Development of an Effector-Memory T Cell AIDS Vaccine

两项非人类灵长类动物的有效性研究已经证明，CMV/SIV载体可以：1)再感染CMV+猕猴(RM)；2)在再感染过程中，以强烈的“效应记忆”(T{EM})偏向，激发强大而持久的SIV特异性CD4+和CD8+T细胞应答；3)在限制剂量直肠攻击高致病性SIVmac239病毒后，完全保护接种的RM免受SIV感染。这些RM表现出的保护作用在突发性和程度上与以前的疫苗不同，受保护的RM在最初感染时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到的水平。保护性与疫苗阶段产生的全部SIV特异性CD8+T细胞的程度相关，并且在绝大多数受保护的RM中12个月内是稳定的。这些数据表明，一种新的保护模式与非常早期的控制一致，可能发生在病毒进入和/或病毒复制和扩增的早期位置，并涉及组织驻留的CD8+T{EM}-因此，CMV载体和“T{EM}”疫苗概念为HIV/AIDS疫苗的开发提供了一种强有力的新途径，并有可能开发成安全有效的HIV/AIDS疫苗。在本计划中，我们寻求：1)提高CMV/SIV载体的效力，以达到接近100%的疫苗保护率；2)在保持免疫原性的同时，降低CMV载体的致病和脱落潜力，以获得足够安全的有效疫苗；3)确定免疫学相关性或保护性，以指导T{EM}“疫苗概念的进一步发展。该方案由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趋向性修饰的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的“全有或全无”保护的免疫学相关性。这些项目将得到核心A(管理)、核心B(非人灵长类)、核心C(致病模型)、核心D(病毒学和免疫监测)和核心E(基因组学)的协助。

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).