Mucosal Immunization with a Conserved HIV Envelope Peptide Cocktail Vaccine

使用保守的 HIV 包膜肽混合物疫苗进行粘膜免疫

• 批准号: 7244130
• 负责人: Jagannadha K Sastry
• 金额: $ 29.44万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244130
• 关键词: Acids; Acquired Immunodeficiency Syndrome; Adjuvant; Adjuvanticity; Antigen-Presenting Cells; Antigens; Applications Grants; Autologous Dendritic Cells; Bicarbonates; Cellular Immunity; Cholera Toxin; Chronic; Codon Nucleotides; Collaborations; Development Plans; Enteral; Epidemic; Epitopes; Freund' s Adjuvant; HIV; HIV Infections; HIV envelope protein; HIV vaccine; Human; Immune response; Immunity; Immunization; Infection; Intestines; Intravenous; Laboratories; Legal patent; Macaca mulatta; Mediating; Medicine; Mucosal Immunity; Mus; Oral; Outcome; Peptide Vaccines; Peptides; Route; Site; Stomach; Surface; Testing; Vaccination; Vaccines; Vaccinia virus; Vagina; Viral; capsule; college; comparative; design; immunogenicity; innovation; mouse model; mucosal vaccination; mucosal vaccine; mutant; novel; pre-clinical; prevent; prophylactic; response; simian human immunodeficiency virus; vaccine evaluation

DESCRIPTION (provided by applicant): A safe and effective HIV vaccine amicable for use in most parts of the world to prevent and/or treat HIV infection through strong mucosal and systemic immunity is an urgent need. This innovation grant proposal will test the potential of a highly conserved HIV envelope peptide cocktail we developed along with a novel cholera toxin mutant as adjuvant for mucosal vaccination, preferably by the oral route. Previous studies demonstrated that prophylactic vaccination with this peptide cocktail delivered by intravenous route using Freund's adjuvant and/or autologous dendritic cells protected rhesus macaques from chronic infection and AIDS by SHIVku2 and SHIV89.6P. A two-codon mutant of cholera toxin, CT2*, we developed (patent pending), was effective as adjuvant for intranasal immunization of mice with the HIV peptides for inducing HIV-specific mucosal and systemic cellular immune responses. We also observed that oral immunization of mice with a CTL-epitope peptide and CT2*, after neutralizing stomach acid with bicarbonate, resulted in induction of antigen-specific CTL responses. We hypothesize that the highly conserved HIV envelope peptide cocktail when combined with CT2* will be an efficient vaccine for mucosal immunization by intranasal as well as oral delivery. To test this hypothesis, we will first confirm whether the two-codon mutant of cholera toxin CT2* we developed will be superior to another well-established single-codon mutant E112K in terms of adjuvanticity. After this, we propose comparative analysis in the mouse model, for delivery of peptide cocktail along with CT2* by the intranasal and oral routes to generate antigen-specific cellular immune responses that will be assessed for protective efficacy against challenge with recombinant vaccinia virus encoding the HIV envelope protein. For oral immunization, we also propose to test a strategy involving encapsulation of the vaccine peptide cocktail in enteric-coated capsules that are designed to dissolve when encountered with acid in the digestive track and deliver the vaccine to intestinal antigen presenting cells (in collaboration with Dr. Michael Barry, Baylor college of Medicine). The optimal mucosal delivery strategy (intranasal or oral) selected from the mouse studies will be used for testing immunogenicity and protective efficacy of the peptide cocktail vaccine admixed with the CT2* adjuvant in rhesus macaques against intra-vaginal pathogenic SHIV challenge. Successful outcome in these studies should enable us to formulate pre-clinical development plan for mucosal vaccination with the peptide cocktail.

描述（由申请人提供）：一种安全有效的艾滋病毒疫苗友好的友好，可在世界大多数地区使用，以防止和/或通过强粘膜和全身免疫来预防和/或治疗艾滋病毒感染。这项创新赠款提案将测试我们开发的高度保守的HIV Invelope肽鸡尾酒的潜力，以及一种新型的霍乱毒素突变体作为粘膜疫苗接种的辅助剂，最好是通过口服途径。先前的研究表明，使用Freund的辅助和/或自体树突状细胞通过静脉途径传递的这种肽鸡尾酒预防性疫苗接种，保护恒河猕猴免受慢性感染和Shivku2和Shiv89.6p的辅助。 我们开发的霍乱毒素CT2*的两型突变体（申请专利）是有效的，可作为辅助物，用于用HIV肽对小鼠的鼻内免疫，用于诱导HIV特异性粘膜和全身性细胞免疫反应。我们还观察到，用碳酸氢盐中和胃酸后，用CTL - 运动肽和CT2*的小鼠进行口服免疫，从而导致抗原特异性CTL反应诱导。我们假设与CT2*结合使用时，高度保守的HIV包膜肽鸡尾酒将是一种有效的疫苗，可通过鼻内和口服递送进行粘膜免疫。为了检验这一假设，我们将首先确认我们开发的霍乱毒素CT2的两型突变体是否优于另一个公认的单型突变体E112K，就辅助性而言。此后，我们提出了小鼠模型中的比较分析，用于通过鼻内和口服途径将肽鸡尾酒以及CT2*提供，以产生抗原特异性的细胞免疫反应，该反应将评估，这些反应将评估，以确保针对挑战的保护功效，以抗挑战，以编码HIV Envelope蛋白质的重组效果。对于口服免疫，我们还建议测试一项涉及肠道涂层胶囊中疫苗肽鸡尾酒的策略，这些蛋白蛋白鸡尾酒旨在在消化轨道中与酸遇到的酸遇到并将疫苗交付给肠道抗原细胞（与医学贝勒学院迈克尔·巴里（Michael Barry of Medicic））。从小鼠研究中选择的最佳粘膜递送策略（鼻内或口服）将用于测试与CT2*佐剂在恒河-猕猴中粘合的肽鸡尾酒疫苗的免疫原性和保护性疗效。在这些研究中，成功​​的结果应使我们能够制定临床前开发计划，以使用肽鸡尾酒进行粘膜疫苗接种。