Elicitation of mucosal immune responses against HIV

引发针对 HIV 的粘膜免疫反应

• 批准号: 9752434
• 负责人: James J Moon
• 金额: $ 65.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-26 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752434
• 关键词: Adjuvant; Animals; Antibody Avidity; Antibody Response; Antibody titer measurement; Antigen Presentation; Antigen-Presenting Cells; Antigens; Artificial nanoparticles; Avidity; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cross Presentation; Cross-Priming; Data; Ebola virus; Engineering; Gastrointestinal tract structure; Glycoproteins; Goals; HIV; HIV-1; HIV-1 vaccine; Helper-Inducer T-Lymphocyte; Immune response; Immunity; Immunization; Immunoglobulin G; Infection; Lipase; Lipids; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Onions; Oryctolagus cuniculus; Outcome; Plasmodium vivax; Property; Protein Subunits; Public Health; Research; Safety; Series; Serum; Structure of germinal center of lymph node; Structure-Activity Relationship; System; T cell response; T-Lymphocyte; Technology; Testing; Vaccination; Vesicle; Viral; Virus Diseases; aluminum sulfate; antigen-specific T cells; base; cervicovaginal; crosslink; cytotoxic; design; immunogenicity; in vivo; lymph nodes; mucosal vaccination; nanoformulation; nanoparticle; nanovaccine; neutralizing antibody; next generation; nonhuman primate; novel; novel vaccines; pathogen; prototype; response; safety study; vaccination strategy; vaccine delivery; vaccine development; vector

Abstract Human immunodeficiency virus (HIV) primarily enters the host and initiates infection through mucosal tissues. Therefore, a vaccination strategy that can elicit cellular and humoral immune responses in mucosal tissues is urgently needed. However, there is currently no approved adjuvant that can achieve robust levels of both T-cell and antibody responses in mucosal tissues. Therefore, there is a critical need for an alternative, effective, and safe strategy for mucosal vaccination. Our long-range goal is to develop vaccine delivery systems that can elicit protective immunity against HIV-1. Our objective here is to engineer nanoparticles for mucosal delivery of HIV-1 antigens and investigate their impact on elicitation of systemic and mucosal immune responses. To that end, we have developed a new nanoparticle (NP) system that can elicit strong cytotoxic CD8+ T lymphocyte (CTL) responses with subunit protein antigens. We show that these new vaccine NPs promote antigen delivery to antigen-presenting cells in vivo, generate CTLs that disseminate to mucosal tissues, including cervicovaginal and gastrointestinal tracts, and protect animals against viral infection. We also show that NPs induce significantly higher antibody titers, lasting > 400 days in mice with greater avidity, durability, and breadth, compared with conventional adjuvants on the market (e.g. alum or Montanide). Based on these preliminary data, we propose to develop a new NP-based strategy for mucosal immunization against HIV-1. We will test our central hypothesis that NPs incorporated with T and B-cell HIV-1 immunogens will elicit concerted cellular and humoral immune responses in mucosal tissues. At the completion of the proposed studies, we will have identified a new vaccination technology that can induce mucosal T and B cell responses against HIV-1. These studies will accelerate HIV-1 vaccine development and advance our understanding of the impact of vaccine delivery systems on mucosal immunity.

抽象的 人免疫缺陷病毒（HIV）主要进入宿主并通过粘膜组织引发感染。 因此，一种可以引起粘膜组织中细胞和体液免疫反应的疫苗接种策略是 迫切需要。但是，目前尚无批准的佐剂可以达到两个T细胞的稳健水平 和粘膜组织中的抗体反应。因此，迫切需要替代，有效和 粘膜疫苗接种的安全策略。我们的远程目标是开发可以 引起对HIV-1的保护性免疫。我们的目的是设计纳米颗粒以进行粘膜递送 HIV-1抗原并研究其对系统性和粘膜免疫反应的启发的影响。到 那一端，我们开发了一种新的纳米颗粒（NP）系统，该系统可以引起强大的细胞毒性CD8+ T 亚基蛋白抗原的淋巴细胞（CTL）反应。我们表明这些新的疫苗NP促进 抗原递送至抗原呈递细胞的体内，产生的CTL会传播到粘膜组织， 包括宫颈阴道和胃肠道，并保护动物免受病毒感染。我们也显示 NP诱导明显更高的抗体滴度，持续> 400天，耐用性，耐用性， 与市场上的常规佐剂（例如明矾或蒙塔尼尼）相比，广度和广度。基于这些 初步数据，我们建议制定一种基于NP的新策略，以针对HIV-1进行粘膜免疫。 我们将检验我们的中心假设，即与T和B细胞HIV-1免疫原合并的NP会引起 粘膜组织中协同的细胞和体液免疫反应。拟议完成时 研究，我们将确定一种可以诱导粘膜T和B细胞反应的新疫苗接种技术 反对HIV-1。这些研究将加速HIV-1疫苗的开发，并提高我们对 疫苗输送系统对粘膜免疫的影响。