The most effective vaccine provides durable and effective immunization at the mucosal and systemic levels. Attenuated live-viruses expressing foreign antigenic sequences have shown tremendous promise as vaccines, although their effectiveness can be limited by proper targeting to the site of infection, such as the mucosal layer. Another technique is DNA-immunization by plasmids carrying antigens expressed from eukaryotic promoters. Delivery of these plasmids by attenuated strains of Salmonella typhimurium has dramatically improved targeting, since S. typhimurium specifically infects macrophages in the mucosa. This technique, however, is limited by transformation of recipient cells only. In contrast, many of the most effective and safe vaccines ever developed are based on live attenuated viruses. This proposal outlines a strategy to combine these two approaches; launching live-virus vaccines from bacterial vectors that target appropriate host cells. By a thorough investigation of both bacterial and host factors critical for interaction, this proposal seeks to take advantage of both attenuated live-virus propagation ability and S. typhimurium targeting proficiency to ultimately develop more practical and effective vaccines against disease. ? ?
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