Vaccine Design to Concentrate Protective Antibodies at the Mucosal Border

描述（由申请人提供）：对SIV减毒活疫苗提供强大保护的机制的研究有可能促进预防艾滋病毒感染的疫苗设计。我们最近在HIV-1向女性传播的siv -恒河猴模型中发现，低聚物gp41的粘膜抗体是SIVmac239 - nef减毒活疫苗对阴道攻击的局部保护的主要相关因素。我们建议通过gp41抗体被动免疫和重组gp41免疫原免疫来重现这些保护作用，重组gp41免疫原针对新生儿Fc-受体阳性的宫颈和阴道上皮。我们将测试这一假设，即集中在女性生殖道入口的抗体将能够在病毒复制和传播的早期阶段拦截病毒，从而防止全身感染。因此，我们的主要重点将是分析抗体的位置和相关的宫颈组织中病毒复制的减少

DESCRIPTION (provided by applicant): Studies of the mechanisms by which SIV live attenuated vaccines provide robust protection have the potential to facilitate design of vaccines to prevent HIV infection. We recently discovered in the SIV-rhesus macaque model of HIV-1 transmission to women that mucosal antibodies to oligomeric gp41 are the principal correlate of the local protection against vaginal challenge conferred by live attenuated SIVmac239¿nef vaccination. We propose to investigate strategies to reproduce these protective effects by passive immunization with gp41 antibodies, and by immunization with recombinant gp41 immunogens that target Ab to the neonatal Fc- receptor positive cervical and vaginal epithelium. We will test the hypothesis that antibodies concentrated at the portals of entry in the female reproductive tract will be able to intercept virus during early phases of viral replication and spread and thereby protect against systemic infection. Our primary focus will therefore be to analyze the location of antibodies and associated decrease in viral replication in cervical tissues in the critical first 7 days following vaginal exposure, when the vulnerable founder population of infected cells must be established and expand locally for a robust systemic infection to ensue. Our Specific aims are 1) to assess protective effects of passive immunization with a rhesus monoclonal antibody with similar reactivity to tissue antibodies to oligomeric gp41 induced by SIVmac239¿nef vaccination; and 2) to determine the location and local protective effects of antibodies elicited by a recombinant oligomeric gp41 to compare with previous results obtained in studies of SIVmac239¿nef vaccination. Insights from these studies hold promise for understanding how to generate and focus an antibody response at the portal of entry at a time when it has the most favorable opportunity to prevent and contain infection. PUBLIC HEALTH RELEVANCE: An effective HIV-1 vaccine is urgently needed, particularly to prevent transmission to women who increasingly bear the brunt of newly acquired infections. The proposed research is based on a protective live attenuated vaccine, and seeks to reproduce these protective effects without the associated safety issues, with novel immunogens and strategies that focus the immune response on intercepting infection at the portal of entry in its early stages of infection when virus is most vulnerable.