Development and In Vivo Characterization of Safety-Enhanced RhCMV/SIV Vectors

安全性增强的 RhCMV/SIV 载体的开发和体内表征

• 批准号: 8416334
• 负责人: Louis J. Picker
• 金额: $ 75.91万
• 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: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416334
• 关键词: AIDS/HIV problem; Adolescent; Alleles; Antibody Formation; Area; Attenuated; Autopsy; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Characteristics; Clinical; Coculture Techniques; Cytomegalovirus; Data; Detection; Development; Disease; Dose-Limiting; Epidemic; Exhibits; Frequencies; Genetic Engineering; Goals; Growth; HIV; HIV Infections; Human; Immune; Immune response; In Vitro; Individual; Infection; Link; Lymphocyte Depletion; Macaca mulatta; Mediating; Memory; Modeling; Murid herpesvirus 1; Nested PCR; Nucleic Acids; Pathogenicity; Pattern; Phase; Plasma; Population; Pregnant Women; Prevalence; Resistance; SIV; SIV Vaccines; Safety; Site; Southern Africa; T cell response; T memory cell; T-Cell Depletion; T-Lymphocyte; Testing; Time; Tissues; Translations; Vaccinated; Vaccines; Viral; Viremia; Virus; Work; base; combat; design; design and construction; efficacy trial; fetal; immunogenic; immunogenicity; in vivo; nonhuman primate; novel; novel strategies; novel vaccines; prophylactic; public health relevance; rectal; response; vaccine development; vector

DESCRIPTION (provided by applicant): We have demonstrated that CMV/SIV vectors can 1) re-infect 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" (TEM) bias, and 3) completely protect ~50% of vaccinated RM from progressive 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. Although occasional viral blips in plasma are observed in protected RM, these decline with time, and after 1 year, protection is unaffected by CD8+ or CD4+ cell depletion, and extensive tissue analysis with ultrasensitive nested PCR has shown only rare detection of ~ single copy SIV nucleic acid and no viable SIV. Protection correlates with the total SIV-specific CD8+ TEM generated during the vaccine phase, and occurs without an anamnestic response. 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+ TEM. Thus, CMV vectors and the "TEM" vaccine concept offer a powerful new approach to HIV/AIDS vaccine development. However, fully replicative CMV vectors are unlikely to be advanced to human use due to the pathogenic potential of CMV. A central goal is therefore to develop CMV vectors that maintain immunogenicity and efficacy, but are safe to use in humans. Fortunately, preliminary data indicates that replication/spread-deficient CMVs can be robustly immunogenic. Here, we will explore the extent to which replication/spread-deficient CMV vectors can be attenuated with respect to pathogenicity and transmissibility, while retaining immunogenicity and efficacy. Three specific aims are proposed: 1) to design, construct and in vitro characterize replication/spread-deficient CMV/SIV vectors, 2) to determine the pathogenicity of replication/spread-deficient CMV/SIV vectors in fetal RM, and 3) to determine the immunogenicity and shedding of replication/spread-deficient CMV/SIV vectors in juvenile RM, and to take the optimal replication/spread deficient vector design to an efficacy trial to determine its ability to protect against limiting dose rectal SIVmac239 challenge.

描述（由申请人提供）：我们已经证明，CMV/SIV媒介可以1）重新感染CMV+恒河猕猴（RM），2）在重新感染，引起有效的SIV特异性CD4+和CD8+ T细胞响应，并具有强烈​​的“效应器记忆”（TEM）偏见（3）完全保护〜50％的limitive 〜50％挑战高度致病的SIVMAC239病毒。这些RM中表现出的保护在其突然性和程度上与以前的疫苗不同，受保护的RM在初始感染后的血浆中表现出病毒爆发，然后立即控制到无法检测到的水平。尽管在受保护的RM中观察到血浆中偶尔的病毒叶片，但随时间下降，1年后，保护不受CD8+或CD4+细胞耗竭的影响，并且具有超敏感PCR的广泛组织分析仅显示出〜单拷贝SIV siv核酸的罕见检测，没有可行的SIV。保护与在疫苗相生成的总SIV特异性CD8+ Tem相关，并且没有吞咽反应。这些数据表明，一种与非常早期控制一致的新型保护模式，可能发生在病毒入口和/或早期的病毒复制和扩增位置，并涉及组织居民CD8+ TEM。因此，CMV载体和“ TEM”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。然而，由于CMV的致病潜力，完全复制的CMV载体不太可能将其用于人类使用。因此，一个核心目标是开发维持免疫原性和疗效但在人类中安全使用的CMV载体。幸运的是，初步数据表明复制/扩散缺陷的CMV可以具有牢固的免疫原性。在这里，我们将探索在致病性和可传播性方面可以减弱复制/扩散缺陷的CMV载体的程度，同时保持免疫原性和功效。 Three specific aims are proposed: 1) to design, construct and in vitro characterize replication/spread-deficient CMV/SIV vectors, 2) to determine the pathogenicity of replication/spread-deficient CMV/SIV vectors in fetal RM, and 3) to determine the immunogenicity and shedding of replication/spread-deficient CMV/SIV vectors in juvenile RM, and to take the最佳复制/扩散矢量设计到有效试验中，以确定其防止限制剂量直肠SIVMAC239挑战的能力。