Development of an Effector-Memory T Cell AIDS Vaccine

两项非人灵长类动物功效研究令人信服地证明CMV/SIV载体可以：1）再感染CMV+恒河猴（RM），2）在再感染期间，引发具有强“效应记忆”（T{EM}）偏好的有效且持续的SIV特异性CD 4+和CD 8 + T细胞应答，和3）在用高致病性SIVmac 239病毒进行有限剂量直肠攻击后，完全保护约50%的接种RM免于进行性SIV感染。这些RM中表现出的保护作用在其突然性和程度上与之前的疫苗不同，受保护的RM在初始感染后在血浆中表现出不同大小的病毒爆发，然后立即控制到无法检测的水平。保护作用与疫苗阶段产生的总SIV特异性CD 8 + T细胞的程度相关，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CD 8 + T{EM}-因此，CMV载体和“T”T{EM}”疫苗概念为艾滋病毒/艾滋病疫苗开发提供了一种强大的新方法，并有可能发展成为一种安全有效的艾滋病疫苗。在本计划中，我们力求：1）增加CMV/SIV载体的效力，以实现接近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，以实现足够安全用于一般人群的有效疫苗，和3）确定免疫相关性或保护以指导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2将使用新的策略来开发复制缺陷和向性修饰的CMV载体，这些载体将保留免疫原性，但减少了脱落和介导疾病的能力。项目3寻求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（发病模型）、核心D（病毒学和免疫学监测）和核心E（基因组学）协助。

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).