This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Concerns about the potential use of variola as an agent of bioterrorism have recently resulted in decisions to re-initiate smallpox vaccination programs. However, the currently available vaccinia virus (VV)-based smallpox vaccines (eg, Dryvax) are associated with high rates of adverse reactions and are not safe for use in immunodeficient individuals or those with a variety of common medical conditions. As such, development of new smallpox vaccines that are substantially safer, but of equivalent or better immunogenic potency than the current VV vaccine preparations is imperative. While certain attenuated strains of VV, especially modified vaccinia Ankara (MVA), have highly desirable safety features and impressive immunogenicity when used to express heterologous antigens, a variety of data suggest that MVA may be an insufficiently immunogenic vaccine to reliably engender protective responses against variola or other highly pathogenic orthopoxviruses. However, we have recently discovered important aspects of the nature of how both replication-competent VV and replication-restricted MVA interact with host dendritic cells (DCs) that suggest promising approaches to increase the protective potential of MVA as a smallpox vaccine. The overall goal of the proposal is to modify the currently available strain of MVA, so that novel vaccine variants are derived with preserved safety profiles, but with substantially enhanced abilities to raise durable, high level cellular and humoral immune responses that are cross-reactive with major virulent orthopoxviruses. To accomplish this goal, we propose to (1) delete from the MVA genome, residual viral immune evasion genes;(2) express within recombinant MVAs specific cytokines and chemokines that promote DC recruitment and activation; and (3) express specific late viral structural gene products from early vaccinia promoters in recombinant MVAs to facilitate induction of increased host protective immune responses against key orthopoxvirus antigens.
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