Immunogenicity of MVA-BN Vaccine Deployed as Mpox Prophylaxis: A Prospective Cohort Study and Analysis of Transcriptomic Predictors of Response

Abstract

Background: Since 2022, mpox has emerged as a salient 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.

Methods: We conducted a prospective cohort study and immunological analysis of responses to MVA-BN in patients attending a vaccination clinic in Oxford, UK. Blood samples were taken at baseline, day 14, day 28, and 28 and 90 days following a second vaccine. A sub-cohort had additional blood samples collected day 1 following their first vaccine (optional additional timepoint). We assessed IgG responses to mpox/vaccinia antigens using Luminex assay (‘MpoxPlex’), and T-cell responses using interferon-g 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 correlated with of type I and II interferon signatures day one post-vaccination (n=18 samples) but negatively correlated 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.

Funding: This work is supported by funding from UKRI to the UK Monkeypox Research Consortium; Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences 2018-I2M-2- 002, the Kennedy Trust for Rheumatology Research (KENN 20 21 02), the John Climax Donation, and a Center for Cooperative Human Immunology (US NIH 5-U19AI142737-05) Infrastructure and Opportunity Fund (IOF) subaward to NMP. This research was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC).

Declaration of Interest: NMP receives consulting fees from Infinitopes. AO is a contributor to WHO Mpox diagnostic guidance. AS is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals, Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work.

Ethical Approval: The study protocol was approved by the UK NHS Ethics committee (London – Surrey Borders Research REC ref 22/PR/1425). All participants provided written informed consent prior to any study procedures.

Keywords: mpox, Vaccine, MVA-BN, Transcriptomics, serology, T cell