B-cell Biology of Mucosal Immune Protection from SIV Challenge

针对 SIV 攻击的粘膜免疫保护的 B 细胞生物学

• 批准号: 8516864
• 负责人: Rama Rao Amara
• 金额: $ 507.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516864
• 关键词: AIDS Vaccines; ALVAC; Acquired Immunodeficiency Syndrome; Adjuvant; Affect; Africa; Animals; Antibodies; Antibody Avidity; Antibody Formation; Antigen-Presenting Cells; Antigens; Avidity; B-Lymphocytes; Binding; Biological Markers; CD8B1 gene; Cause of Death; Cells; Cellular biology; Collaborations; Communication; DNA; DNA Vaccines; DNA/MVA vaccine; Databases; Development; Dose; Drug Formulations; Encapsulated; Enhancing Antibodies; Ensure; Female; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV vaccine; HIV-1; Homing; Immune; Immune response; Immunity; Immunoglobulin A; Immunologic Memory; Individual; Infection; Influenza Hemagglutinin; Life; Ligands; Longevity; Macaca; Macaca mulatta; Mediating; Modeling; Modified Vaccinia Virus Ankara; Molds; Persons; Phase III Clinical Trials; Poxviridae; Proteins; Reagent; Research Project Grants; Role; SIV; Science; Serum; Sexually Transmitted Diseases; Systems Biology; T cell response; T-Lymphocyte; Testing; TimeLine; Toll-like receptors; Vaccinated; Vaccines; Vagina; Viral; Viral Antibodies; Virus; aluminum sulfate; base; dissemination research; efficacy testing; efficacy trial; human subject; improved; nanoparticle; neutrophil; novel; novel strategies; poxvirus vectors; rectal; repository; response; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): The development of a safe and effective vaccine against HIV-1 is critical for curtailing the spread of a primarily sexually transmitted disease that is now affecting more than 30 million persons worldwide. While a recent poxvirus-protein immunogen efficacy trial conferred modest protection from acquisition, the correlates of protection are unknown. In the SIV infection model in Rhesus macaques, up to 70% of animals, vaccinated with GM-CSF enhanced DNA priming, MVA boosted, then subjected to a heterologous (E660), multiple low dose rectal challenge, were protected from acquisition and a clear correlate of protection was E660 Env binding antibody avidity. The Emory Consortium for B-Cell Biology of Mucosal Immune Protection from SIV Challenge, using highly collaborative approaches, will define through advanced immunological and systems biology approaches the underlying mechanisms for enhanced antibody avidity and protection. The Consortium will incorporate four research projects and four science support cores, in addition to an Administrative core to achieve this goal. Project 1 will identify the mechanisms by which GM-CSF mediates enhanced protection from low dose SIV vaginal challenge, and will determine whether addition of an optimized protein boost further enhances protection. Project 2 will investigate the potential and underlying mechanism for TLR-4 and TLR-7 ligands, delivered in a novel synthetic nanoparticle formulation and recently shown to dramatically improve antibody responses to influenza HA, to enhance the quality of protective mucosal B-cell and T-cell responses to SIV VLPs. Project 3 will determine the effects of GM-CSF and nanoparticle delivered TLR ligand adjuvants on follicular T-cells and their function in molding the quality of the humoral immune response, while Project 4 will similarly investigate the potential for these adjuvanting approaches to activate a subset of IL-21 producing N{BH} neutrophils equipped with B cell helper function. The projects will be supported by an NHP Core, which will provide and maintain genetically characterized female macaques for the studies. Additional Cores will allow characterization of the antiviral antibody response at the level of single cells and mucosal secretions, and a B-cell biomarker core will develop unique reagents for defining the B-cell response in this rhesus model. The Administrative Core will ensure effective communication and collaboration between projects and Cores through database and repository management and will be responsible for maintaining timelines, fiscal responsibility, and dissemination of research results.

描述（由申请人提供）：开发一种安全有效的 HIV-1 疫苗对于遏制这种主要通过性传播的疾病的传播至关重要，这种疾病目前影响着全世界超过 3000 万人。虽然最近的一项痘病毒蛋白免疫原功效试验提供了适度的保护，防止感染，但保护的相关性尚不清楚。在恒河猴的 SIV 感染模型中，高达 70% 的动物在接种 GM-CSF 增强型 DNA 引发、MVA 加强疫苗接种，然后进行异源 (E660)、多次低剂量直肠攻击后，免受感染，并且明确保护的相关性是E660 Env结合抗体亲合力。埃默里大学针对 SIV 挑战的粘膜免疫保护的 B 细胞生物学联盟将采用高度协作的方法，通过先进的免疫学和系统生物学方法来定义增强抗体亲合力和保护的基本机制。除了行政核心之外，该联盟还将纳入四个研究项目和四个科学支持核心，以实现这一目标。项目 1 将确定 GM-CSF 介导针对低剂量 SIV 阴道攻击的增强保护的机制，并将确定添加优化的蛋白质增强剂是否会进一步增强保护。项目 2 将研究 TLR-4 和 TLR-7 配体的潜在和潜在机制，这些配体以新型合成纳米颗粒制剂形式提供，最近显示可显着改善抗体对流感 HA 的反应，从而提高保护性粘膜 B 细胞和 T 细胞的质量-细胞对SIV VLP的反应。项目 3 将确定 GM-CSF 和纳米颗粒递送的 TLR 配体佐剂对滤泡 T 细胞的影响及其在塑造体液免疫反应质量中的功能，而项目 4 将类似地研究这些佐剂方法激活子集的潜力产生具有 B 细胞辅助功能的 N{BH} 中性粒细胞的 IL-21。这些项目将得到 NHP 核心的支持，该核心将为研究提供和维持具有基因特征的雌性猕猴。额外的核心将允许在单细胞和粘膜分泌水平上表征抗病毒抗体反应，B 细胞生物标志物核心将开发独特的试剂来定义该恒河猴模型中的 B 细胞反应。行政核心将通过数据库和存储库管理确保项目和核心之间的有效沟通和协作，并将负责维护时间表、财务责任和研究成果的传播。