The global landscape of smallpox vaccination history and implications for current and future orthopoxvirus susceptibility: a modelling study

Abstract

Background: More than four decades after the eradication of smallpox, the ongoing 2022 monkeypox outbreak and increasing transmission events of other orthopoxviruses necessitate a greater understanding of the global distribution of susceptibility to orthopoxviruses. We aimed to characterise the current global landscape of smallpox vaccination history and orthopoxvirus susceptibility.

Methods: We characterised the global landscape of smallpox vaccination at a subnational scale by integrating data on current demography with historical smallpox vaccination programme features (coverage and cessation dates) from eradication documents and published literature. We analysed this landscape to identify the factors that were most associated with geographical heterogeneity in current vaccination coverage. We considered how smallpox vaccination history might translate into age-specific susceptibility profiles for orthopoxviruses under different vaccination effectiveness scenarios.

Findings: We found substantial global spatial heterogeneity in the landscape of smallpox vaccination, with vaccination coverage estimated to range from 7% to 60% within admin-1 regions (ie, regions one administrative level below country) globally, with negligible uncertainty (99·6% of regions have an SD less than 5%). We identified that geographical variation in vaccination coverage was driven mostly by differences in subnational demography. Additionally, we found that susceptibility for orthopoxviruses was highly age specific based on age at cessation and age-specific coverage; however, the age profile was consistent across vaccine effectiveness values.

Interpretation: The legacy of smallpox eradication can be observed in the current landscape of smallpox vaccine protection. The strength and longevity of smallpox vaccination campaigns globally, combined with current demographic heterogeneity, have shaped the epidemiological landscape today, revealing substantial geographical variation in orthopoxvirus susceptibility. This study alerts public health decision makers to non-endemic regions that might 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.

Funding: US National Institutes of Health and US National Science Foundation.

Figure 1.. The global landscape of smallpox vaccination.

(A) Population smallpox vaccination coverage at the admin-1 scale globally. (B) Relationship between the current average national population smallpox vaccination coverage and (left) average national smallpox vaccination coverage near cessation, (middle) the year that routine smallpox vaccination ceased within the country, and (right) the proportion of the country’s current population that was born before 1980. The black lines are based on linear regressions of the data, and are meant to guide the eye, rather than assert a linear relationship. Outlier countries are Australia and New Zealand (low coverage), Cuba (early cessation), and the United Kingdom (low coverage).

Figure 2.. The role of demography and vaccination in shaping the current smallpox vaccination landscape.

We illustrate differences in current vaccination coverage due to three counterfactual scenarios: (A) All countries ceased routine smallpox vaccination in 1984. (B) All countries achieved 100% vaccination coverage before cessation. (C) All administrative regions have the same global average age distribution.

Figure 3.. Demography drives susceptibility differences, with magnitude determined by vaccine effectiveness and differences by age group determined by waning.

We illustrate susceptibility profiles for countries with varying vaccination cessation dates and reported coverages. Vaccine effectiveness values ranging from 30 to 90% are shown, which overlap with reported estimates in the literature for monkeypox, Variola major, and Variola minor (see Figure S31), under overall population waning. We additionally illustrate an individual-level waning scenario with 1·4% per year since time of vaccination, assuming all eligible individuals were vaccinated by 5 years of age or in 1980, whichever is earlier.