"Extended dosing" immunization to enhance humoral immunity to next-generation vaccines

“延长剂量”免疫增强对下一代疫苗的体液免疫

• 批准号: 10638732
• 负责人: Darrell J Irvine
• 金额: $ 46.94万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-14 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638732
• 关键词: 2019-nCoV; Address; Adjuvant; Animal Model; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antigens; Automobile Driving; B-Lymphocytes; Beds; Binding; Bolus Infusion; Cells; Clonality; Clone Cells; Collagen; Complement; Computer Analysis; Computer Models; Disease; Dose; Drug Kinetics; Effectiveness; Feedback; Future Generations; Generations; Goals; HIV; Human; Humoral Immunities; Immune response; Immunity; Immunization; Immunoglobulin Somatic Hypermutation; Immunologics; Inflammation; Injections; Kinetics; Licensing; Lymphocyte Activation; Mediating; Memory B-Lymphocyte; Messenger RNA; Modeling; Output; Pattern; Periodicity; Phenotype; Plasma Cells; Proliferating; RNA; RNA vaccine; Reaction; Regimen; Replicon; Role; Specificity; Structure of germinal center of lymph node; Subunit Vaccines; Testing; Translating; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Variant; Viral; Virus; Work; cell type; chemokine; clinically relevant; cytokine; design; draining lymph node; in vivo; neutralizing antibody; novel vaccines; pathogen; response; vaccine trial

Project Summary/Abstract The majority of licensed vaccines are thought to elicit protection mediated by humoral immunity. A key determinant of the specificity and affinity of the antibody response is the germinal center (GC) response elicited by immunization, wherein B cells enter GCs to undergo cyclic rounds of proliferation and somatic hypermutation to evolve higher-affinity antibodies, followed by exit from the GC to become long-lived plasma cells or memory B cells. Effective GC responses are thought to be critical for difficult pathogens such as HIV, and even for easily- neutralized viruses such as SARS-CoV-2, effective and long-lived GC responses are associated with more effective cross-neutralization of viral variants. Hence, optimizing GC responses is fundamental to vaccines broadly. In recent work, we have studied how vaccine kinetics– the temporal pattern of antigen and adjuvant exposure during immunization– impact humoral immunity and GC reaction in particular. Our preliminary studies have revealed that prolonged delivery of antigen to draining lymph nodes over a period of 2-3 weeks substantially alters the immune response. One particularly effective immunization approach, which we term “extended dosing” (ext-dosing) immunization, involves administering a given total dose of vaccine antigen and adjuvant as a half-dozen injections over two weeks in an escalating-dose pattern. Ext-dosing enhances the magnitude of the GC response in both small and large animal models and increases the clonality (number of distinct B cell clones participating in the GC), leading to enhanced neutralizing antibody production. These dramatic effects of ext-dosing vaccination warrant close study to understand how and why this strategy is so effective. As ext-dosing through repeat injections is not practical for human immunization, we are also highly motivated to develop alternate strategies to achieve the same immunologic effects without the need for 6 or more injections. To address these goals, our specific aims are (1) define how antigen exposure kinetics govern the immune response elicited by ext-dosing immunization, (2) determine how adjuvant exposure kinetics impact the immune response in ext-dosing, (3) test strategies to achieve “extended-dosing” effects using bolus subunit vaccine administration, and (4) to evaluate the potential for ext-dosing-like effects in mRNA vaccines. Altogether, these studies will both clarify fundamental concepts underlying effective primary immune responses and develop new translationally-relevant approaches to enhance immune responses elicited by subunit and mRNA vaccines. We test-bed these concepts using clinically-relevant antigens and adjuvants, and aim to pursue strategies we expect to be broadly applicable to vaccines independent of disease target.

项目摘要/摘要 人们认为，大多数有执照的疫苗都会引起由体液免疫介导的保护。钥匙 抗体反应的特异性和亲和力的决定因素是引起生发中心（GC）响应 通过免疫，其中B细胞输入GC进行循环循环增殖和体细胞超变态 进化高亲和力抗体，然后从GC退出以成为长寿命的浆细胞或记忆 B细胞。有效的GC反应被认为对于困难的病原体，例如HIV，甚至对于轻松 - 中和病毒（例如SARS-COV-2），有效和长寿的GC反应与更多有关 病毒变体的有效跨性和中和化。因此，优化GC反应是疫苗的基础 广泛。在最近的工作中，我们研究了阴道动力学是如何 - 抗原的临时模式和调整 免疫期间的暴露 - 尤其会影响体液免疫学和GC反应。我们的初步研究 已经表明，在2-3周内，抗原延长了抗原向排水淋巴结的递送 改变免疫响应。一种特别有效的免疫化方法，我们称其为“扩展 剂量”（延伸剂量）免疫抑制作用，涉及给定总剂量的疫苗抗原并调整 在两周内以升级的剂量模式进行六次注射。延长剂量增强了幅度 小动物模型和大型动物模型中的GC响应，并增加了克隆性（不同的B细胞的数量 参加GC的克隆，导致中和抗体产生增强。这些戏剧性的影响 扩展剂量的疫苗警告仔细研究，以了解该策略如何以及为什么如此有效。作为延期剂量 通过重复注射对于人类免疫不实用，我们也很有动力发展 无需6个或更多注射的替代策略即可实现相同的免疫作用。到 解决这些目标，我们的具体目的是（1）定义抗原暴露动力学如何控制免疫 通过扩展剂量免疫抑制引起的反应，（2）确定调整暴露动力学如何影响免疫 （3）使用推注亚基疫苗实现“扩展剂量”效果的测试策略的响应 给药和（4）评估mRNA疫苗中延伸剂量样作用的潜力。这些，这些 研究都将阐明有效初次免疫回避的基本概念并开发新的基本概念 与翻译相关的方法来增强亚基和mRNA疫苗引起的免疫反应。我们 使用临床上的抗原和调节器测试这些概念，并旨在追求我们期望的策略 广泛适用于独立于疾病靶标的疫苗。