Elicitation of mucosal immune responses against HIV

引发针对 HIV 的粘膜免疫反应

• 批准号: 9539522
• 负责人: James J Moon
• 金额: $ 48.94万
• 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/9539522
• 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.

摘要 人类免疫缺陷病毒(HIV)主要通过粘膜组织进入宿主并引发感染。 因此，一种可以在粘膜组织中诱导细胞和体液免疫反应的疫苗接种策略是 急需之物。然而，目前还没有批准的佐剂可以达到这两种T细胞的强劲水平 以及粘膜组织中的抗体反应。因此，迫切需要一种替代、有效和 粘膜疫苗接种的安全策略。我们的长期目标是开发能够 诱导对HIV-1的保护性免疫。我们的目标是设计用于粘膜递送的纳米颗粒 并研究其对系统和粘膜免疫反应的影响。至 为此，我们开发了一种新的纳米颗粒(NP)系统，可以诱导出强大的细胞毒性CD8+T细胞 淋巴细胞(CTL)对亚单位蛋白抗原的反应。我们发现这些新的疫苗NPs能促进 将抗原递送到体内的抗原提呈细胞，产生CTL并传播到粘膜组织， 包括宫颈、阴道和胃肠道，并保护动物免受病毒感染。我们还展示了 NPs能显著提高小鼠的抗体效价，可持续400天，具有更强的亲和力，耐受性， 与市场上的常规佐剂(如明矾或蒙太尼)相比，它具有更大的广度和广度。基于这些 根据初步数据，我们建议开发一种新的基于NP的黏膜免疫策略来对抗HIV-1。 我们将检验我们的中心假设，即与T和B细胞HIV-1免疫原结合的NPs将诱导 粘膜组织中的协同细胞和体液免疫反应。在完成建议的 研究表明，我们将发现一种新的疫苗接种技术，可以诱导粘膜T和B细胞反应 对抗HIV-1。这些研究将加速HIV-1疫苗的开发，并增进我们对 疫苗投放系统对粘膜免疫的影响。