The global landscape of susceptibility to orthopoxviruses: The legacy of smallpox vaccination
Authors: Taube Juliana C. , Rest Eva C. , Lloyd-Smith James O. , Bansal Shweta 
Published: July 2022

AbstractBackgroundMore than four decades after the eradication of smallpox, the ongoing 2022 monkeypox out-break and increasing transmission events of other orthopoxviruses necessitate a deeper understanding of the global distribution of susceptibility to orthopoxviruses, as shaped by the landscape of smallpox vaccination pre-eradication.MethodsWe characterize the fine-scale global spatial landscape of orthopoxvirus vulnerability based on geographical heterogeneity in demography and past smallpox vaccination program features, including vaccination coverage and cessation dates. For the United States, we also consider the role of immigration in shaping the landscape of protection.FindingsWe find significant global spatial heterogeneity in the landscape of orthopoxvirus susceptibility, with monkeypox susceptibility ranging from near 57% to near 96% within admin-1 regions globally, with negligible uncertainty in most regions. We identify that this variation is driven largely by differences in sub-national demography.InterpretationThe legacy of smallpox eradication can be observed in the current landscape of susceptibility for orthopoxviruses, including monkeypox. The strength and longevity of the smallpox vaccination campaign in each nation shape the epidemiological landscape today and reveal significant geographic variation in vulnerability. Our work alerts public health decision-makers to non-endemic regions that may be at greatest risk in the case of widespread and sustained transmission in the 2022 monkeypox outbreak and highlights the importance of demography and fine-scale spatial dynamics in predicting future public health risks from orthopoxviruses.FundingResearch reported in this publication was supported by the National Institutes of Health under award number R01GM123007 (SB) and National Science Foundation DEB-1557022 (JOL-S).Research in ContextEvidence before this studyWe searched the Red Book, WHO eradication documents, Bulletin of the World Health Organization and Morbidity and Mortality Weekly Report digital archives, and published literature and reports via Google Scholar and PubMed for data on smallpox vaccination coverage rates and cessation dates for each country. Search terms included: “smallpox vaccination cessation”,”end of smallpox vaccination”, “stop smallpox vaccination”, “smallpox vaccination coverage”, “smallpox scar surveys”, and “smallpox serum surveys”, combined with each country name. While the Red Book covers much of the smallpox eradication efforts in Africa, Asia, and South America, information on countries in Europe, Central America, the Middle East, and Oceania was sparse and scattered.Added value of this studyWe characterize the fine-scale global spatial landscape of orthopoxvirus vulnerability based on geographical heterogeneity in demography and past smallpox vaccination program features, including vaccination coverage and cessation dates. We find significant spatial heterogeneity in orthopoxvirus susceptibility, driven in large part by age structure, specifically what proportion of the population in a region was born before smallpox vaccination cessation. We contribute an open (and living) database of all subnational susceptibility estimates and uncertainties as an immediate resource for the global health community working on the monkeypox outbreak.Implications of all of the available evidenceOur findings highlight the need to consider spatial clustering of susceptible individuals and the importance of fine-scale spatial analysis in light of increased risk of orthopoxvirus emergence. In the event that transmission becomes widespread during the 2022 global monkeypox outbreak, our vulnerability map can inform public health efforts on identifying non-endemic regions and age cohorts at greatest risk, allocation of scarce vaccine supplies, and predicting transmission dynamics in concert with data on contact patterns, mobility and real-time prevalence.