Persistent modulation of microbiota to enhance HIV vaccination

持续调节微生物群以增强艾滋病毒疫苗接种

基本信息

批准号：
9191341
负责人：
Nichole Rose Klatt
金额：
$ 108.69万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191341
关键词：
Adjuvant Animals Antibodies Antibody Response Antigen-Presenting Cells Avidity B-Lymphocytes Binding Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Communication Cell physiology Cellular Immunity Coculture Techniques Combined Modality Therapy Combined Vaccines Complex DNA DNA Vaccines DNA delivery Frequencies Gastrointestinal tract structure HIV Helper-Inducer T-Lymphocyte Humoral Immunities Immune response Immunity Immunization Immunoglobulin A Immunoglobulin Class Switching Immunology Infection Inflammation Innate Immune Response Macaca Measurement Measures Mediating Modeling Morphogenesis Mucosal Immune Responses Mucosal Immunity Mucous Membrane Natural Immunity Nature Phenotype Physiology Plasma Play Probiotics Proteins Recombinant Proteins Recombinants Research Role SIV Signal Transduction Site Specificity Structure of germinal center of lymph node Surface T cell response T-Lymphocyte Tissues Vaccinated Vaccination Vaccine Design Vaccines Virus adaptive immune response adaptive immunity env Gene Products gut microbiome immune function immunogenicity immunoregulation improved innate immune function innovation lymph nodes microbial community microbiome microbiota mucosal site mucosal vaccine neutralizing antibody novel novel strategies novel vaccines particle prevent probiotic therapy prophylactic protective effect public health relevance rectal response simian human immunodeficiency virus transmission process vaccination strategy vaccine efficacy vaccine response vaccine-induced immunity

项目摘要

DESCRIPTION (provided by applicant): Given the highly complex nature of HIV, including the challenges of protecting mucosal surfaces from transmission and high variability of the virus, developing innovative vaccination strategies is crucial. Indeed, despite extensive research, a fully efficacious vaccine to prevent HIV transmission remains elusive, and there is limited understanding of correlates of protection, particularly at mucosal surfaces. Recently, the importance of the microbiome in mucosal immunity have become appreciated, and here we hypothesize that we can exploit the microbiome to induce protective vaccine responses. Here we propose a novel HIV vaccination approach that uses persistent probiotic therapy as an adjuvant to enhance immunogenicity and protection induced by a potent combined vaccine strategy. Our vaccine consists of concurrently administered SIV (gag p55) and HIV (gp140) DNA + HIV gp140 trimer protein. Recent studies have provided evidence that combining DNA and protein for vaccination elicits increased vaccine specific cellular and humoral immunity, In addition, our preliminary studies provocatively demonstrated that probiotic treatment in SIV-uninfected macaques results in increased T follicular helper cells in lymph nodes, IgA expressing B cells in mucosal tissues, increased antigen presenting cells in mucosal tissues, and increased multifunctional T cells, as well as decreased proliferation and activation of CD4+ T cells. Thus, we hypothesize that combining the potent immunomodulatory effects of beneficial microbiota manipulation with a novel vaccine platform that should induce robust cellular and humoral immunity will result in unprecedented high levels of vaccine specific responses in both mucosal and systemic tissues, resulting in protection from rectal SHIV challenge. There are several innovative aspects of this vaccine design, including: (i.) Modulation of the microbiota with probiotics to enhance mucosal vaccine responses; (ii.) utilization of a novel dual SHIV DNA-HIV gp140 protein vaccination platform; (iii.) novel measurements of potential vaccination correlates will be measured including microbiome morphogenesis, homeostatic mucosal responses, innate immune responses, and T follicular helper and germinal center B cell responses, in addition to standard correlates of vaccination (antibody and T cell responses).

描述（由申请人提供）：鉴于艾滋病毒的高度复杂性，包括保护粘膜表面免受传播的挑战和病毒的高变异性，尽管进行了广泛的研究，但开发创新的疫苗接种策略确实至关重要。 HIV 传播仍然难以捉摸，而且对保护相关性的了解有限，特别是在粘膜表面，最近，人们认识到微生物组在粘膜免疫中的重要性，在这里我们追求我们可以利用这一点。微生物组诱导保护性疫苗反应。在此，我们提出了一种新的 HIV 疫苗接种方法，该方法使用持久性益生菌疗法作为佐剂，以增强有效的联合疫苗策略诱导的免疫原性和保护作用。我们的疫苗由同时施用的 SIV (gag p55) 和 HIV (gp140) DNA + HIV gp140 三聚体组成。最近的研究表明，结合 DNA 和蛋白质进行疫苗接种可增强疫苗特异性细胞和体液免疫。此外，我们的初步研究令人兴奋地证明，益生菌治疗未感染 SIV。猕猴导致淋巴结中滤泡辅助性T细胞增加、粘膜组织中表达IgA的B细胞增加、粘膜组织中抗原呈递细胞增加、多功能T细胞增加，以及CD4+T细胞增殖和活化减少。将有益微生物群操纵的有效免疫调节作用与能够诱导强大的细胞和体液免疫的新型疫苗平台相结合，将在粘膜和全身组织中产生前所未有的高水平疫苗特异性反应，从而产生保护作用来自直肠 SHIV 挑战。该疫苗设计有几个创新方面，包括：(i.) 用益生菌调节微生物群以增强粘膜疫苗反应；(ii.) 利用新型 SHIV DNA-HIV gp140 蛋白双重疫苗接种平台；除了标准相关性之外，还将测量潜在疫苗接种相关性的新测量方法，包括微生物组形态发生、稳态粘膜反应、先天免疫反应、滤泡辅助性 T 细胞和生发中心 B 细胞反应疫苗接种（抗体和 T 细胞反应）。