Immunogenicity of MVA-BN vaccine deployed as mpox prophylaxis: a prospective, single-centre, cohort study and analysis of transcriptomic predictors of response

Background: Since 2022, mpox has emerged as a global health threat, with two clades (I and II) causing outbreaks of international public health concern. The third generation smallpox vaccine modified vaccinia Ankara, manufactured by Bavarian Nordic (MVA-BN), has emerged as a key component of mpox prevention. To date, the immunogenicity of this vaccine, including determinants of response, has been incompletely described, especially when MVA-BN has been administered intradermally at a fifth of the registered dose (so-called fractionated dosing), as recommended as a dose-sparing strategy. The aim of this study was to explore the immunogenicity of MVA-BN and baseline determinants of vaccine response in an observational public-health response setting. Methods: We conducted a prospective cohort study and immunological analysis of responses to MVA-BN in patients attending a sexual health vaccination clinic in Oxford, UK. Blood samples were taken at baseline, day 14, and day 28 after first vaccine, and 28 and 90 days following a second vaccine. A subcohort had additional blood samples collected day 1 following their first vaccine (optional timepoint). We assessed IgG responses to mpox and vaccinia antigens using Luminex assay (MpoxPlex) using generalised linear mixed modelling, and T-cell responses using IFN-γ enzyme-linked immunospot and activation-induced marker assay. Associations between blood transcriptomic signatures (baseline, day 1) and immunogenicity were assessed using differential expression analysis and gene set enrichment methods. Findings: We recruited 34 participants between Dec 1, 2022 and May 3, 2023 of whom 33 received fractionated dosing. Of the 30 without previous smallpox vaccination, 14 (47%) seroconverted by day 28, increasing to 25 (89%) 90 days after second vaccination. However, individuals seronegative on day 28 had persistently lower responses compared with individuals seropositive on day 28 (numerically lower antibody responses to six of seven dynamic antigens in the MPoxPlex assay, p<0·05). Serological response on day 28 was positively associated with type I and II interferon signatures 1 day after vaccination (n=18; median module score 0·13 vs 0·06; p=1·1 × 10⁻⁶), but negatively associated with these signatures at baseline (normalised enrichment score −2·81 and −2·86, respectively). Interpretation: Baseline inflammatory states might inhibit MVA-BN serological immunogenicity by inhibiting the upregulation of MVA-induced innate immune signalling. If confirmed mechanistically, these insights could inform improved vaccination strategies against mpox in diverse geographic and demographic settings. Given the likelihood of vaccine supply limitations presently and in future outbreak settings, the utility of dose-sparing vaccine strategies as a general approach to maximising population benefit warrants further study. Funding: UKRI via the UK Monkeypox Research Consortium, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the Kennedy Trust for Rheumatology Research, the John Climax Donation, the Medical Research Council (UK), the Wellcome Trust, the Center for Cooperative Human Immunology (National Institutes of Health), and the National Institute for Health and Care Research Oxford Biomedical Research Centre.