Immune engineering of optimized sequential immunization strategies for HIV vaccines

项目摘要 临床前研究和早期人体试验被动评估广泛转移 中和抗体(BNAbs)表明，一种能够诱导bNAbs的疫苗将提供 有效预防艾滋病毒感染。然而，通过诱导bNAb的难度 疫苗接种引起了该领域对基于顺序免疫的疫苗策略的关注 旨在引导发育中的B细胞反应。这些顺序免疫策略的范围 从生殖系靶向到谱系导向设计到免疫聚焦，以及它们的组合。 虽然从结构生物学的角度来看合乎逻辑，但重要的免疫学问题仍然存在 对于这种疫苗没有应答：在这样的策略中，顺序免疫原应该在什么时间间隔 用药吗？来自抗原特异性但非中和B细胞的竞争是如何 前体影响疫苗“放牧”？这一顺序免疫过程是否受到 有限的T细胞有帮助？此外，由4次或4次以上注射组成的疫苗将是对 在全球范围内实施。我们如何让这样的疫苗变得实用？在此阶段，R61/R33 应用，我们建议在小动物模型中进行系统研究来评估基本的 疫苗免疫学面临这样的策略问题。我们提出了几种新的方法来 检查并可能解决这些问题：在目标1中，我们将描述 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 细胞，在目标3中，我们开发了使用增强的T细胞帮助的疫苗，并在 目标4，我们提出了在单次免疫后启用顺序免疫原暴露的技术 注射。我们将在疫苗的背景下测试这些概念，目的是诱导针对 CD4结合位点(VRC01类反应)和Env融合肽，生理学地使用 相关条件。这些免疫策略中影响最大的将被降选为 在HIV的动物模型R33阶段在非人类灵长类动物(NHP)中进行测试 最接近人类的免疫接种。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、疫苗递送系统、 新的佐剂，以及T细胞在罕见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.