Influence of Population Immunosuppression and Past Vaccination on Smallpox Reemergence

C. Raina MacIntyre; Valentina Costantino; Xin Chen; Eva Segelov; Abrar Ahmad Chughtai; Anthony Kelleher; Mohana Kunasekaran; John Michael Lane


Emerging Infectious Diseases. 2018;24(4):646-653. 

In This Article

Abstract and Introduction


We built a SEIR (susceptible, exposed, infected, recovered) model of smallpox transmission for New York, New York, USA, and Sydney, New South Wales, Australia, that accounted for age-specific population immunosuppression and residual vaccine immunity and conducted sensitivity analyses to estimate the effect these parameters might have on smallpox reemergence. At least 19% of New York's and 17% of Sydney's population are immunosuppressed. The highest smallpox infection rates were in persons 0–19 years of age, but the highest death rates were in those ≥45 years of age. Because of the low level of residual vaccine immunity, immunosuppression was more influential than vaccination on death and infection rates in our model. Despite widespread smallpox vaccination until 1980 in New York, smallpox outbreak severity appeared worse in New York than in Sydney. Immunosuppression is highly prevalent and should be considered in future smallpox outbreak models because excluding this factor probably underestimates death and infection rates.


Smallpox virus was eradicated in 1980 but remains a category A bioterrorism agent.[1] The only official stocks of the virus are in the United States and Russia,[2] but unofficial stocks could be present elsewhere. Advances in synthetic biology of poxviruses and availability of the full variola genome sequence make synthesis of smallpox virus in the laboratory possible.[3] Smallpox could reemerge as a result of bioterrorism or a laboratory accident;[4] thus, smallpox is a high priority for preparedness planning.[5] Given that smallpox is eradicated, mathematical models enable researchers to predict the effects of a smallpox epidemic, but these predictions depend critically on the assumptions of the mathematical model.

Many researchers who have developed smallpox models have been optimistic about residual vaccine-induced immunity and assumed a case-fatality ratio (CFR) of 30%, whereas estimates of outbreaks in nonimmune populations suggest a CFR of 50%–70%.[6] Given the absence of smallpox in the world for nearly 40 years and loss of immunologic boosting from wild-type infection, the CFR of an epidemic today might be higher.

The immunologic status of the population has also changed dramatically in the decades since smallpox eradication. A larger proportion of the population today is unvaccinated, and residual immunity in persons who were vaccinated before 1980 is waning.[7] In addition, the prevalence of HIV, advances in transplantation, and therapies for cancer and many autoimmune conditions have resulted in unprecedented rates of immunosuppression.[8] In 1980, when smallpox was eradicated, HIV had not yet manifested a high global burden of disease. Similarly, bone marrow transplantation was in its infancy, and heart–lung transplantations had not yet occurred. The fact that the proportion of unvaccinated and immunosuppressed persons in the population is increasing has not yet been adequately considered in estimations of the effect of reemergent smallpox.

Persons born after 1980 have no immunity to smallpox because they have never been exposed to wild-type virus or been vaccinated. For vaccinated cohorts, immunity wanes over time, and the highest protection is present during the first 5 years after vaccination, possibly waning to zero within 5–10 years.[9] Furthermore, immunosenescence is a predictable, exponential decline in immune function that occurs after 50 years of age[10] and reduces the body's ability to fight infection and respond to vaccines.[11] This phenomenon further adds to immunosuppression in countries with an aging population. The aim of this study was to estimate the effect of reemerging smallpox in New York, New York, USA, and Sydney, New South Wales, Australia, 2 large cities with different vaccination histories for which estimates could be made on the population's immunologic status.