The term “disease” refers to case-patients with clinical symptoms caused by either smallpox or serious vaccine-related adverse events. The phrase “serious vaccine-related adverse events” includes death, postvaccinial encephalitis, and progressive vaccinia. Each serious side-effect requires medical care, such as vaccinia immunoglobulin, hospitalization, or a number of visits to a physician’s office. In 1968, the rate of postvaccinial encephalitis and progressive vaccinia among first time vaccinees ranged from approximately 0.3 to 1.2 in 100,000 for those aged 1–19 years, 0.7 to 4 in 100,000 for those <1 year of age, and 0 to 1.4 in 100,000 for those >20 years of age (20,21). As most preevent vaccinees are likely to adults, I used a rate of 1/100,000 vaccinees (P _SideEffect, Table). Vaccine-related adverse events such as eczema vaccinatum, soreness or redness at site of vaccination, headache, and mild and temporary nausea are not considered to be serious vaccine-related adverse events in the model. A risk for eczema vaccinatum occurs in about 1 in 100,000 primary vaccinations (20), which can result in serious consequences requiring intensive medical care, and even (rarely) death (6). I thus underestimate the risk for vaccine-related adverse events, biasing the model toward acceptance of vaccination.

If net risk for disease is >0, then the risk for disease from smallpox is greater than the risk for serious vaccine-related adverse events, and a person would chose preexposure vaccination. If the net risk for disease is <0, then the risk for serious vaccine-related adverse events is greater than the risk for smallpox, and an individual person would chose no preexposure vaccination.

I use the model to evaluate the net risk for disease faced by a person who is a member of one of the following three groups: 1) The general population. The model compares the risk of being a smallpox patient before an attack is detected to the risk for serious vaccine-related adverse events from preexposure vaccination. The risk of being an actual smallpox patient is modeled by setting the risk for transmission at 1 (Table). Two populations “at risk” are modeled: a population of 9 million, representing a metropolitan area assumed to be the sole target, and the entire U.S. population of approximately 280 million. 2) The healthcare community. For a healthcare worker (HCW) who faces potential exposure to smallpox as a result of caring for a person with smallpox, the risk of contracting smallpox from the patient is compared with the risk for serious vaccine-related adverse events attributable to preexposure vaccination. 3) A smallpox investigation team. For a person who is trained to be deployed to investigate potential patients or attacks (i.e., deliberately seek out potential smallpox patients and material that may be contaminated by smallpox), the risk for contracting smallpox from the patient or other source of smallpox (e.g., aerosol, container) is compared with the risk for serious vaccine-related adverse events from preexposure vaccination. Investigation team members will take precautions to reduce risk for transmission (e.g., wear gloves, face masks, and gowns), reducing risk for transmission to an assumed 0.4 (no data exist regarding the actual reduction in risk attributable to using such barrier precautions).

For all scenarios, after an attack is detected, I assume that appropriate responses will be taken, including effective isolation of patients (2) and vaccination of susceptible contacts. Thus, the results only apply up to the point of discovery of the bioterrorist event.

In the model, I assume that persons considering preexposure vaccination value equally the risk for disease from either smallpox or from serious vaccine-related adverse events. In reality, a person may be more worried about contacting a clinical case of smallpox than of experiencing serious vaccine-related adverse events. The risk of dying from smallpox vaccine is approximately 1:1,000,000 vaccinees (20,21), while the death rate due to smallpox may be as high as 30% of all unvaccinated clinical cases (23,24). Using the relative risk of death, I set a comparative value of 1 case of smallpox = 35 cases of serious vaccine-related adverse events (P_Valuation = 1/35 = 0.02857).² Other sensitivity analyses include increasing the number of cases of smallpox before detection of the attack from 1,000 to 100,000 (Table), and setting the risk for serious vaccine-related adverse events to either 1 in 10,000 or 1 in 1,000,000. The former represents the risk of experiencing probable vaccine-related myo/pericarditis, as measured during the current smallpox vaccination program among civilians (25). The latter is the risk, measured in the 1960s, of serious vaccine-related adverse events (e.g., postvaccinial encephalitis and progressive vaccinia) among revaccinees (20,21).

The model can used to evaluate a person’s perspective of the risks and benefits of receiving a smallpox postexposure vaccination. I considered a person who has been exposed to somebody who may or may not have smallpox. To model such uncertainty, I set P_R = 1, and let P_E range from 1 in 10 to 1 in 100,000. I then assumed either a postexposure vaccine efficacy of 10% (P_VEpost, Sensitivity analyses, Table) and a risk for transmission of 70% (P_T, Sensitivity analyses, Table), or a postexposure vaccine efficacy of 60% and a risk for transmission of 35%. Additional sensitivity analyses can further vary the values for transmission and efficacy of postexposure vaccination.

I also considered the case in which a person has been exposed to a definite smallpox case (i.e., P_R = 1, P_E = 1). I examined the risk-benefit of postexposure vaccination using a range of risks for vaccine-related adverse events, from 1 in 500 vaccinees to 1 in 100,000 vaccinees. This range encompasses the risks for serious vaccine-related adverse events faced by those without any contraindications for receiving the vaccine, as well as those who would have contraindications for receiving preexposure vaccination (e.g., pregnant women, those with auto-immune diseases, HIV-positive persons). I modeled a “worst case” approach and assumed that postexposure vaccine efficacy would only be 1% (representing, for example, a delay of several days between exposure and being offered the vaccine). The risk for transmission was set at either 1% or 30%, representing possible scenarios, for example, the person considering postexposure vaccination was appropriately wearing gloves, gown, and mask in the presence of the infected person or only had a very brief contact.

No data exist that record the percentage of persons in a cohort who remain free from smallpox over time (in years) after immunization against smallpox.³ Data from relatively small studies describe levels (titers) of vaccine-induced neutralizing antibodies for up to 50 years after vaccination or revaccination (28,29). No data correlate antibody titers to immunity from disease. Without data describing the duration of protection afforded by a single vaccination, the current model does not consider the need for additional revaccinations over time. Thus, the results for this model only apply to the primary vaccinations. The model does not discount risk over-time, although some evidence exists that persons have a high discount rate for personal health issues (30).

If a member of the general population of 280 million were to equate 1 case of smallpox to 35 cases of serious vaccine-related adverse events, they would accept preexposure vaccination only if the risk for a smallpox attack approached 1 in 10 (Figure 2a). However, if the risk for attack is assumed to be 1 in 100, then the person would have to equate 1 case of smallpox to 290 cases of serious vaccine-related adverse events to accept preexposure vaccination (data not shown). If a person assumes both that the initial attack would cause 100,000 cases before detection and that 1 case of smallpox is equivalent to 35 cases of serious vaccine related adverse events, then the risk for attack would have to be >1 in 1,000 to accept preexposure vaccination (Figure 2b).

Assuming a risk for serious vaccine-related adverse events of 1 in 10,000 (25) and the same values used to produce Figure 1a, a person in a population of 9 million would not accept vaccination even if the risk for attack were 1 in 2. When the same risk for adverse events is used in considering the scenarios evaluated in Figure 2b (100,000 cases before detection, valuation of 1 case smallpox = 35 cases of vaccine-related adverse events), the risk for attack would have to be >8 in 1,000 before accepting vaccination (results not shown).

For a person in a population of 280 million who is considering preexposure revaccination with a risk for serious vaccine-related adverse events of 1 in 1,000,000, even at a 1 in 10 risk for smallpox attack, the net risk is <0, and the decision criteria would indicate not accepting revaccination (scenario assumed 1,000 smallpox cases before discovery of the attack, and setting P_Valuation = 1:1). In the same scenario, if P_Valuation = 1:35, then the risk for a smallpox attack would have to be >1 in 125 for a person to accept revaccination. For a HCW to accept preexpsoure vaccination, the risk for attack would have to be >1 in 700 (risk for contact = 1-in-1,000; P_Valuation = 1:1; revaccination P_SideEffect = 1-in-1,000,000). If the HCW assumed that the risk for contact increased to 1 in 100, then the risk for attack would have to be >1 in 7,000 in order to accept revaccination.

After uncertain exposure to smallpox (e.g., contact with a person who may or may not be infectious with smallpox), the decision criteria would indicate acceptance of postexposure vaccination if the risk for exposure is thought to be >1 in 21,000; the risk for transmission is assumed to be 35%, and efficacy of postexposure vaccine is 60% (Figure 3a). If the risk for transmission is assumed to be 70%, but postexposure vaccine efficacy only 10% (e.g., postexposure vaccination offered several days after potential exposure), vaccination would be accepted only if the risk for exposure is assumed to be >1 in 8,000 (Figure 3a). If postexposure vaccine efficacy were set at 98%, and risk for transmission at 70%, then risk for actual exposure to smallpox would have to be >1 in 69,000 in order to accept postexposure (data not shown).

For persons who have had a definite exposure to smallpox, the only time that postexposure vaccination would not be accepted is if vaccine efficacy was <1%, risk of transmission was <1%, and the risk for serious vaccine-related adverse events were >1 in 5,000 (Figure 3b). In the same scenario, if the risk for transmission were 30%, postexposure vaccination would accepted even if risk for serious vaccine-related adverse events were 1 in 500 (Figure 3b).

Figures 1 and 2 show that the single most influential variable impacting the net risk for disease, and therefore the decision to accept preexposure vaccination, was the probability of attack of smallpox. For persons in the general population, the second most important variable is the valuation of one case of smallpox relative to cases of serious vaccine-related adverse events (P_Valuation). For a HCW or a member of an investigation team, the second most important variable was the risk for contact with a smallpox patient or infectious material.