"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.

项目概要/摘要 大多数获得许可的疫苗被认为能引起体液免疫介导的保护作用。 抗体反应的特异性和亲和力的决定因素是引发的生发中心 (GC) 反应 通过免疫，B细胞进入GC进行循环增殖和体细胞超突变 进化出更高亲和力的抗体，然后从GC中退出，成为长寿命的浆细胞或记忆细胞 B 细胞有效的 GC 反应被认为对于 HIV 等困难病原体，甚至对于容易发生的病原体至关重要。 中和病毒，如 SARS-CoV-2，有效且长寿命的 GC 反应与更多相关 因此，优化 GC 反应是疫苗的基础。 在最近的工作中，我们研究了疫苗动力学——抗原和佐剂的时间模式。 免疫期间的暴露——尤其影响体液免疫和 GC 反应。 研究表明，在 2-3 周的时间内将抗原长时间递送至引流淋巴结 改变免疫反应是一种特别有效的免疫方法，我们称之为“延长免疫”。 “剂量”（额外剂量）免疫，涉及施用给定总剂量的疫苗抗原和佐剂 两周内以递增剂量模式进行六次注射可增强剂量。 小型和大型动物模型中的 GC 反应，并增加克隆性（不同 B 细胞的数量） 参与 GC 的克隆），导致中和抗体产生增强。 额外给药疫苗接种需要密切研究，以了解这种策略如何以及为何如此有效。 通过重复注射对于人类免疫来说是不切实际的，我们也非常积极地开发 无需注射 6 次或更多次即可实现相同免疫效果的替代策略。 为了实现这些目标，我们的具体目标是（1）定义抗原暴露动力学如何控制免疫 额外给药免疫引起的反应，(2) 确定佐剂暴露动力学如何影响免疫 延长给药的反应，（3）测试使用推注亚单位疫苗实现“延长给药”效果的策略 (4) 评估 mRNA 疫苗的额外给药效应的潜力。 研究将阐明有效初级免疫反应的基本概念并开发新的 增强亚单位和 mRNA 疫苗引发的免疫反应的翻译相关方法。 使用临床相关抗原和佐剂测试这些概念，并旨在追求我们期望的策略 广泛适用于独立于疾病目标的疫苗。