SMALLPOX VACCINATION ON ENDOTHELIAL FUNCTION AND HUMAN GENE EXPRESSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This protocol is designed to study the effects of smallpox vaccination on endothelial resistance and gene expression in subjects participating in the Aventis Pasteur smallpox vaccine (APSV) study. Smallpox immunization, using infection with vaccinia virus, is associated with a considerable degree of active, systemic inflammation. Epidemiological and observational studies suggest an association between both inflammation and infection and the risk of develping cardiovascular disease. Widespread use of vaccinia virus infection to immunize large segments of the population against the bioterrorist threat of smallpox will result in infection and considerable systemic inflammation in large numbers of people at risk for coronary artery disease. Previous studies found that vaccination with a killed, inactivated vaccine resulted in temporary, but profound dysfunction of arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. These findings illustrate that even mild systemic inflammatory response is associated with significant alteration in endothelial function associated with an increased risk of cardiovascular events. Since vaccinia infection is associated with an intense and more long-lasting inflammatory response, these investigators hypothesize that current strategies of smallpox immunization will have more pronounced and durable effects on endothelial resistance, C-reactive protein, and cytokine expression than did the prior study on the effects of vaccination. Thus the risk of inducing cardiovascular disease with vaccination would be significant. The second aspect of this protocol is to perform microarray analysis in recipients of smallpox vaccine. In recent years, microarrays have been used to examine host changes in gene expression in cells infected or exposed to HIV-1, CMV, coxsackievirus, hepatitis B and hepatitis C viruses. While several in vivo animal studies have been conducted to evaluate changes in gene expression in a host animal infected with a pathogen, there are few data reported in humans infected with pox viruses. In this study, we will examine the effects of orthopox infection (vaccinia) as a surrogate marker of human orthopox infection (smallpox). Therefore, these investigators propose a pilot study to measure endothelial resistance, C-reactive protein in 24 volunteers participating in the APSV study prior to vaccinia innoculation, at visit 4 and 5 (the days of most intense inflammation: days 6-8 and 9-11), and following the healing of the vaccinia lesion on visit 8 (days 51-61). Cytokine and other gene expression will be assessed prior to vaccination at the two subsequent visits (prior to peak inflammation), and two months.