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

• 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
• 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

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，针对寡聚体gp41的粘膜抗体是通过减毒活疫苗SIVmac239nef产生的局部保护作用的主要相关因素。我们建议通过用gp41抗体被动免疫和重组gp41免疫原免疫新生儿Fc受体阳性的宫颈和阴道上皮来研究复制这些保护作用的策略。我们将测试这一假设，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，从而防止系统性感染。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，必须建立和扩大感染细胞的脆弱的创始群体，以便随后发生强大的系统性感染。我们的具体目标是：1)评估与SIVmac239nef疫苗诱导的针对寡聚体gp41的组织抗体具有相似反应性的恒河猴单抗被动免疫的保护效果；以及2)确定重组寡聚体gp41诱导的抗体的位置和局部保护作用，以与以前在SIVmac239？nef疫苗研究中获得的结果进行比较。来自这些研究的见解为理解如何在有最有利的机会预防和控制感染的时候，在入口处产生和集中抗体反应提供了希望。 公共卫生相关性：迫切需要一种有效的艾滋病毒-1疫苗，特别是为了防止传播给日益首当其冲地承受新感染的妇女。拟议的研究以保护性减毒活疫苗为基础，寻求在没有相关安全问题的情况下再现这些保护作用，使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的入口处拦截感染。