Targeting CD4 T follicular helper cells for enhancing HIV vaccine induced humoral immunity

靶向 CD4 T 滤泡辅助细胞增强 HIV 疫苗诱导的体液免疫

• 批准号: 10374194
• 负责人: Swaminathan Smita Iyer
• 金额: $ 77.39万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-12 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374194
• 关键词: AIDS prevention; Adjuvant; Aging; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Area; Avidity; B cell differentiation; B-Lymphocytes; Blood Circulation; Cells; Clinical; DNA; Data; Development; Disease Management; Epidemic; Exposure to; Foundations; Frequencies; Funding; Gene Expression Profile; Generations; Glycoproteins; Goals; HIV; HIV Antibodies; HIV vaccine; HIV-1; Healthcare Systems; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; IgG1; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Immunologics; Inflammatory; Inflammatory Response; Innate Immune Response; Knowledge; Licensure; Longevity; Macaca mulatta; Mediating; Memory B-Lymphocyte; Mucous Membrane; Outcome; Patients; Phenotype; Plasma Cells; Production; Proteins; Regimen; Research; Research Project Grants; SIV; Secondary Immunization; Serum; Specificity; Structure; Surface; T-Lymphocyte; Testing; Vaccination; Vaccines; Variant; antiretroviral therapy; base; design; evidence base; health care availability; improved; innovation; neutralizing antibody; pandemic disease; preclinical study; prevent; rectal; response; simian human immunodeficiency virus; transmission process; vaccine acceptance; vaccine efficacy; vaginal mucosa

Project Summary Anti-retroviral therapy (ART) has dramatically altered the HIV pandemic landscape by rendering the disease manageable - but still incurable. Significant barriers are associated with the global implementation of ART that limit its utility for sustainable prevention of HIV. Moreover, the intersection of aging-related conditions and the consequences of long-term ART will have a substantial impact on the healthcare system as well as on HIV patients. These challenges underscore the need to pursue strategies that will provide both sustainable HIV prevention and a functional HIV cure. The results of the RV144 trial indicate that vaccination may prevent HIV transmission in humans and that durability of anti-envelope (Env) HIV antibodies may be the key to this protection. Efforts to improve upon the RV144 trial have demonstrated that booster immunizations increase serum anti-Env antibody titers only transiently. This “anti-Env antibody persistence problem” impedes our efforts to develop an effective HIV vaccine. This proposal is designed to improve our functional understanding of the immunological mechanism involved in producing durable HIV Env antibodies in both the systemic circulation and the rectal and vaginal mucosa. To accomplish this, we will be using a DNA-prime/Protein-boost vaccine regimen in rhesus macaques. Aim 1 of this research project is focused on establishing how Th1 versus Th1/Th17 priming impacts innate inflammatory response, Env TFH frequencies, phenotype, transcriptional profile, and B cell helper capacity, as well as systemic and mucosal anti-Env antibody titers. Aim 2 will determine whether combining the state-of-the-art soluble Env mimic, an Env SOSIP trimer protein immunogen with a highly potent and robust adjuvant (to induce Th1/Th17 response, results in increased production of a high-quality, long- lasting anti-Env antibodies relative to Th1 vaccine regimen. We will further investigate whether vaccine-mediated induction of the polyfunctional TFH response improves protection when faced with a mucosal simian HIV challenge. These preclinical studies will establish the mechanistic and experimental foundations to identify how TFH helper cell profiles impact anti-Env antibody longevity and vaccine efficacy and will lay the necessary, evidence-based foundation for the design of a successful HIV vaccine.

项目摘要 抗逆转录病毒疗法（ART）通过使疾病急剧改变了HIV大流行景观 可以管理 - 但仍然无法治愈。重大障碍与全球艺术实施有关 限制其可持续预防艾滋病毒的效用。此外，与衰老相关条件的交集和 长期艺术的后果将对医疗保健系统以及艾滋病毒产生重大影响 患者。这些挑战强调了追求将提供可持续艾滋病毒的战略的必要性 预防和功能性HIV治疗。 RV144试验的结果表明疫苗接种可能预防HIV 人类的传播以及抗Envelope（Env）HIV抗体的耐用性可能是这样的关键 保护。改善RV144试验的努力表明，增强免疫抑制增加了 血清抗ENV抗体滴度仅瞬时。这种“抗ENV抗体持久性问题”阻碍了我们 开发有效的HIV疫苗的努力。该建议旨在提高我们的功能理解 在全身性中产生耐用的HIV ENV抗体涉及的免疫机制 循环以及直肠和阴道粘膜。为此，我们将使用DNA-PRIME/蛋白质增强 恒河猕猴中的疫苗方案。该研究项目的目标1侧重于确定TH1如何与 TH1/TH17启动会影响先天的炎症反应，ENV TFH频率，表型，转录曲线， 和B细胞辅助剂的容量，以及全身和粘膜抗ENV抗体滴度。 AIM 2将确定 是否结合最新的可溶性Env Mimic，ENV SOSIP三聚体蛋白免疫原 潜在和稳健的调整（诱导Th1/Th17响应，导致高质量，长期产生的产生 相对于Th1疫苗方案，持续的抗凝胶抗体。我们将进一步研究疫苗介导的 诱导多功能TFH响应在面对粘膜邻虫HIV时可改善保护 挑战。这些临床前研究将建立机械和实验基础，以确定 TFH辅助细胞轮廓会影响抗ENV抗体的寿命和疫苗效率，并将构成必要的， 基于证据的基础，用于设计成功的HIV疫苗。