Recombinant Lactobacillus as an Oral Mucosal Vaccine Against HIV-1

重组乳杆菌作为抗 HIV-1 的口腔粘膜疫苗

• 批准号: 7932516
• 负责人: Gregg A Dean
• 金额: $ 20.74万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932516
• 关键词: Address; Adjuvant; Adjuvanticity; Affect; Agonist; Animal Model; Anthrax disease; Antigens; Bacteria; Bacterial Genome; Brucella abortus; Cells; Chimeric Proteins; DNA Vaccines; Dendritic Cells; Dose; Engineering; Exposure to; Family; Feline Immunodeficiency Virus; Felis catus; Flagellin; Food; Food Preservation; Gagging; Gastrointestinal tract structure; Genes; Genus Cola; HIV; HIV-1; Helicobacter pylori; Human; Human Papillomavirus; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Infection; Intestines; Lactobacillus; Lymphoid Tissue; Measures; Mediating; Methods; Modeling; Molecular Genetics; Mucosal Immune Responses; Mucous Membrane; Names; Oral; Oral Administration; Oral cavity; Oral mucous membrane structure; Organism; Oropharyngeal; Plasmids; Preserved Foods; Probiotics; Process; Production; Protocols documentation; Recombinants; Research; Role; Rotavirus; SARS coronavirus; Serum; Site; Source; Surface; T-Lymphocyte; TLR5 gene; Testing; Tetanus Toxin; Time; Vaccines; Vagina; Virus; Virus Diseases; Virus Replication; bioprocess; cytokine; immunogenic; immunogenicity; in vivo; lactic acid bacteria; member; mucosa-associated lymphoid tissue; mucosal vaccine; oral vaccine; pathogen; reproductive; response; transmission process; vector; vector vaccine

DESCRIPTION (provided by applicant): Transmission of HIV-1 occurs predominately at mucosal surfaces and therefore a successful vaccine against HIV-1 must induce mucosal humoral and cellular immune responses. Lactic acid bacteria have been used for centuries to process and preserve food and are well known for their probiotic activities. Recently members of the lactic acid bacteria family have been explored as vaccine vectors. Lactobacillus gasseri is a common commensal of the human oral cavity and gastrointestinal tract and may be particularly useful as an oral mucosal vaccine vector against HIV-1. L. gasseri colonizes the oral cavity and serves as a source for colonization of the intestinal tract. In addition, L. gasseri activates dendritic cells and stimulates cytokine production that leads to Th1 polarization of T cells. In preliminary studies, recombinant L. gasseri expressing HIV-1 Gag induced serum IgG, mucosal IgA and cell mediated responses measured in the colon and reproductive tract after a single oral dose. Here we propose to better determine the dose, distribution and persistence of L. gasseri after oral immunization. We will then refine L. gasseri as an immunogen by co-expressing flagellin as a means to stimulate the innate immune system through TLR5 and determining whether L. gasseri can deliver a DNA vaccine for the eukaryotic expression of Env. The role of regulatory T cells in mucosal immunization will be assessed by depleting Treg concomitant with oral immunization. Finally, a robust challenge study will be performed to determine whether L. gasseri can induce protective immunity. These studies will be performed using the cat/FIV model of HIV-1 since cats have oropharyngeal mucosa associated lymphoid tissue similar to humans, can be economically studied using statistically relevant numbers, and can be vaginally challenged with pathogenic FIV using cell-associated and cell-free virus. Project Narrative: Transmission of HIV-1 occurs predominately at mucosal surfaces and therefore a successful vaccine against HIV-1 must induce mucosal humoral and cellular immune responses. Lactobacillus gasseri is a common probiotic bacterium found in the human oral cavity and gastrointestinal tract and as such may be a particularly effective vaccine vector against HIV-1. Studies proposed here will investigate strategies to engineer recombinant L. gasseri that can induce a protective immune response against HIV-1 via the oral mucosa.

描述（由申请人提供）：HIV-1的传播主要发生在粘膜表面，因此针对HIV-1的成功疫苗必须诱导粘膜体液和细胞免疫反应。乳酸细菌已经使用了几个世纪来处理和保存食物，并以其益生菌活性而闻名。最近，乳酸菌家族的成员被探索为疫苗载体。 Gasseri乳酸杆菌是人口腔和胃肠道的常见共生，并且可能作为针对HIV-1的口服粘膜疫苗载体特别有用。 L. gasseri定居于口腔，并作为肠道定植的来源。此外，Gasseri乳杆菌会激活树突状细胞并刺激导致T细胞Th1极化的细胞因子产生。在初步研究中，表达HIV-1 GAG的重组L. gasseri诱导血清IgG，粘膜IgA和单个口服剂量后在结肠和生殖道中测得的细胞介导的反应。在这里，我们建议更好地确定口服免疫后Gasseri的剂量，分布和持久性。然后，我们将通过共表达鞭毛蛋白作为一种手段来通过TLR5刺激先天免疫系统，并确定Gasseri是否可以为Env的真核表达提供DNA疫苗，从而将L. gasseri作为一种免疫原。调节性T细胞在粘膜免疫中的作用将通过耗尽Treg伴随口服免疫来评估。最后，将进行一项强大的挑战研究，以确定Gasseri是否可以诱导保护性免疫。这些研究将使用HIV-1的CAT/FIV模型进行，因为CAT具有与人类相似的咽粘膜相关的淋巴组织相关的淋巴组织，可以使用统计相关的数字进行经济研究，并且可以使用与细胞相关的和无细胞的病毒在致病性FIV中阴道挑战。项目叙述：HIV-1的传播主要发生在粘膜表面，因此针对HIV-1的成功疫苗必须诱导粘膜体液和细胞免疫反应。 Gasseri乳杆菌是在人口腔和胃肠道中发现的一种常见益生菌细菌，因此可能是针对HIV-1的特别有效的疫苗载体。此处提出的研究将研究为重组L. gasseri设计的策略，以通过口腔粘膜诱导针对HIV-1的保护性免疫反应。