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Background & Aims: Millions of people worldwide are infected chronically with HBV, which results in significant morbidity and mortality. Therapeutic vaccination is a strategy that aims to induce functional cure by restoring cellular immunity to HBV. Previously we have shown the candidate HBV immunotherapeutic vaccine ChAdOx1-HBV, encoding all major HBV antigens and a genetic adjuvant (shark invariant chain), is highly immunogenic in mice. Methods: Here we report the results of HBV001, a first-in-human, phase I, non-randomised, dose-escalation trial of ChAdOx1-HBV assessed in healthy volunteers and patients with chronic HBV (CHB). Results: Vaccination with a single dose of ChAdOx1-HBV was safe and well tolerated in both healthy and CHB cohorts. Vaccination induced high magnitude HBV-specific T cell responses against all major HBV antigens (core, polymerase, and surface) in healthy volunteers. Responses were detected but lower in patients with CHB. T cells generated by vaccination were cross-reactive between HBV C and D genotypes. Conclusions: ChAdOx1-HBV is safe and immunogenic in healthy volunteers and patients with CHB. In further studies, ChAdOx1-HBV will be used in combination with other therapeutic strategies with an aim to overcome the attenuated immunogenicity in patients with CHB. Impact and implications: Therapeutic vaccine ChAdOx1-HBV, a novel treatment for chronic hepatitis B infection (CHB), has been shown to be immunogenic in preclinical studies. In HBV001, a first-in-human phase I study, we show vaccination with ChAdOx1-HBV is safe and generates high magnitude T cell responses in healthy volunteers and lower levels of responses in patients with CHB. This is an important first step in the development of ChAdOx1-HBV as part of a wider therapeutic strategy to induce hepatitis B functional cure, and is of great interest to patients CHB and clinicians treating the condition. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT04297917).

There are varying data concerning the effect of prior anti-vector immunity on the T-cell response induced by immunisation with an identical vectored vaccine containing a heterologous antigen insert. To determine whether prior exposure to ChAdOx1-SARS-CoV2 immunisation (Vaxzevria®) impacts magnitudes of antigen-specific T-cell responses elicited by subsequent administration of the same viral vector (encoding HBV antigens, ChAdOx1-HBV), healthy volunteers that had received Vaxzevria® (n = 15) or the Pfizer or Moderna mRNA COVID-19 vaccine (n = 11) between 10 and 18 weeks prior were recruited to receive a single intramuscular injection of ChAdOx1-HBV. Anti-ChAdOx1-neutralising antibody titers were determined, and vector or insert-specific T-cell responses were measured by a gamma-interferon ELISpot and intracellular cytokine staining (ICS) assay using multiparameter flow cytometry. Participants were followed for three months after the ChAdOx1-HBV injection, which was well-tolerated, and no dropouts occurred. The baseline ChAdOx1 neutralisation titers were higher in the Vaxzevria® cohort (median of 848) than in the mRNA cohort (median of 25). T-cell responses to HBV antigens, measured by ELISpot, were higher on day 28 in the mRNA group (p = 0.013) but were similar between groups on day 84 (p = 0.441). By ICS, these differences persisted at the last time point. There was no clear correlation between the baseline responses to the adenoviral hexon and the subsequent ELISpot responses. As vaccination within 3 months using the same viral vector backbone affected the insert-specific T-cell responses, a greater interval after prior adenoviral immunisation using heterologous antigens may be warranted in settings in which these cells play critical roles.

Summary: Background: Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis virus-based COVID-19 vaccine candidate. Methods: In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo. In Part 1, younger (18–54 years) and, in Part 2, older (≥55 years) adults seronegative for SARS-CoV-2 nucleocapsid received one of four V590 dose levels (5.00 × 105; 2.40 × 106; 1.15 × 107; or 5.55 × 107 plaque-forming units [pfu]) or placebo. In Part 3, a single V590 dose level (5.55 × 10⁷ pfu) or placebo was administered to younger SARS-CoV-2 seropositive adults. Primary endpoints included adverse events (AEs) and for Parts 1 and 2 anti-SARS-CoV-2 serum neutralising antibody responses measured by 50% plaque reduction neutralisation (PRNT50) assay at Day 28. Registration NCT04569786 [P001-02]. Findings: 232 participants were randomised and 219 completed the study. In seronegative participants, anti-SARS-CoV-2 spike-specific antibody responses to V590 were low and comparable to placebo across the lower dose levels. At the highest dose level (5.55 × 107 pfu), anti-SARS-CoV-2 spike-specific PRNT50 was 2.3-fold higher than placebo. The most frequently reported AEs were injection-site pain (38.4%), headache (15.1%) and fatigue (13.4%). Interpretation: V590 was generally well-tolerated. However, Day 28 anti-SARS-Cov-2 spike-specific antibody responses in seronegative participants following a single intramuscular administration of V590 were not sufficient to warrant continued development. Funding: The study was funded by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.