The cessation of mandatory prophylactic vaccination hasresulted in over half of the global population being potentially naïveto OPXV threats. Despite decades of continuous research to increasevaccine safety without a loss in efficacy, and the creation of 2nd gen-eration vaccines (live VACV propagated in cell lines), 3rd generationvaccines (attenuated VACV) [9] and subunit vaccines [10,11]; onlyone vaccine (Acambis 2000) has been licensed for use at this time[12]. However, the use of Acambis 2000 continues to be limiteddue to its adverse event profile [13]. Recommendations to vacci-nate U.S. health care workers and laboratorians have previouslymet with low compliance rates, largely due to the known risk ofSAE’s following vaccination [14]. In addition, a sizable proportion ofthe global population is contraindicated for vaccination with Acam-bis 2000 due to various health conditions [15]. The development ofmedical countermeasures and safer vaccines that are efficaciousagainst OPXV is an ongoing effort – one which requires an under-standing of 1st, 2nd, 3rd and subunit vaccine efficacy in both pre-and post-exposure scenarios