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: 10588202
• 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: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10588202
• 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; 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.

项目概要 临床前研究和早期人体试验评估被动转移广泛 中和抗体 (bnAbs) 表明能够引发 bnAbs 的疫苗将提供 然而，通过诱导bnAbs的难度。 疫苗接种已引起该领域对基于序贯免疫的疫苗策略的关注 这些顺序免疫策略旨在指导正在发育的 B 细胞反应。 从种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 此类疫苗尚无答案：在这样的策略中，连续免疫原应以什么间隔进行 如何进行来自抗原特异性但非中和性 B 细胞的竞争？ 前体影响疫苗“引导”是否阻碍了这种顺序免疫过程？ T细胞帮助有限？此外，包含4次或更多注射的疫苗将是一个挑战 我们如何在这个阶段使这种疫苗实用化？ 应用程序，我们建议在小动物模型中进行系统研究，以评估基本原理 我们提出了几种针对此类策略的疫苗免疫学问题。 检查并可能解决这些问题：在目标 1 中，我们将描述以下因素的免疫学特征： 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 在疫苗接种过程中，我们开发了利用增强 T 细胞帮助的疫苗，并在目标 3 中 目标 4，我们提出了能够在单次免疫原暴露后连续暴露的技术 我们将在疫苗的背景下测试这些概念，旨在引发针对 bnAb 的抗体。 CD4 结合位点（VRC01 类反应）和 Env 融合肽，使用生理学 这些免疫策略中最有影响力的将被淘汰。 在 R33 阶段（HIV 动物模型）对非人类灵长类动物 (NHP) 进行测试 我们的工作以欧文、克罗蒂的最新进展为指导。 和 Silvestri 实验室了解 GC 动力学、bnAb B 细胞竞争、疫苗输送系统、 新型佐剂和 T 细胞的作用有助于罕见的 B 细胞募集。

项目成果

Targeted modulation of immune cells and tissues using engineered biomaterials.

使用工程生物材料定向调节免疫细胞和组织。

• DOI: 10.1038/s44222-022-00016-2
• 发表时间: 2023-01-30
• 期刊: Nature reviews bioengineering
• 作者: P. Yousefpour;Kaiyuan Ni;D. Irvine
• 通讯作者: D. Irvine

Co-Anchoring of Engineered Immunogen and Immunostimulatory Cytokines to Alum Promotes Enhanced-Humoral Immunity.

工程免疫原和免疫刺激细胞因子与明矾的共同锚定可促进增强的体液免疫。

• 发表时间: 2022-07
• 影响因子: 4.6
• 作者: Chang, Jason Y H;Agarwal, Yash;Rodrigues, Kristen A;Momin, Noor;Ni, Kaiyuan;Read, Benjamin J;Moyer, Tyson J;Mehta, Naveen K;Silva, Murillo;Suh, Heikyung;Melo, Mariane B;Wittrup, K Dane;Irvine, Darrell J
• 通讯作者: Irvine, Darrell J

Optimization of storage conditions for lipid nanoparticle-formulated self-replicating RNA vaccines.

脂质纳米颗粒配制的自我复制 RNA 疫苗储存条件的优化。

• 发表时间: 2023-01
• 作者: Kim, Byungji;Hosn, Ryan R;Remba, Tanaka;Yun, Dongsoo;Li, Na;Abraham, Wuhbet;Melo, Mariane B;Cortes, Manuel;Li, Bridget;Zhang, Yuebao;Dong, Yizhou;Irvine, Darrell J
• 通讯作者: Irvine, Darrell J