Eliciting VRC01-like bNAbs by Specifically Designed Env Immunogens

描述（由申请人提供）：我们的IPCAVD计划资助的主要目标是在人体中评价重组Env免疫原，这些免疫原专门设计用于激活B细胞，产生针对HIV Env的CD 4结合位点（CD 4-BS）的广泛中和抗体（bnAb）。我们的研究是基于我们项目参与者的两个关键观察：a）确定了诱导抗CD 4-BS bnAb的最早障碍，即重组Env不能接合和激活产生此类抗体的生殖系B细胞受体（BCR）;和B）开发了一种重组Env蛋白，其独特地能够做到这一点，即，激活表达某些已知的最广泛和有效的抗HIV中和抗体，即“VRCOI”类抗体的生殖系BCR的B细胞。我们的提案利用了我们在免疫原设计方面的卓越专业知识;在B细胞免疫学方面无与伦比的专业知识;开发了允许在免疫过程中对疫苗特异性BCR进行深度测序的工具;提供了适当的动物模型，以在临床前验证我们的免疫原刺激表达所需BCR的B细胞扩增的能力;以及HVTN进行艾滋病毒疫苗临床试验的独特专业知识。具体来说，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分赠款。博士--西雅图BioMed的Stamatatos（IPCAVD项目的总PI和项目一的负责人）正在领导我们的“免疫原设计”工作。萨瑟博士也在西雅图生物医学，Nussenzweig博士（洛克菲勒大学）和罗林斯博士在华盛顿大学/西雅图儿童是共同领导的“临床前评估"我们的免疫原（项目二）。Julie McElrath博士（Fred哈钦森中心和HVTN）将监督我们选择的免疫原（项目四）的临床试验。

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).