Development of an Effector-Memory T Cell AIDS Vaccine

效应记忆 T 细胞艾滋病疫苗的开发

• 批准号: 8681307
• 负责人: Louis J. Picker
• 金额: $ 337.74万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681307
• 关键词: AIDS Vaccines; AIDS/HIV problem; Adolescent; Adult; Advisory Committees; Animal Model; Animal Welfare; Area; Autopsy; Bioinformatics; Biological Assay; Blood; CD8B1 gene; California; Cells; Characteristics; Clinical; Clinical Research; Coculture Techniques; Communication; Complex; Cytomegalovirus; Data; Decision Making; Detection; Development; Diagnostic; Disease; Dose-Limiting; Down-Regulation; Ensure; Epidemic; Epitopes; Exhibits; Flow Cytometry; Gene Expression Profile; Genetic Engineering; Genomics; Goals; Growth; HIV; HIV Infections; Human; Immune; Immune response; Immunologics; Immunology; Immunology procedure; Immunosuppression; In Vitro; Infection; Leadership; Macaca mulatta; Mediating; Memory; Microarray Analysis; Modeling; Modification; Molecular; Monitor; National Cancer Institute; Pathogenesis; Pathogenicity; Pattern; Peptide antibodies; Peptides; Performance; Phase; Plasma; Population; Prevalence; Primates; Process; Production; Protocols documentation; Quality Control; Reagent; Regimen; Relative (related person); Reporting; Research; Research Personnel; SIV; Safety; Saliva; Services; Site; Southern Africa; Specimen; Specimen Handling; Standardization; Stem cell transplant; Strategic Planning; T cell response; T memory cell; T-Lymphocyte; Techniques; Tissues; Translations; Tropism; United States National Institutes of Health; Urine; Vaccinated; Vaccines; Viral; Virus; Work; administrative database; animal care; attenuation; base; combat; combinatorial; comparative efficacy; cytokine; design; experience; fetal; immunogenicity; in vivo; innovation; insight; nonhuman primate; novel; novel strategies; novel vaccines; pathogen; pre-clinical; prevent; programs; prophylactic; rectal; response; transmission process; vaccine development; vector; virology

Two nonhuman primate efficacy studies have convincingly demonstrated that CMV/SIV vectors can: 1) reinfect CMV+ rhesus macaques (RM), 2) during re-infection, elicit potent and persistent SIV-specific CD4+ and CD8+ T cell responses with a strong "effector memory" (T{EM}) bias, and 3) completely protect ~50% of vaccinated RM from progressive SIV infection after limiting dose rectal challenge with the highly pathogenic SIVmac239 virus. The protection manifested in these RM is distinct from previous vaccines in its abruptness and extent, with protected RM exhibiting a viral burst in plasma of varying size upon initial infection, followed by immediate control to undetectable levels. Protection correlates with the extent of total SIV-specific CD8+ T cells generated during the vaccine phase, and is stable in the vast majority of protected RM for >12 months. These data indicate a novel pattern of protection consistent with very early control, likely taking place at the site of viral entry and/or early sites of viral replication and amplification, and involving tissue-resident CD8+ T{EM}- Thus, CMV vectors and the "T{EM}" vaccine concept offer a powerful new approach to HIV/AIDS vaccine development, and have the potential to be developed into a safe and effective HIV/AIDS vaccine. In this Program, we seek to: 1) increase the potency of CMV/SIV vectors so as to achieve rates of protection closer to 100% of vaccines, 2) reduce the pathogenic and shedding potential of CMV vectors, while retaining immunogenicity, so as to achieve an effective vaccine that is safe enough for use in a general human population, and 3) determine immunologic correlates or protection to guide further development of the T{EM}" vaccine concept. The program is composed of 3 projects, and 5 cores. Projects 1 and 2 will use novel strategies to develop replication-deficient and tropism-modified CMV vectors that will retain immunogenicity, but have reduced shedding and capacity to mediate disease. Project 3 seeks to enhance CMV/SIV vector immunogenicity with both combinatorial vaccine approaches and CMV vector modification, and will determine immunologic correlates ofthe novel "all or none" protection associated with these vectors. These projects will be assisted by Core A (Administration), Core B (Nonhuman Primate), Core C (Pathogenesis Models), Core D (Virology and Immunology Monitoring), and Core E (Genomics).

两项非人灵长类动物功效研究令人信服地表明，CMV/SIV载体可以：1)再次感染CMV+恒河猴（RM）， 2)在再次感染期间，引发有效和持续的SIV特异性CD4+和CD8+ T细胞反应，具有很强的“效应记忆”（T{EM}） bias，以及3)在高致病性SIVmac239病毒的有限剂量直肠攻击后，完全保护约50%的接种过疫苗的恒河猴免受SIV进进性感染。在这些RM中表现出的保护在其突发性和程度上与以前的疫苗不同，受保护的RM在初始感染时表现出不同大小的血浆病毒爆发，随后立即控制到无法检测到的水平。保护作用与疫苗期产生的siv特异性CD8+ T细胞总量相关，并且在绝大多数受保护的RM中稳定存在100 - 12个月。这些数据表明了一种与早期控制一致的新保护模式，可能发生在病毒进入位点和/或病毒复制和扩增的早期位点，并涉及组织驻留CD8+ T{EM}-因此，巨细胞病毒载体和“T{EM}”疫苗概念为艾滋病毒/艾滋病疫苗开发提供了一种强有力的新方法，并有可能开发成安全有效的艾滋病毒/艾滋病疫苗。在这个项目中，我们寻求：1)提高CMV/SIV载体的效力，使其保护率接近疫苗的100%；2)在保持免疫原性的同时，降低CMV载体的致病性和脱落潜力，从而获得一种足够安全的疫苗，可用于一般人群；3)确定免疫相关因素或保护作用，以指导T{EM}”疫苗概念的进一步发展。该计划由3个项目和5个核心组成。项目1和项目2将使用新的策略来开发复制缺陷和嗜性修饰的巨细胞病毒载体，这些载体将保留免疫原性，但减少脱落和介导疾病的能力。项目3旨在通过组合疫苗方法和CMV载体修饰来增强CMV/SIV载体的免疫原性，并将确定与这些载体相关的新型“全或无”保护的免疫学相关性。这些项目将由核心A（管理），核心B（非人灵长类动物），核心C（发病机制模型），核心D（病毒学和免疫学监测）和核心E（基因组学）协助。