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: 8495905
• 负责人: Louis J. Picker
• 金额: $ 338.36万
• 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/8495905
• 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).

两项非人灵长类功效研究令人信服地证明，CMV/SIV 载体可以：1) 重新感染 CMV+ 恒河猴 (RM)，2) 在重新感染过程中，引发有效且持久的 SIV 特异性 CD4+ 和 CD8+ T 细胞反应，具有强大的“效应器”记忆”(T{EM}) 偏差，以及 3) 在使用有限剂量直肠攻击后，完全保护约 50% 的接种 RM 免受进行性 SIV 感染高致病性 SIVmac239 病毒。这些 RM 所表现出的保护作用在突然性和程度方面与以前的疫苗不同，受保护的 RM 在初次感染时在血浆中表现出不同大小的病毒爆发，随后立即控制到不可检测的水平。保护作用与疫苗阶段产生的 SIV 特异性 CD8+ T 细胞总数相关，并且在绝大多数受保护的 RM 中稳定>12 个月。这些数据表明一种与非常早期控制一致的新型保护模式，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，并涉及组织驻留的 CD8+ T{EM}- 因此，CMV 载体和“T{EM}”疫苗概念为艾滋病毒/艾滋病疫苗的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。在该计划中，我们力求：1) 提高 CMV/SIV 载体的效力，以达到接近 100% 疫苗的保护率，2) 降低 CMV 载体的致病性和脱落潜力，同时保留免疫原性，从而获得足够安全、适合一般人群使用的有效疫苗，以及 3) 确定免疫相关性或保护作用，以指导 T{EM}" 疫苗概念的进一步开发。该计划由 3 个项目组成，以及项目 1 和 2 将使用新策略来开发复制缺陷型和趋向性修饰的 CMV 载体，该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 旨在通过组合增强 CMV/SIV 载体的免疫原性。疫苗方法和 CMV 载体修饰，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）协助。核心 B（非人类灵长类动物）、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）。