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Modeling Smallpox in 2018: The Role of the Immunosuppressed Population

Amesh A. Adalja, MD, FACP, FACEP, FIDSA, March 13, 2018

Although smallpox is the only human infectious disease that has been eradicated from the planet, it remains one of the most feared infectious diseases because of its virulence and transmissibility, coupled with the existence of a largely immunologically naïve population. The immunological gap that human populations have to smallpox arises from the cessation of routine vaccination against the disease as well as waning of immunity in those who were vaccinated decades ago. A new modeling study, published in Emerging Infectious Diseases, attempts to understand what a smallpox outbreak would look like in 2 major cities in the modern context of waning immunity, immunosuppressed individuals, and people who have never been vaccinated.


New York City and Sydney Populations Simulated

In this modeling study, MacIntyre and colleagues constructed a standard SEIR model of a smallpox outbreak in Sydney, Australia, and New York City. Populations were stratified by age as well as by immunosuppressed status (using estimates that are available). Assumptions were made concerning the vaccine status of populations. 

In New York, it was assumed that 80% of those aged 40 to 69 were vaccinated, and in Sydney, where widespread smallpox vaccination did not occur, 30% of those born before 1980 were assumed to be vaccinated. The authors estimated, based on a prior study, that smallpox immunity to severe disease wanes 1.41% per year after vaccination. Behavior modification adjustments were made to contact rates to account for symptomatic cases diminishing their social interaction. Hemorrhagic, flat, ordinary, and vaccine-modified forms of disease were included, with different probabilities assigned to specific cohorts.


Immunosuppression Drives Deaths

Running the model, it was shown that those aged 5 to 19 were at the highest risk of infection, with death rates peaking in the 65- to 69-year age group, and peaking 60 days after the start of the outbreak. In New York, another peak of deaths of smaller magnitude was noted in those aged 35 to 39. Death peaks reflected the age demographics in which immunocompromised individuals cluster, while transmission was driven by higher contact rates of younger demographics. Vaccine-induced immunity attenuated death rates in the 40- to 65-year age group in New York. At peak infection rates in the model, New York reached a 0.496/1,000 population rate, while Sydney reached 0.452/1,000 population in 70 days. Death rates reached 0.151 deaths/1,000 population in New York and 0.133/1,000 in Sydney by day 70.


Planning for All Populations

This study, if its assumptions are correct, concretizes an important aspect of planning for a smallpox outbreak in the modern era: The sheer number of immunosuppressed individuals will magnify the impact of the virus. With the advent of organ and bone marrow transplants, autoimmune disease therapies, and HIV, in New York 1 in 5 and in Sydney 1 in 6 individuals is immunosuppressed. Even waning vaccine immunity is outweighed by this factor.

In the event of the reemergence of smallpox through a lab accident or as a biological weapon, the smallpox vaccine is the chief medical countermeasure that will be deployed to halt its spread. The standard smallpox vaccines (ACAM, Dryvax) are contraindicated in immunosuppressed individuals, and this population has now grown sizable enough to have an impact on the trajectory of the outbreak and contribute to the number of severe cases and deaths. An important component of pandemic preparedness will be protecting immunosuppressed people through alternative vaccines (eg, MVA, LC16m8) that are safer for this population.



MacIntyre CR, Costantino V, Chen X, et al. Influence of population immunosuppression and past vaccination on smallpox reemergence. Emerg Infect Dis 2018;24(4). Accessed March 11, 2018.