Background.  First- and second-generation smallpox vaccines are contraindicated 
in individuals infected with human immunodeficiency virus (HIV). A new smallpox 
vaccine is needed to protect this population in the context of biodefense 
preparedness. The focus of this study was to compare the safety and 
immunogenicity of a replication-deficient, highly attenuated smallpox vaccine 
modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods. 
 An open-label, controlled Phase II trial was conducted at 36 centers in the 
United States and Puerto Rico for HIV-infected and healthy subjects. Subjects 
received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by 
assessment of adverse events, focused physical exams, electrocardiogram 
recordings, and safety laboratories. Immune responses were assessed using 
enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization 
test (PRNT). Results.  Five hundred seventy-nine subjects were vaccinated at 
least once and had data available for analysis. Rates of ELISA seropositivity 
were comparably high in vaccinia-naive healthy and HIV-infected subjects, 
whereas PRNT seropositivity rates were higher in healthy compared with 
HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with 
no adverse impact on viral load or CD4 counts. There were no cases of 
myo-/pericarditis reported. Conclusions.  Modified vaccinia Ankara was safe and 
immunogenic in subjects infected with HIV and represents a promising smallpox 
vaccine candidate for use in immunocompromised populations.