Role of antigen valency and pattern recognition receptor ligands in HPV vaccine-induced durable B cell memory

抗原效价和模式识别受体配体在 HPV 疫苗诱导的持久 B 细胞记忆中的作用

• 批准号: 10510115
• 负责人: Erin M Scherer
• 金额: $ 23.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510115
• 关键词: 2019-nCoV; Address; Adjuvant; Adjuvanticity; Anogenital venereal warts; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Attenuated Vaccines; B-Cell Antigen Receptor; B-Lymphocytes; Basic Science; Binding; Biophysics; Bone Marrow; Cancer Etiology; Communicable Diseases; DNA; DNA Binding; DNA Vaccines; Dependence; Development; Differentiated Gene; Dose; Generations; Goals; HIV-1; Hepatitis B Virus; Human Characteristics; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 16; Human papillomavirus HPV L1 protein; Humoral Immunities; Immune; Immunity; Immunize; Immunodominant Epitopes; Influenza; Knowledge; Learning; Ligands; Longevity; Malignant Neoplasms; Memory B-Lymphocyte; Modeling; Molecular Conformation; Mus; Nucleic Acids; Pathway interactions; Pattern recognition receptor; Pertussis; Plasma Cells; Plasmablast; Play; Public Health; Recombinant DNA; Recombinants; Reporting; Research; Role; Structure of germinal center of lymph node; Subunit Vaccines; Testing; Time; Typhoid Fever; Up-Regulation; Vaccines; Viral Antigens; Virus-like particle; Wild Type Mouse; Work; aluminum sulfate; base; design; human pathogen; improved; neutralizing antibody; pathogen; plasma cell differentiation; response; sensor; vaccine development; vaccine trial; vaccine-induced antibodies; vaccinology

ABSTRACT Most vaccines protect by generating antibodies. Live attenuated vaccines induce lasting humoral immunity; however, humoral immunity for many subunit vaccines wanes over time. Because live attenuated vaccines may not be feasible for all pathogens or recipients, the development of subunit vaccines that elicit potent and long- lived antibody responses is essential. Vaccinology has focused for decades on developing subunit vaccines that elicit robust and/or broad antibody responses to human pathogens. However, it is crucial to public health that subunit vaccines also generate durable antibody responses. Thus, basic research is needed to know how to reliably design such vaccines. The highly effective 9-type human papillomavirus subunit vaccine (HPV-9) protects against nine HPV types that commonly cause cancer (e.g., HPV 16). Moreover, its antibody durability is superior to that of many other approved subunit vaccines. Thus, HPV-9 represents a model subunit vaccine for studying the generation of robust and enduring antibody responses. Unlike most other subunit vaccines, HPV vaccines are comprised of a highly repetitive, high valency antigen: virus like particles (VLP). Each VLP HPV type assembles from 360 units of its major capsid protein, L1. In addition, L1 binds DNA, and HPV-9 contains recombinant L1 DNA. Whether high antigen valency or antigen-associated DNA generally enhances the formation of durable B cell memory is not well studied. With regard to HPV, L1 VLPs elicit higher peak neutralizing antibody responses than L1 pentamers and anti-VLP antibody responses depend on MyD88, a component of a DNA sensing pathway. What is lacking is an understanding of whether vaccine DNA enhances the magnitude of antibody responses to HPV-9 and whether antigen valency or vaccine DNA plays a role in the induction of durable HPV-specific B cell memory. This proposal will address those gaps through two aims. The first aim is to test the dependency of peak and long-lived HPV-9-elicited B cell responses on DNA sensors. Wildtype mice and mice deficient in various DNA sensing pathways will be immunized with HPV-9 or alum. Before and at various time points after each HPV-9 dose, HPV-specific neutralizing antibody, memory B cell, and bone marrow plasma cell responses will be analyzed. In this way, the role of DNA sensing in stimulating peak, recall, and long-term (≥12 months) B cell responses will be assessed. The second aim is to evaluate the dependency of long-lived HPV-specific B cell memory on antigen valency. Mice will be immunized with three doses of monomeric HPV 16 L1 (1-mers), HPV 16 L1 pentamers (5-mers), or HPV 16 L1 VLPs (360-mers). Before and at various times after each antigen dose, HPV 16-specific neutralizing antibody, germinal center B cell, memory B cell, and bone marrow plasma cell responses will be analyzed. Responses to 1-mer, 5-mer, and 360-mer antigens will be compared. In this way, the role of antigen valency in the induction of long-term B cell memory will be tested. This work will advance knowledge of how HPV-9 achieves durable antibody responses and inform the development of vaccines with longer-lasting humoral immunity and improved protection against other pathogens.

抽象的 大多数疫苗通过产生抗体来提供保护。减毒活疫苗可诱导持久的体液免疫； 然而，许多亚单位疫苗的体液免疫随着时间的推移而减弱。因为减毒活疫苗可能 并非对所有病原体或接受者都可行，因此开发能够引起有效且长期的亚单位疫苗 活的抗体反应至关重要。数十年来，疫苗学一直致力于开发亚单位疫苗 引发对人类病原体的强烈和/或广泛的抗体反应。然而，对公共卫生至关重要的是 亚单位疫苗还能产生持久的抗体反应。因此，需要基础研究来了解如何 可靠地设计此类疫苗。高效9型人乳头瘤病毒亚单位疫苗（HPV-9） 预防九种通常导致癌症的 HPV 类型（例如 HPV 16）。此外，其抗体耐久性 优于许多其他已批准的亚单位疫苗。因此，HPV-9 代表了一种亚单位疫苗模型 用于研究强健且持久的抗体反应的产生。与大多数其他亚单位疫苗不同，HPV 疫苗由高度重复、高效价的抗原组成：病毒样颗粒（VLP）。每个VLP HPV type 由 360 个单位的主要衣壳蛋白 L1 组装而成。此外，L1 结合 DNA，HPV-9 包含 重组L1 DNA。无论是高抗原效价还是抗原相关 DNA 通常都会增强 持久 B 细胞记忆的形成尚未得到充分研究。对于 HPV，L1 VLP 引发更高的中和峰值 L1 五聚体的抗体反应和抗 VLP 抗体反应取决于 MyD88，它是 DNA 传感途径。目前缺乏的是对疫苗 DNA 是否会增强病毒感染程度的了解 针对 HPV-9 的抗体反应以及抗原效价或疫苗 DNA 是否在诱导中发挥作用 持久的 HPV 特异性 B 细胞记忆。该提案将通过两个目标来解决这些差距。第一个目标是 测试峰值和长寿命 HPV-9 引发的 B 细胞反应对 DNA 传感器的依赖性。野生型小鼠和 缺乏各种 DNA 传感途径的小鼠将使用 HPV-9 或明矾进行免疫。在各种之前和之后 每次 HPV-9 剂量后的时间点、HPV 特异性中和抗体、记忆 B 细胞和骨髓血浆 将分析细胞反应。这样，DNA传感在刺激峰值、回忆和长期记忆中的作用 （≥12 个月）将评估 B 细胞反应。第二个目标是评估长寿的依赖性 HPV 特异性 B 细胞对抗原价的记忆。小鼠将接受三剂单体 HPV 16 免疫 L1（1 聚体）、HPV 16 L1 五聚体（5 聚体）或 HPV 16 L1 VLP（360 聚体）。之前和之后的不同时间 每个抗原剂量、HPV 16 特异性中和抗体、生发中心 B 细胞、记忆 B 细胞和骨 将分析骨髓浆细胞反应。对 1 聚体、5 聚体和 360 聚体抗原的反应将是 比较的。通过这种方式，将测试抗原效价在诱导B细胞长期记忆中的作用。这 这项工作将增进对 HPV-9 如何实现持久抗体反应的了解，并为开发提供信息 具有更持久的体液免疫和更好的针对其他病原体的保护的疫苗。