Smallpox (variola) virus is considered a Category A bioterrorism agent due to 
its ability to spread rapidly and the high morbidity and mortality rates 
associated with infection. Current recommendations recognize the importance of 
oral antivirals and call for having at least two smallpox antivirals with 
different mechanisms of action available in the event of a smallpox outbreak. 
Multiple antivirals are recommended due in large part to the propensity of 
viruses to become resistant to antiviral therapy, especially monotherapy. 
Advances in synthetic biology heighten concerns that a bioterror attack with 
variola would utilize engineered resistance to antivirals and potentially 
vaccines. Brincidofovir, an oral antiviral in late stage development, has proven 
effective against orthopoxviruses in vitro and in vivo, has a different 
mechanism of action from tecovirimat (the only oral smallpox antiviral currently 
in the US Strategic National Stockpile), and has a resistance profile that 
reduces concerns in the scenario of a bioterror attack using genetically 
engineered smallpox. Given the devastating potential of smallpox as a bioweapon, 
preparation of a multi-pronged defense that accounts for the most obvious 
bioengineering possibilities is strategically imperative.