Vaccine Design to Concentrate Protective Antibodies at the Mucosal Border

将保护性抗体集中在粘膜边界的疫苗设计

基本信息

批准号：
8403858
负责人：
ASHLEY T. HAASE
金额：
$ 84.39万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-25 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403858
关键词：
Animals Antibodies Antibody Formation Antigens Attenuated Attenuated Live Virus Vaccine CD4 Positive T Lymphocytes Cells Cervical Cervix Uteri Chimeric Proteins Data Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Epithelium Epitopes Experimental Models Fc Receptor Female Founder Generation HIV Infections HIV-1 Immune response Immunization Immunoglobulin G Infection Intercept Life Location Macaca Macaca mulatta Modeling Monoclonal Antibodies Neonatal Passive Immunization Phase Plasma Cells Positioning Attribute Property Recombinants Research Reserve Cell SIV Safety Signal Transduction Staging Systemic infection Testing Time Tissues Vaccinated Vaccination Vaccine Design Vaccines Vagina Viral Viral Load result Virus Western Blotting Woman base design in vivo insight neonatal Fc receptor novel prevent protective effect reproductive research study transmission process

项目摘要

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.

描述（由申请人提供）：对 SIV 减毒活疫苗提供强有力保护的机制的研究有可能有助于设计预防 HIV 感染的疫苗，我们最近在 SIV-恒河猴模型中发现了 HIV-1 向女性传播的情况。针对寡聚 gp41 的粘膜抗体是减毒活 SIVmac239 赋予的针对阴道攻击的局部保护的主要相关性。我们建议研究通过使用 gp41 抗体进行被动免疫以及使用将 Ab 靶向新生儿 Fc 受体阳性宫颈和阴道上皮的重组 gp41 免疫原来重现这些保护作用的策略。在女性生殖道的入口处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是分析抗体和病毒的位置。宫颈组织中病毒复制的相关减少在阴道暴露后关键的前 7 天内，必须建立脆弱的受感染细胞群并在局部扩大，以实现强大的全身感染，我们的具体目标是 1) 评估恒河猴单克隆抗体被动免疫的保护作用。与 SIVmac239 诱导的寡聚 gp41 组织抗体具有相似的反应性nef 疫苗接种；2) 确定重组寡聚 gp41 引发的抗体的位置和局部保护作用，以与 SIVmac239 研究中获得的结果进行比较这些研究的见解有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。公共卫生相关性：迫切需要一种有效的 HIV-1 疫苗，特别是为了防止传播给越来越多地遭受新感染的女性。拟议的研究基于保护性减毒活疫苗，并寻求在不产生这些保护作用的情况下重现这些保护作用。相关的安全问题，采用新的免疫原和策略，将免疫反应集中在病毒最脆弱的感染早期阶段拦截入口处的感染。