The cessation of mandatory prophylactic vaccination has resulted in over half of the global population being potentially naïve to OPXV threats. Despite decades of continuous research to increase vaccine safety without a loss in efficacy, and the creation of 2nd generation vaccines (live VACV propagated in cell lines), 3rd generation vaccines (attenuated VACV) [9] and subun it vaccines [10,11]; only one 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 of the global population is contraindicated for vaccination with Acam-bis 2000 due to various health conditions [15]. The development of medical countermeasures and safer vaccines that are efficacious against 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