Predicting vaccine effectiveness in Mpox
Authors: Berry Matthew T. , Khan Shanchita R. , Schlub Timothy E. , Notaras Adriana , Kunasekaran Mohana , Grulich Andrew E. , MacIntyre C Raina , Davenport Miles P. , Khoury David S. 
Published: November 2023

AbstractThe Modified Vaccinia Ankara vaccine developed by Bavarian Nordic (MVA-BN) was widely deployed to prevent Mpox during the 2022 global outbreak. This vaccine was initially approved for Mpox based on its reported immunogenicity and effectiveness in animal models, rather than evidence of clinical efficacy. However no validated correlate of protection after vaccination has been identified. Here we performed a systematic search and meta-analysis of the available data to test whether vaccinia-binding ELISA endpoint titer is predictive of vaccine effectiveness against Mpox. We observe a significant correlation between vaccine effectiveness and vaccinia-binding antibody titers, consistent with the existing assumption that antibody levels may be a correlate of protection. Combining this data with analysis of antibody kinetics after vaccination, we predict the durability of protection after vaccination and the impact of dose spacing. Although further work is required to validate this correlate, this study provides the first evidence-based approach for using antibody measurements to predict the effectiveness of Mpox vaccination.Mpox virus (formerly Monkeypox) is a zoonotic virus endemic in West Africa, with significant outbreaks in 1980-1986 and in 1997-19981, resulting in over 20,000 total recorded cases. Prior to 2017, these outbreaks were typically small and initiated by zoonotic transmission followed by self-terminating human-to-human chains of transmission2. However, since 2017, there has been a resurgence of Mpox in Nigeria, Democratic Republic of the Congo (DRC) and other parts of Africa, attributed to waning immunity from smallpox vaccines and accumulation of cohorts that have never been vaccinated against smallpox3. In 2022, a global outbreak of Mpox resulted in 91000+ confirmed cases in 115 countries and established chains of human-human transmission leading to a renewed focus on vaccination as a preventative measure for Mpox4.Although there is no Mpox-specific vaccine, first generation smallpox vaccination was observed to protect individuals against Mpox infection during the 1980-1986 Mpox outbreak in the DRC (then Zaire)5-8, with an estimated vaccine effectiveness of approximately 85%5, and this has also been observed in similar subsequent studies9-11. However, the livereplicating vaccinia vaccines (first and second-generation) have significant risks of serious vaccine adverse events12, which led to the development of the third-generation Modified Vaccinia Ankara live-attenuated (replication deficient) vaccine (MVA-BN). Prior to the 2022 Mpox outbreak, MVA-BN was approved by the FDA for use as a Smallpox and Mpox vaccine (two doses of 1 × 108TCID via subcutaneous injection). Given the challenge of directly assessing the efficacy of this vaccine in an RCT, regulatory approval was based on demonstrated non-inferior immunogenicity profile and improved safety compared to the second-generation ACAM2000 vaccine13. In particular, comparing vaccinia neutralizing antibody titers induced by vaccination of MVA-BN and ACAM2000, it was deemed “reasonable to expect that this regimen of the vaccine is effective in smallpox vaccinia-naïve as well as in smallpox vaccine experienced individuals”13. This was supported by studies in nonhuman primates implicating antibodies directly in mediating protection against lethal Mpox challenge14.Analysis of case data during the 2022 global outbreak indicates that the MVA-BN vaccine is effective for prevention of Mpox15-20, and affirms the decisions to use these vaccines during the outbreaks. However, important questions remain to be addressed. Firstly, how does MVA-BN effectiveness compare with the protection conferred by the live replicating smallpox vaccines, and how many doses are required? Further, is the protection from MVA-BN vaccination expected to be durable, and will further booster doses be required to confer durable protection against Mpox and protect individuals in potential future outbreaks?Here we address these questions by aggregating the available data on the effectiveness of different vaccinia-based vaccination regimes in protection against Mpox. We compare protection from first generation smallpox vaccines with the protection conferred by one or two doses of the MVA-BN vaccine. Further, given the assumed role of antibodies, we aggregate data on vaccinia-specific ELISA endpoint titers (here after referred to as vaccinia-binding titers) after MVA-BN vaccination (which have been shown to correlate with neutralizing antibody titers to Mpox after vaccinia vaccination21), and study the relationship between antibody levels and effectiveness. Finally, we analyze the kinetics of antibody decay over time to predict the duration of protection afforded by 1, 2 or 3 doses of vaccination. This work offers a data-driven approach to support public health decision making on Mpox vaccination and boosting campaigns.