Eliciting VRC01-like bNAbs by Specifically Designed Env Immunogens

描述(由申请人提供)：我们IPCAVD计划赠款的主要目标是在人类身上评估重组环境免疫原，这种重组环境免疫原专门设计用于激活B细胞，这些B细胞产生针对HIV环境病毒的CD4结合部位(CD4-BS)的广谱中和抗体(BNAbs)。我们的研究基于本计划参与者所做的两个关键观察：a)确定了诱导抗CD4-BS bNAbs的最早障碍，即重组Env无法结合和激活产生此类抗体的生殖系B细胞受体(BCR)；b)开发了一种唯一能够做到这一点的重组Env蛋白，即激活表达一些已知的最广泛和最有效的抗HIV中和抗体，即‘VRCOI’类抗体的种系BCR的B细胞。我们的建议利用了我们在免疫原设计方面的卓越专业知识；在B细胞免疫学方面的无与伦比的专业知识；开发可在免疫过程中对疫苗特异性BCR进行深度测序的工具；提供适当的动物模型，以在临床前验证我们的免疫原刺激表达所需BCR的B细胞扩张的能力；以及HVTN进行HIV疫苗临床测试的独特专业知识。具体地说，我们的团队由具有不同专业知识的个人组成，他们有记录在案的合作记录，并指导和参与了大型多组成部分赠款。西雅图生物医学院的Stamatatos博士(IPCAVD项目的总体PI和项目一的负责人)领导着我们的免疫原设计工作。Sather博士也在西雅图生物医学中心，Nussenzweig博士(洛克菲勒大学)和罗林斯博士在西雅图大学/西雅图儿童医院共同领导我们的免疫原临床前评估(项目二)。Julie McElrath博士(弗雷德·哈钦森中心和HVTN)将监督我们选定的免疫原的临床测试(项目四)。

DESCRIPTION (provided by applicant): The main goal of our IPCAVD Program grant is to evaluate, in humans, recombinant Env immunogens that are specifically designed to activate B cells that produce broadly neutralizing antibodies (bnAbs) against the CD4-binding site (CD4-BS) of the HIV Env. Our studies are based on two key observations made by the participants of our Program: a) the identification of the earliest roadblock in the elicitation of anti-CD4-BS bnAbs, namely the inability of recombinant Env to engage and activate germline B cell receptors (BCRs) that give rise to such antibodies; and b) the development of a recombinant Env protein that is uniquely capable of doing exactly that i.e., to activate B cells expressing germline BCRs of some of the most broad and potent anti-HIV neutralizing antibodies known, namely the 'VRCOI' class antibodies. Our proposal takes advantage of our excellent expertise in immunogen-design; an unparalleled expertise in B cell immunology; the development of tools that allow for the deep-sequencing of vaccine-specific BCRs during the course of immunization; the availability of the appropriate animal models to validate pre-clinically the ability of our immunogens to stimulate the expansion of B cells expressing the desired BCRs; and the unique expertise of the HVTN to conduct clinical testing of HIV vaccines. Specifically, our team is composed of individuals with diverse expertise that have a documented record of collaboration and have directed and participated in large multi-component grants. Dr.- Stamatatos (overall PI of this IPCAVD Program and Leader of Project One) at Seattle BioMed is leading our 'immunogen design' efforts. Dr. Sather also at the Seattle BioMed, Dr. Nussenzweig (The Rockefeller University) and Dr. Rawlings at UW/Seattle Children's are co-leaders of the 'preclinical evaluation' of our immunogens (Project Two). Dr. Julie McElrath (Fred Hutchinson Center and the HVTN) will oversee the clinical testing of our selected immunogen (Project Four).