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


With each passing year, population immunosuppression is a more influential determinant than residual vaccine immunity of the severity of a smallpox epidemic. Although the spread of disease is highest in younger age groups, driven mostly by their higher contact rates, higher death rates were seen in older populations, reflecting the prevalence of immunosuppression.

The differences between New York, which has high vaccination coverage (an estimated ≈22% of the population), and Sydney, which has low (≈10%) vaccination coverage, demonstrate that residual immunity assumptions are not as influential in Sydney as in New York. However, the consideration of population immunosuppression, from medical conditions to iatrogenic factors, strongly affects disease transmission and deaths in both cities. This large population subset must be considered when modeling the impact of any infectious disease outbreak. We estimated conservatively that almost 1 in 5 persons in New York and 1 in 6 persons in Sydney (and higher for the 60–64-year age group) are living with some degree of immunosuppression. Although New York has higher rates of immunosuppression for the 25–84-year age groups, Sydney has higher rates than New York for the youngest (0–19 years) and the oldest (>85) populations.

Residual immunity affects age-specific infection and death rates, with both cities showing the highest infection rates for unvaccinated young persons 5–19 years of age. However, death rates rise after 40 years of age, despite higher vaccination coverage in this age group. For Sydney, even an assumption of higher immunity does not affect the infection or death rates greatly because of the low vaccine coverage before 1980. However, residual immunity becomes more influential if we use more optimistic assumptions of waning immunity. Note that persons who have been vaccinated would mount a more robust and rapid response to revaccination in the event of an outbreak and might be better protected after postexposure vaccination. Obtaining a vaccination history and checking for a consistent scar are necessary parts of outbreak management.

Although immunosuppression is a major determinant of the size and distribution of a smallpox outbreak, this fact should not be a major determinant of vaccination policy. Immunosuppression should continue to be an absolute contraindication for vaccination of persons who are not true contacts. Ensuring that persons with immunosuppression (including healthcare workers) avoid contact with persons with smallpox (if possible) should be a priority. Smallpox would always be more pathogenic than vaccinia virus, so any patient with a bona fide exposure to smallpox should be vaccinated with a fully potent vaccinia strain, such as ACAM2000.[44] If such patient develops a serious complication, such as eczema vaccinatum or progressive vaccinia, the patient can be treated with ST-246 (Siga Technologies, New York, NY, USA).[45]

Our study is subject to some limitations. We used an underestimate of immunosuppression; other conditions causing immunosuppression, such as diabetes, were not considered. We also used conservative estimates for the increased risk for infection in immunosuppressed persons and grouped persons with severe and moderate immunosuppression into single categories because of the absence of more specific data to categorize them further by degree of immunosuppression. The contact matrix we used was estimated in a study conducted in the United Kingdom in 2006, which might not necessarily reflect New York or Sydney social contact patterns.[37] Furthermore, contacts with symptomatic infectious patients will probably drop to near zero once an outbreak has been confirmed and patients are well isolated, assuming adequate health system capacity for isolation and treatment of smallpox patients. The data in the model on age-specific rates of smallpox were obtained from hospitalized patients,[9] which might overestimate the rates of severe disease in the model outputs.

The speed and vigor with which smallpox control efforts are implemented should be major aspects of control efforts and need to be tested in a model that accounts adequately for immunosuppression. Ensuring adequate hospital care and isolation facilities will also help in epidemic control. During the Ebola epidemic in West Africa, lack of beds resulted in widespread community transmission, and modeling showed that 70% of patients needed to be in treatment facilities to control the epidemic.[46] The response to severe acute respiratory syndrome, with its rapid control despite the lack of a vaccine or antiviral agent, showed that patient isolation can be very successful.[47] Experiences with severe acute respiratory syndrome, Ebola, and Middle East respiratory syncytial coronavirus also illustrate the heavy toll on healthcare workers,[48] who should be assumed to be at high risk for infection in the event of a smallpox outbreak.

Given waning smallpox vaccine immunity (nearly 4 decades since eradication and a dwindling vaccinated population), the influence of population immunosuppression is greater than that of residual vaccine immunity, yet has not been adequately considered in smallpox epidemic modeling. Advances in medicine and new endemic diseases, such as HIV, have resulted in almost 1 in 5 persons living with immunosuppression in large metropolitan cities. Immunosuppression must be considered in preparedness planning and poses a challenge for vaccination strategies during potential smallpox outbreaks.