B-cell Biology of Mucosal Immune Protection from SIV Challenge

描述（由申请人提供）：研制一种安全有效的艾滋病毒-1疫苗对于遏制目前影响全世界3 000多万人的主要性传播疾病的传播至关重要。虽然最近的痘病毒蛋白免疫原有效性试验提供了适度的保护，但保护的相关因素尚不清楚。在恒河猴SIV感染模型中，高达70%的动物接种了GM-CSF增强的DNA引物，MVA增强，然后接受异源（E660），多次低剂量的直肠攻击，免受感染，并且明显相关的保护是E660 Env结合抗体的亲和力。Emory粘膜免疫保护b细胞生物学联盟采用高度协作的方法，将通过先进的免疫学和系统生物学方法确定增强抗体亲和力和保护的潜在机制。该联盟将包括四个研究项目和四个科学支持核心，以及一个行政核心来实现这一目标。项目1将确定GM-CSF介导对低剂量SIV阴道攻击增强保护的机制，并将确定添加优化的蛋白增强剂是否进一步增强保护。项目2将研究TLR-4和TLR-7配体的潜力和潜在机制，以一种新的合成纳米颗粒配方递送，最近被证明可以显著提高抗体对流感HA的反应，提高保护性粘膜b细胞和t细胞对SIV VLPs的反应质量。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方面的功能，而项目4将类似地研究这些佐剂方法激活IL-21产生具有B细胞辅助功能的N{BH}中性粒细胞亚群的潜力。这些项目将得到NHP核心的支持，该核心将为研究提供和维护具有遗传特征的雌性猕猴。额外的核心将允许在单细胞和粘膜分泌物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、财政责任和研究成果的传播。

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. PUBLIC HEALTH RELEVANCE: The Emory Consortium for B-Cell Biology of Mucosal Immune Protection from SIV Challenge will define and characterize the mechanistic basis for enhanced protection from acquisition of SIV infection, and will explore novel approaches to increase further the level of protection. Results from these studies will be directly applicable to HIV vaccine development in human subjects. Project 1: Immune Correlates for GM-CSF Mediated Enhancement of Vaccine Efficacy (Project Leader Rama Amara) Description as provided by applicant: The acquired immunodeficiency syndrome caused by HIV-1 is the leading cause of death in Africa and the fourth leading cause of death worldwide. The recent RV144 phase-3 trial (Thai trial) testing the efficacy of an AIDS vaccine consisting of a poxvirus vector (ALVAC) prime and protein boost demonstrated a modest efficacy where 25% of the vaccinated individuals were protected from HIV-1 infection. These results are highly encouraging; however the immune correlates for this protection are yet to be identified but suggest a role for non-neutralizing Ab in protection. Furthermore, the protection in the Thai trial appeared to be short lived (for the first six months) and there is a need for developing approaches that sustain immunological memory of vaccine elicited responses. Our ongoing studies in rhesus macaques demonstrated a similar protection from heterologous repetitive mucosal SIV challenges by a DNA prime and poxvirus (modified vaccinia Ankara) boost vaccine (DNA/MVA). In addition, co-delivery of granulocyte and macrophage colony stimulating factor (GM-CSF) DNA with our vaccine DNA significantly enhanced the protection mediated by the DNA/MVA vaccine from 25% to 70%. GM-CSF did not adjuvant the anti-viral CD8 T cell responses but enhanced the avidity of binding Ab specific to the Env and promoted generation of anti-viral IgA in rectal secretions. Importantly, the avidity of binding Ab against the challenge virus Env strongly correlated with enhanced protection against acquisition of SIV infection. These and results from other studies highlight an important role for other non-neutralizing activities of antibody in protection. The overall goals of this project are to identify the mechanisms of GM-CSF-mediated enhancement of protection against a mucosal SIV challenge and to test the effect of a protein boost for enhancing this protection against acquisition of heterologous repetitive intravaginal SIV challenges in rhesus macaques. In our specific aim 1, we will investigate the immune correlates for GM-CSF mediated enhanced protection. Here we will test the hypothesis that GM-CSF enhances the breadth, avidity, cytolytic activity and mucosal homing of anti-Env binding Ab in serum and mucosal secretions by modulating function of antigen presenting cells and T helper responses. In our specific aim 2, we will test whether addition of a protein boost, adjuvated with either alum or a combination of toll-like receptor ligands encapsulated in nanoparticles, to the GM-CSF-adjuvanted DNA/MVA vaccine will further enhance the longevity of protective immunity against acquisition of heterologous repetitive intravaginal SIV challenge.