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

基本信息

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
项目类别：
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

项目摘要

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。然而，许多亚单位疫苗的体液免疫会随着时间的推移而减弱，因为减毒活疫苗可能会减弱。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几十年来，疫苗学一直致力于开发亚单位疫苗。引发针对人类病原体的强烈和/或广泛的抗体反应，但这对公共卫生至关重要。亚单位疫苗也能产生持久的抗体反应，因此需要基础研究来了解如何产生持久的抗体反应。可靠地设计出此类疫苗，即高效的 9 型人乳头瘤病毒亚单位疫苗（HPV-9）。可以预防九种通常导致癌症的 HPV 类型（例如 HPV 16），而且其抗体持久性强。优于许多其他已批准的亚单位疫苗，因此，HPV-9 代表了一种模型亚单位疫苗。与大多数其他亚单位疫苗不同，HPV 是用于研究强效且持久的抗体反应的产生。疫苗由高度重复、高效价的抗原组成：病毒样颗粒 (VLP)。 HPV-9 型由其主要衣壳蛋白 L1 的 360 个单位组装而成。此外，L1 结合 DNA，并且 HPV-9 含有。无论是高抗原效价还是抗原相关DNA，重组L1 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 会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 传感途径缺乏了解疫苗 DNA 是否会增强 DNA 的强度。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该提案将通过两个目标来解决这些差距。测试 HPV-9 引发的 B 细胞反应峰值和长寿命对 DNA 传感器的依赖性。缺乏各种 DNA 传感途径的小鼠将在不同的时间之前和之后用 HPV-9 或明矾进行免疫。每次 HPV-9 剂量后的时间点、HPV 特异性中和抗体、记忆 B 细胞和骨髓血浆通过这种方式，我们可以分析 DNA 传感在刺激峰值、回忆和长期方面的作用。（≥12 个月）将评估 B 细胞反应，第二个目的是评估长寿的依赖性。 HPV 特异性 B 细胞对抗原价的记忆将用三剂单体 HPV 16 免疫小鼠。 L1（1-mers）、HPV 16 L1 五聚体（5-mers）或 HPV 16 L1 VLP（360-mers）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对 1 聚体、5 聚体和 360 聚体抗原的反应。通过这种方式，可以测试抗原效价在诱导B细胞长期记忆中的作用。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。