Immune engineering of optimized sequential immunization strategies for HIV vaccines

HIV疫苗序贯免疫策略优化的免疫工程

• 批准号: 10383728
• 负责人: Shane P Crotty
• 金额: $ 77.91万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383728
• 关键词: Acceleration; Adjuvant; Animal Model; Antibody Response; Antigens; B-Cell Development; B-Lymphocytes; Binding Sites; Clinical; Data; Development; Epitopes; HIV; HIV Infections; HIV immunization; HIV vaccine; Human; Immune response; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Immunologics; Immunology; Injections; Kinetics; Knock-in; Knock-out; Malignant Neoplasms; Memory B-Lymphocyte; Modernization; Mus; Mutation; Peptides; Phase; Physiological; Process; Production; RNA; RNA vaccine; Regimen; Role; Science; Series; Specificity; Structure of germinal center of lymph node; System; T-Lymphocyte; Technology; Testing; Vaccination; Vaccines; Work; adoptive B cell transfer; base; chemotherapy; cost; design; immunoengineering; improved; memory CD4 T lymphocyte; mouse model; neutralizing antibody; nonhuman primate; novel; novel strategies; pragmatic implementation; preclinical study; recruit; response; structural biology; vaccination strategy; vaccine delivery; vaccine development; vaccine strategy

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.

项目摘要 临床前研究和早期人类试验，评估被动地广泛转移的人类试验 中和抗体（BNAB）表明能够引起BNAB的疫苗提供 有效保护艾滋病毒感染。但是，通过 疫苗使该领域的重点是基于顺序免疫的疫苗策略 是指导发展的B细胞响应。这些顺序免疫刺激策略范围 从生殖线靶向到谱系引导的设计，再到免疫焦点及其组合。 从结构生物学的角度来看，逻辑是逻辑的，但重要的免疫学问题仍然存在 未接受此类疫苗的反应：在这样的策略中，应以何种间隔应进行连续免疫剂 被管理？抗原特异性但非中和B细胞的竞争如何 前体影响疫苗“牧羊”吗？这是该顺序免疫抑制过程被阻碍 有限的T细胞帮助？此外，包括4种或更多注射的疫苗将是一个挑战 全球实施。我们如何使这样的疫苗实用？在此阶段R61/R33中 应用，我们建议在小动物模型中进行系统研究以评估基本 疫苗免疫学问题面临此类策略。我们提出了几种新颖的方法 检查并有可能解决这些问题：在AIM 1中，我们将表征的免疫学 交错的顺序免疫抑制作用，在AIM 2中，我们开发了一种删除竞争者b的方法 疫苗期间的细胞，在AIM 3中，我们使用增强的T细胞帮助开发疫苗，在 AIM 4，我们提出技术以在一次性之后实现顺序免疫原料暴露 注射。我们将在旨在引起bnabs的疫苗的背景下测试这些概念 CD4结合位点（VRC01类响应）和Env Fusion肽，使用物理 相关条件。这些免疫策略中最具影响力 在R33期，非人类灵长类动物（NHP）的测试，艾滋病毒的动物模型 接近人类的免疫接种。我们的工作以欧文，克罗蒂（Crotty）的最新进展为指导 和Silvestri实验室了解GC动力学，BNAB B细胞竞争，疫苗输送系统， 新型的调节器和T细胞在稀有B细胞募集中的帮助。