Project 1: Immunogen Design and Delivery

项目摘要/摘要 开发有效的艾滋病毒疫苗仍然是一项重大挑战。HIV疫苗的先前策略 旨在诱导保护性T细胞反应、非中和抗体、广谱中和抗体的设计 (BNAbs)，或三者的某种组合，但未能预防感染。有一个不断增长的 一致认为，成功的基于bNab的疫苗的关键要素将是其以下能力：i)有效激活 并扩增多种罕见的天然bNab编码的B细胞前体；ii)免疫聚焦这些B细胞对 HIV Env三聚体上的规范保守的bNab表位，远离靶标表位；以及iii)亲和力- 通过异种疫苗接种成熟这些广度反应。本申请中提出的研究设计 解决了bNab诱导的每个关键方面。这笔赠款旨在通过一种新的策略来激发bNAbs 通过合理设计的种系靶向三聚体联合启动编码稀有B细胞前体的HIV bNab 免疫原，并通过不同的异源三聚体助剂扩大其广度。项目%1包括三个 目的：Aim#1将开发一种针对罕见的V2-顶端和V3-糖链bNab编码的HIV三聚体免疫原 前体B细胞。利用体外定向反向疫苗工程平台，我们将开发种系靶向 对V2顶点和V3-葡聚糖bNab Ucas表现出增强亲和力的引爆免疫原用作引爆 免疫原能激活稀有的bNab B细胞前体到这些部位。目的#2将调查引爆效率 GT-三聚体免疫原通过各种疫苗平台传递，在体内激活V2-顶端和V3-糖链 BNab B细胞前体在各种bNab前体动物模型中的表达。其目标是生成一个健壮的 表位特异的记忆B细胞反应，可以进一步向广度提升。Aim#3将调查 使用新设计的不同HIV三聚体来扩大中和广度的各种增强策略 V2-顶端和V3-葡聚糖特异的bNab B细胞反应。如果成功，这项研究将是此类研究中的第一项， 代表了针对艾滋病毒的合理疫苗设计战略的新范例。

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.