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: 10629386
• 负责人: Erin M Scherer
• 金额: $ 19.56万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629386
• 关键词: 2019-nCoV; 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; Capsid Proteins; Communicable Diseases; DNA; DNA Binding; DNA Vaccines; Dependence; Development; Differentiated Gene; Dose; Generations; Goals; HIV-1; Hepatitis B Virus; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 16; Humoral Immunities; Immune; Immunity; Immunize; Immunodominant Epitopes; Influenza; Knowledge; Learning; Ligands; Longevity; Malignant Neoplasms; Memory B-Lymphocyte; Modeling; Molecular Conformation; Mus; Nature; Nucleic Acids; Pathway interactions; Pattern recognition receptor; Pertussis; Plasma Cells; Plasmablast; Public Health; Recombinant DNA; Recombinants; Reporting; Research; Role; Structure of germinal center of lymph node; Subunit Vaccines; Testing; Time; Typhoid Fever; Up-Regulation; Vaccines; Virus-like particle; Wild Type Mouse; Work; aluminum sulfate; design; human pathogen; improved; monomer; 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.

摘要 大多数疫苗通过产生抗体来保护。减毒活疫苗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 由于并非对所有病原体或受体都可行，因此开发亚单位疫苗可以引发强效且长期的免疫反应。 活的抗体反应是必不可少的。几十年来，疫苗学一直专注于开发亚单位疫苗， 引发对人类病原体的强烈和/或广泛的抗体应答。然而，对公共卫生至关重要的是， 亚单位疫苗还产生持久的抗体应答。因此，需要进行基础研究，以了解如何 可靠地设计这种疫苗。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，它的抗体持久性 优于许多其它批准的亚单位疫苗的上级。因此，HPV-9代表了亚单位疫苗的模型 用于研究产生强大和持久的抗体反应。与大多数其他亚单位疫苗不同，HPV 疫苗由高度重复的、高效价的抗原：病毒样颗粒（VLP）组成。每个VLP HPV 型由360个单位的主要衣壳蛋白L1组装而成。此外，L1结合DNA，HPV-9含有 重组L1 DNA。无论是高抗原价还是抗原相关DNA通常都会增强免疫应答。 持久的B细胞记忆的形成没有得到很好的研究。关于HPV，L1 VLP引起更高的中和峰 L1五聚体的抗体应答和抗VLP抗体应答依赖于MyD 88，MyD 88是L1五聚体的组分。 DNA传感途径。目前缺乏的是对疫苗DNA是否能增强 对HPV-9的抗体应答，以及抗原价或疫苗DNA是否在诱导HPV-9抗体应答中起作用。 持久的HPV特异性B细胞记忆。本提案将通过两个目标来弥补这些差距。第一个目标是 测试峰值和长寿命HPV-9引发的B细胞应答对DNA传感器的依赖性。野生型小鼠和 用HPV-9或明矾免疫各种DNA感应途径缺陷的小鼠。在此之前， 每次HPV-9给药后的时间点、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。通过这种方式，DNA传感在刺激峰值、回忆和长期 将评估（≥12个月）B细胞应答。第二个目的是评估长寿的依赖性 HPV特异性B细胞对抗原价态的记忆。小鼠将用三个剂量的单体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）。在此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、生殖中心B细胞、记忆B细胞和骨 分析骨髓浆细胞反应。对1-mer、5-mer和360-mer抗原的应答将是 比较了以这种方式，将测试抗原价在诱导长期B细胞记忆中的作用。这 这项工作将推进HPV-9如何实现持久抗体应答的知识， 疫苗具有更持久的体液免疫力，并改善对其他病原体的保护。