Immunogenicity of MVA-BN vaccine deployed as mpox prophylaxis: a prospective 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 1/5th the registered dose (‘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 sub-cohort had additional blood samples collected day 1 following their first vaccine (optional timepoint). We assessed IgG responses to mpox/vaccinia antigens using Luminex assay (‘MpoxPlex’) via generalised linear mixed modelling, and T-cell responses using interferon- 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 of whom 33 received fractionated dosing. Of those without prior smallpox vaccination (n=30), 50% seroconverted by day 28, and while this increased to 89% by day 90 post second vaccination, individuals seronegative on day 28 demonstrated persistently lower responses compared to day 28 seropositive individuals. Serological response on day 28 positively associated with type I and II interferon signatures day one post-vaccination (n=18 samples) but negatively associated with these signatures at baseline. Interpretation: Baseline inflammatory states may inhibit MVA-BN serological immunogenicity by inhibiting the upregulation of MVA-induced innate immune signalling. If confirmed mechanistically these insights may inform improved vaccination strategies against mpox in diverse geographic and demographic settings. Given the likelihood of vaccine supply limitations in the current context and in future outbreak settings, the utility of dose-sparing vaccine strategies as a general approach to maximising population benefit warrants further study