Immune engineering of optimized sequential immunization strategies for HIV vaccines

项目摘要 广泛评估被动转移的临床前研究和早期人体试验 中和抗体（bnAbs）表明，能够引发bnAbs的疫苗将提供 有效预防艾滋病毒感染。然而，诱导bnAb通过 疫苗接种已导致该领域关注基于顺序免疫接种的疫苗策略 旨在指导B细胞反应的发展。这些顺序免疫策略包括 从生殖系靶向到谱系引导设计到免疫聚焦及其组合。 虽然从结构生物学的角度来看是合乎逻辑的，但重要的免疫学问题仍然存在 在这种策略中，连续免疫原 管理？抗原特异性但非中和性B细胞的竞争 前体影响疫苗“放羊”？这种顺序免疫过程是否受到 有限的T细胞帮助？此外，由4次或更多次注射组成的疫苗将是一个挑战， 在全球范围内实施。我们如何使这种疫苗实用化？本阶段R61/R33 应用，我们建议在小动物模型中进行系统的研究，以评估基本的 疫苗免疫学问题面临这样的战略。我们提出了几种新颖的方法， 检查，并可能解决这些问题：在目标1中，我们将描述免疫学的特点， 交错顺序免疫，在目标2中，我们开发了一种删除竞争对手B的方法 在目标3中，我们开发了采用增强的T细胞帮助的疫苗， 目标4，我们提出了技术，使连续免疫原暴露后，单一的 注射我们将在疫苗的背景下测试这些概念，旨在引发针对 CD 4结合位点（VRC 01类反应）和Env融合肽，使用生理学方法 相关条件。这些免疫策略中最有效的将被向下选择， 在R33阶段，在非人灵长类动物（NHP）中进行测试， 最接近人类的免疫。我们的工作是由欧文，克罗蒂， 和Silvestri实验室在了解GC动力学，bnAb B细胞竞争，疫苗输送系统， 新的佐剂和T细胞在罕见的B细胞募集中的作用。

Project Summary Preclinical studies and early stage human trials evaluating passively transferred broadly neutralizing antibodies (bnAbs) suggest that a vaccine capable of eliciting bnAbs would provide effective protection from HIV infection. However, the difficulty of inducing bnAbs through vaccination has led to a focus in the field on vaccine strategies based on sequential immunizations meant to guide the developing B cell response. These sequential immunization strategies range from germline targeting to lineage-guided design to immunofocusing, and combinations thereof. While logical from a structural biology perspective, important immunological questions remain unanswered for such vaccines: In such a strategy, at what interval should sequential immunogens be administered? How does competition from antigen-specific but non-neutralizing B cell precursors impact vaccine “shepherding”? Is this sequential immunization process hindered by limited T cell help? In addition, vaccines comprised of 4 or more injections will be a challenge to implement globally. How do we make such a vaccine practical? In this phase R61/R33 application, we propose systematic studies in small animal models to evaluate fundamental vaccine immunology issues facing such strategies. We proposed several novel approaches to examine, and potentially solve, these issues: In aim 1 we will characterize the immunology of staggered sequential immunizations, in aim 2 we develop an approach to delete competitor B cells during vaccination, in aim 3 we develop vaccines employing augmented T cell help, and in aim 4, we propose technologies to enable sequential immunogen exposure following a single injection. We will test these concepts in the context of vaccines aiming to elicit bnAbs against the CD4 binding site (VRC01-class responses) and the Env fusion peptide, using physiologically relevant conditions. The most impactful of these immunization strategies will be downselected for testing in non-human primates (NHP) during the R33 phase, the animal model for HIV immunization closest to humans. Our work is guided by recent advances by the Irvine, Crotty, and Silvestri labs in understand GC kinetics, bnAb B cell competition,vaccine delivery systems, novel adjuvants, and roles of T cell help in rare B cell recruitment.