Project 1: Immunogen Design and Delivery

项目概要/摘要 研制有效的艾滋病毒疫苗仍然是一项重大挑战。HIV疫苗的早期策略 设计旨在引发保护性T细胞应答、非中和抗体、广泛中和抗体 （bnAb），或三者的某种组合，但未能保护免受感染。人们越来越 成功的基于bnAb的疫苗的关键要素将是其以下能力的共识：i）有效激活 并扩增多种罕见的幼稚bnAb编码B细胞前体; ii）免疫聚焦这些B细胞应答， 在HIV Env三聚体上的典型的、保守的bnAb表位，并且远离脱靶表位;和iii）亲和力- 通过异源接种使这些应答成熟到广度。本申请中提出的研究设计 解决了bnAb诱导的每个关键方面。该基金旨在通过一种新的策略来吸引bnAbs， 通过合理设计的生殖系靶向三聚体结合了编码罕见B细胞前体的HIV bnAb的引发 免疫原和扩大其广度与不同的异源三聚体加强。项目1包括三个 目的：目的#1将开发一种HIV三聚体免疫原，其可以靶向罕见的V2-顶点和V3-聚糖bnAb编码 前体B细胞。利用体外定向反向工程疫苗平台，开发生殖系靶向的 对V2顶点和V3-聚糖bnAb UCA表现出增强的亲和力以用作引发的引发免疫原 免疫原对这些位点的活性稀有bnAb B细胞前体。目标#2将研究 通过各种疫苗平台递送的GT-三聚体免疫原，以在体内激活V2-顶点和V3-聚糖 bnAb B细胞前体在各种bnAb前体表达动物模型中的表达。其目的是产生一个强大的 表位特异性记忆B细胞应答，其可以进一步向广度增强。目标#3将调查 使用新设计的多种HIV三聚体的各种加强策略， V2-顶端和V3-聚糖特异性bnAb B细胞应答。如果成功，这项研究将是同类研究中的第一项， 代表了HIV疫苗合理设计策略的新范例。

PROJECT SUMMARY/ABSTRACT The development of an effective HIV vaccine remains a major challenge. Previous strategies for HIV vaccine design aimed to elicit protective T cell responses, non-neutralizing antibodies, broadly neutralizing antibodies (bnAbs), or some combination of the three but have failed to protect against infection. There is a growing consensus that critical elements to a successful bnAb-based vaccine will be its ability to: i) efficiently activate and expand multiple rare naïve bnAb-encoding B cell precursors; ii) immunofocus these B cell responses to canonical, conserved bnAb epitopes on the HIV Env trimer and away from off-target epitopes; and iii) affinity- mature these response to breadth by heterologous vaccinations. The study design proposed in this application addresses each of the critical aspects of bnAb elicitation. The grant aims to elicit bnAbs by a novel strategy that combines priming of HIV bnAb encoding rare B cell precursors by rationally designed germline-targeting trimer immunogens and expand their breadth with diverse heterologous trimer boosts. The project 1 includes three aims: Aim #1 will develop an HIV trimer immunogen that can target rare V2-apex and V3-glycan bnAb-encoding precursor B cells. Using in-vitro directed reverse vaccine engineering platform, we will develop germline-targeting priming immunogen that exhibits enhanced affinity for V2 apex and V3-glycan bnAb UCAs to utilize as a priming immunogen to active rare bnAb B cell precursors to these sites. Aim #2 will investigate the priming efficiency of GT-trimer immunogen delivered through various vaccine platforms, to in vivo activate V2-apex and V3-glycan bnAb B cell precursors in various bnAb precursor expressing animal models. The aim is to generate a robust epitope specific memory B cell response that could be further boosted toward breadth. Aim #3 will investigate various boost strategies using newly designed diverse HIV trimers to expand the neutralization breadth of the V2-apex and V3-glycan specific bnAb B cell responses. If successful, the study will be the first of its kind, would represent a new paradigm for rational vaccine design strategies for HIV.