Eliciting VRC01-like bNAbs by Specifically Designed Env Immunogens

描述（由申请人提供）：我们的IPCAVD项目资助的主要目标是在人类中评估重组Env免疫原，该免疫原专门设计用于激活B细胞，产生针对HIV Env的cd4结合位点（CD4-BS）的广泛中和抗体（bnAbs）。我们的研究基于我们项目参与者的两个关键观察：a)确定了激发抗cd4 - bs bnAbs的最早障碍，即重组Env无法参与和激活产生此类抗体的种系B细胞受体（bcr）；b)开发一种重组Env蛋白，这种蛋白具有独特的功能，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。我们的提案利用了我们在免疫原设计方面的优秀专业知识；在B细胞免疫学方面无与伦比的专业知识；开发能够在免疫过程中对疫苗特异性bcr进行深度测序的工具；适当的动物模型的可用性来验证我们的免疫原在临床前刺激表达所需bcr的B细胞扩增的能力；以及HVTN在进行艾滋病毒疫苗临床试验方面的独特专业知识。具体来说，我们的团队由具有不同专业知识的个人组成，他们有合作的记录，并指导和参与了大型的多组件资助。西雅图生物医学中心的Stamatatos博士（IPCAVD项目总负责人和项目一负责人）领导着我们的“免疫原设计”工作。西雅图生物医学中心的Sather博士、洛克菲勒大学的Nussenzweig博士和西雅图大学/西雅图儿童医院的Rawlings博士是我们免疫原临床前评估（项目二）的共同领导者。Julie McElrath博士（Fred Hutchinson中心和HVTN）将监督我们选定的免疫原（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).