Elicitation of mucosal immune responses against HIV

引发针对 HIV 的粘膜免疫反应

• 批准号: 9271737
• 负责人: James J Moon
• 金额: $ 9.41万
• 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/9271737
• 关键词: Adjuvant; Adopted; Animals; Antibodies; Antibody Response; Antigen-Presenting Cells; Antigens; Artificial nanoparticles; Asorbicap; Avidity; B-Lymphocytes; Binding; CD8-Positive T-Lymphocytes; Chitosan; Cleaved cell; Coomassie blue; Cross Presentation; Cross-Priming; Data; Ebola virus; Endopeptidase K; Engineering; Epitopes; Ferritin; Gastrointestinal tract structure; Generations; Genotype; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Homo; Immune response; Immunity; Immunization; Immunoglobulin G; Infection; Length; Lipase; Lipids; Marketing; Membrane; Modeling; Molecular; Molecular Conformation; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Negative Staining; Onions; Oryctolagus cuniculus; Outcome; Oxis; Peptide Hydrolases; Plasmodium vivax; Property; Protein Subunits; Public Health; Research; Resistance; Rest; Safety; Series; Serum; Side; Site; Son of Sevenless Proteins; Staining method; Stains; Structure; Structure of germinal center of lymph node; Structure-Activity Relationship; System; T cell response; T-Lymphocyte; Technology; Testing; Thyroglobulin; Trypsin; Vaccination; Vesicle; Viral; Virus; Virus Diseases; Weight; abstracting; aluminum sulfate; base; cervicovaginal; chymotrypsin; comparative; crosslink; cytotoxic; design; dimer; env Gene Products; gp160; immunogenicity; in vivo; lymph nodes; monomer; mucosal vaccination; multiple myeloma M Protein; nanoformulation; nanoparticle; nanovaccine; neutralizing antibody; next generation; nonhuman primate; novel; novel vaccines; pathogen; prototype; reconstruction; 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，可以在粘膜组织中引发细胞和体液免疫应答的疫苗接种策略是可行的。 迫切需要。然而，目前还没有批准的佐剂可以实现T细胞免疫和免疫调节的稳健水平。 和粘膜组织中的抗体应答。因此，迫切需要一种替代的，有效的， 粘膜接种的安全策略。我们的长期目标是开发疫苗输送系统， 引发针对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 研究HIV-1抗原对激发全身和粘膜免疫应答的影响。到 为此，我们开发了一种新的纳米颗粒（NP）系统，可以引发强细胞毒性CD 8 + T细胞， 淋巴细胞（CTL）与亚单位蛋白抗原的反应。我们表明，这些新的疫苗纳米颗粒促进 在体内将抗原递送至抗原呈递细胞，产生散布至粘膜组织的CTL， 包括子宫颈阴道和胃肠道，并保护动物免受病毒感染。我们还表明 NPs在小鼠中诱导显著更高的抗体滴度，持续> 400天，具有更大的亲和力，持久性， 和广度，与市场上的常规佐剂（例如明矾或Montanide）相比。基于这些 初步数据，我们建议开发一种新的NP为基础的策略，粘膜免疫抗HIV-1。 我们将测试我们的中心假设，即与T细胞和B细胞HIV-1免疫原结合的NP将引起 在粘膜组织中协调的细胞和体液免疫应答。在完成拟议的 研究，我们将确定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，并促进我们对HIV-1的理解。 疫苗递送系统对粘膜免疫的影响。