipients within 56 days of vaccination (median 18·0 IU/mL). The median peak virus neutralising antibody concentrations within 56 days were 0·7 IU/mL (range 0·0-54·0 IU/mL) for the low-dose group, 18·0 IU/mL (0·7-18·0 IU/mL) for the middle-dose group, and 18·0 IU/mL (6·0-486·0 IU/mL) for the high-dose group. Nine participants returned for the additional follow-up after 1 year. Of these nine participants, virus neutralising antibody titres of more than 0·5 IU/mL were maintained in six of seven who had received middle-dose or high-dose ChAdOx2 RabG. Within 7 days of administration of the first dose of a licensed rabies vaccine, nine participants had virus neutralising antibody titres of more than 0·5 IU/mL.

Interpretation: In this study, ChAdOx2 RabG showed an acceptable safety and tolerability profile and encouraging immunogenicity, supporting further clinical evaluation.

Funding: UK Medical Research Council and Engineering and Physical Sciences Research Council.

Figure 1. Trial profile

Figure 2. Solicited adverse events following vaccination with ChAdOx2 RabG

For each of the individual-solicited local (A) and systemic (B) reactions, the maximum severity reported by each volunteer over the 7 days after vaccination is shown. In addition, to provide a global view of reactogenicity, the highest graded of all local and all systemic reactions is shown for each volunteer.

Figure 3. Rabies virus neutralising antibody responses

Virus neutralising antibody responses at each measured timepoint are shown for group 1 (low dose, A), group 2 (middle dose, B) and group 3 (high dose, C). Arrowheads indicate administration of Rabipur (an inactivated rabies vaccine), with samples having been collected before Rabipur administration on applicable days. Each datapoint represents an individual volunteer, with lines connecting datapoints from an individual. Horizontal dashed line indicates 0·5 IU/mL (indicator of adequate vaccination). The same data are in the appendix (p 10).

Figure 4. Rabies glycoprotein-binding antibody responses

Total glycoprotein-binding IgG responses at each measured timepoint are shown for group 1 (low dose, A), group 2 (middle dose, B), and group 3 (high dose, C). Arrowheads indicate administration of Rabipur (an inactivated rabies vaccine), with samples having been collected before Rabipur administration on applicable days. Each datapoint represents an individual volunteer, with lines connecting datapoints from an individual. Endpoint titres of glycoprotein-binding immunoglobulin isotypes and subclasses at day 28 after administration of ChAdOx2 RabG are shown (D). Each datapoint represents an individual volunteer.