Vaccine Design to Concentrate Protective Antibodies at the Mucosal Border

描述（由申请方提供）：SIV减毒活疫苗提供强大保护的机制研究有可能促进预防HIV感染的疫苗设计。我们最近在HIV-1传播给女性的SIV-恒河猴模型中发现，寡聚gp 41的粘膜抗体是减毒SIVmac 239 nef活疫苗接种所赋予的局部保护抵抗阴道攻击的主要相关物。我们建议研究策略，以重现这些保护作用的被动免疫与gp 41抗体，免疫重组gp 41免疫原，目标抗体的新生儿Fc受体阳性宫颈和阴道上皮。我们将检验这样的假设，即集中在女性生殖道入口处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宫颈组织中病毒复制的相关减少 在阴道暴露后的关键的前7天内，此时必须建立受感染细胞的脆弱创始者群体并在局部扩增，以便随后发生强有力的全身感染。我们的具体目的是1）评估用恒河猴单克隆抗体被动免疫的保护作用，该单克隆抗体与SIVmac 239 <$nef疫苗接种诱导的寡聚gp 41的组织抗体具有相似的反应性;和2）确定重组寡聚gp 41引发的抗体的定位和局部保护作用，以与SIVmac 239 <$nef疫苗接种研究中获得的先前结果进行比较。从这些研究中获得的见解有希望了解如何在最有利的机会预防和遏制感染时在入口处产生和集中抗体反应。

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.