The smallpox antiviral tecovirimat has recently been purchased by the U.S. 
Strategic National Stockpile. Given significant uncertainty regarding both the 
contagiousness of smallpox in a contemporary outbreak and the efficiency of a 
mass vaccination campaign, vaccine prophylaxis alone may be unable to control a 
smallpox outbreak following a bioterror attack. Here, we present the results of 
a compartmental epidemiological model that identifies conditions under which 
tecovirimat is required to curtail the epidemic by exploring how the interaction 
between contagiousness and prophylaxis coverage of the affected population 
affects the ability of the public health response to control a large-scale 
smallpox outbreak. Each parameter value in the model is based on published 
empirical data. We describe contagiousness parametrically using a novel method 
of distributing an assumed R-value over the disease course based on the relative 
rates of daily viral shedding from human and animal studies of cognate 
orthopoxvirus infections. Our results suggest that vaccination prophylaxis is 
sufficient to control the outbreak when caused either by a minimally contagious 
virus or when a very high percentage of the population receives prophylaxis. As 
vaccination coverage of the affected population decreases below 70%, vaccine 
prophylaxis alone is progressively less capable of controlling outbreaks, even 
those caused by a less contagious virus (R0 less than 4). In these scenarios, 
tecovirimat treatment is required to control the outbreak (total number of cases 
under an order of magnitude more than the number of initial infections). The 
first study to determine the relative importance of smallpox prophylaxis and 
treatment under a range of highly uncertain epidemiological parameters, this 
work provides public health decision-makers with an evidence-based guide for 
responding to a large-scale smallpox outbreak.