Optimizing Immunogenicity of Lactobacillus as a Mucosal Vaccine Against HIV-1

优化乳酸菌作为 HIV-1 粘膜疫苗的免疫原性

基本信息

批准号：
7494877
负责人：
Gregg A Dean
金额：
$ 22.28万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-15 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7494877
关键词：
Address Adjuvant Adjuvanticity Affect Agonist Anthrax disease Antibody Formation Antigens Bacteria Bacterial Genome Brucella Cell surface Cells Cytoplasm Cytosol DNA Vaccines Dendritic Cells Development Engineering Flagellin Food Food Preservation Gagging Gastrointestinal tract structure Genes HIV HIV vaccine HIV-1 Helicobacter pylori Human Human Papillomavirus Immune Immune response Immunization Indigenous Intestines Investigation Kinetics Lactobacillus Location Luciferases Measures Mediating Methods Molecular Genetics Mucosal Immune Responses Mucous Membrane Mus Organism Preserved Foods Prevention Probiotics Process Production Public Health Purpose Recombinant Proteins Recombinants Research Rotavirus SARS coronavirus Site Surface T-Lymphocyte TLR5 gene Tetanus Toxin Vaccines Virus Replication bioprocess cytokine functional genomics gastrointestinal immunogenic immunogenicity in vivo lactic acid bacteria mucosa-associated lymphoid tissue mucosal vaccine novel oral vaccine pathogen protein expression response transmission process vector vector vaccine

项目摘要

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. Lactobacillus is a very common commensal of the human gastrointestinal tract and is used commercially to process and preserve food, thus it is safe and unlikely to stimulate anti-vector immune responses. Futhermore, Lactobacillus is easy to manufacture, store and is highly manipulatable as the functional genomics are well understood. The well-known probiotic activities are due at least in part to the interaction of Lactobacillus with dendritic cells. Lactobacillus activates DC and stimulates cytokine production that leads to Th1 polarization of T cells. We have performed preliminary immunogenicity studies and demonstrated proof-of-principle for the use of Lactobacillus as a vaccine vector against HIV-1 but the vector must be further optimized to increase immunogenicity. In the studies proposed here, we will investigate the host/vector interaction to determine the kinetics and location of gastrointestinal colonization by recombinant Lactobacillus and whether recombinant protein expression affects the indigenous flora. The optimal subcellular location for HIV-1 antigen expression will be determined and a comprehensive assessment of mucosal and systemic humoral and cellular immune responses will be performed in mice. To further increase immunogenicity, flagellin will be expressed by the Lactobacillus as a method to increase innate immune activation in the gastrointestinal tract via TLR5 stimulation. Together these studies will determine whether Lactobacillus is worth further development as an oral vaccine vector against HIV-1. PUBLIC HEALTH RELEVANCE: The purpose of these studies is to develop a novel HIV vaccine strategy using Lactobacillus. A vaccine using lactobacilli would be safe, inexpensive to manufacture, and could be delivered orally. If successful, this strategy could have a significant impact on HIV prevention.

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。乳杆菌是人类胃肠道的非常普遍的共生，并在商业上用于加工和保存食物，因此它是安全的，不可能刺激抗媒介免疫反应。 FUTHERMORE，乳酸杆菌易于制造，存储，并且可以很好地操纵，因为功能性基因组学众所周知。众所周知的益生菌活性至少部分是由于乳杆菌与树突状细胞的相互作用。乳杆菌激活直流并刺激细胞因子的产生，从而导致T细胞的Th1极化。我们已经进行了初步的免疫原性研究，并证明了将乳酸杆菌用作HIV-1的疫苗载体的原则证明，但必须进一步优化载体以提高免疫原性。在此处提出的研究中，我们将研究宿主/载体的相互作用，以确定重组乳酸乳杆菌的胃肠道定植的动力学和位置，以及重组蛋白表达是否影响本地菌群。将确定用于HIV-1抗原表达的最佳亚细胞位置，并将在小鼠中对粘膜和全身性体液和细胞免疫反应进行全面评估。为了进一步提高免疫原性，乳杆菌将通过TLR5刺激来增加胃肠道的先天免疫激活的方法。这些研究共同确定乳酸杆菌是否值得作为针对HIV-1的口服疫苗载体进一步发展。公共卫生相关性：这些研究的目的是使用乳杆菌制定一种新型的HIV疫苗策略。使用乳杆菌的疫苗是安全的，制造便宜的，并且可以口服。如果成功，该策略可能会对预防HIV产生重大影响。