Effectiveness of one dose of MVA-BN smallpox vaccine against monkeypox in England using the case-coverage method

Background Like many other countries worldwide, the UK experienced a national outbreak of monkeypox disease in May 2022, with case numbers rising rapidly, mainly among gay, bisexual and other men who have sex with men (GBMSM). To control the outbreak, Modified Vaccinia Ankara–Bavaria Nordic (MVA-BN), an attenuated smallpox vaccine, was offered to high-risk GBMSM. We assessed the effectiveness of a single MVA-BN dose against monkeypox disease in high-risk GBMSM. Methods Monkeypox cases in England were sent questionnaires collecting information on demographics, vaccination history and symptoms. Returned questionnaires with a rash onset date (or alternative proxy) between July 04 and October 09, 2022 were included. Females, heterosexual men, and those with missing vaccination information were excluded. Vaccine effectiveness was calculated using the case-coverage method where vaccine coverage among cases is compared to coverage in the eligible population, estimated from doses given to GBMSM and the estimated size of high-risk GBMSM. Sensitivity analysis included +/-20% differences in estimated high-risk GBMSM population size. Findings Vaccine uptake among eligible GBMSM increased steadily from July 2022, reaching 47% by October 09, 2022. Of the 363 confirmed cases, 8 occurred ≥14 days after vaccination, 32 within 0-13 days after vaccination, and the rest were unvaccinated. The estimated vaccine effectiveness ≥14 days after a single dose was 78% (95% CI: 54%-89%), with a range of ±7% in sensitivity analyses. Vaccine effectiveness within 0–13-days after vaccination was -4% (95% CI: -50% to 29%). Interpretation A single MVA-BN dose was highly protective against monkeypox disease among high-risk GBMSM. Funding None Evidence before this study We searched PubMed using the terms ‘monkeypox’, ‘MVA’ and ‘vaccine’, with no time limit, and used the snowball process to identify additional relevant publications. We also searched websites of regulatory authorities (FDA, EMA) for any data used during the regulatory approval processes. We also scoped pre-print databases vaccine effectiveness studies during the current outbreak. Only publications related to the Modified Vaccinia Ankara – Bavaria Nordic (MVA-BN) vaccine were included. In the UK, MVA-BN was offered to high-risk GBMSM to control a national outbreak which began in May 2022. MVA-BN is now licensed against smallpox in the US, Europe and the UK, there are, however, limited data on vaccine effectiveness against monkeypox. Preclinical studies indicated two vaccine doses were immunogenic and generated antibody levels considered protective against smallpox. Vaccine-induced antibodies are also cross-protective against monkeypox virus in vitro and in animal models. A recent, as yet unpublished, Israeli study estimated 79% vaccine effectiveness after one dose in high-risk GBMSM, while a US study reported unvaccinated individuals to be 14 times more likely to develop monkeypox disease than vaccinated persons. Added value of this study Few countries have recommended or introduced large-scale vaccination against the current global outbreak of monkeypox disease among GBMSM in non-endemic countries. The offer of MVA-BN to high-risk GBMSM through sexual health clinics in England provided a unique opportunity to rapidly assess vaccine effectiveness after a single dose using the case-coverage method, which involves comparing vaccine coverage in cases to vaccine coverage in the eligible population. Our vaccine effectiveness estimate of 78% at least 14 days after one MVA-BN dose is consistent with Israeli estimates and provided additional evidence of a lack of protection during the first 13 days after vaccination. Implications of all the available evidence A single dose of MVA-BN is highly protective against monkeypox disease and provides a useful tool for outbreak control when rapid protection may be needed. Given the lack of effectiveness in the first 13 days after the first dose and a median incubation period of 8-9 days after exposure to the virus, vaccination is likely to be most effective when offered as pre-exposure rather than prophylaxis. Because of the high vaccine effectiveness after one MVA-BN dose, in outbreaks where number of at-risk individuals exceed vaccine supply of two-doses, there may be benefit in prioritising delivery of first doses at the expense of delaying the second dose. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the UK Health Security Agency ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UK Health Security Agency Research Ethics and Governance Group waived ethical approval for this work. The study was conducted in accordance with the relevant guidelines and regulations under permissions granted to UK Health Security Agency (UKHSA, formerly Public Health England) under Regulation 3 of The Health Service (Control of Patient Information) Regulations 2020 and under Section 251 of the NHS Act 2006 (United Kingdom legislation). Specifically, all data were collected within the statutory approvals granted to the UKHSA for infectious disease surveillance and control. Information was held securely and in accordance with the Data Protection Act 2018 (United Kingdom legislation) and Caldicott Principles (UK, ). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript.