OPTIMIZE THE IMMUNOGENICITY OF MVA-BASED AIDS VACCINES

优化基于 MVA 的艾滋病疫苗的免疫原性

• 批准号: 8357426
• 负责人: DAVID A GARBER
• 金额: $ 7.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357426
• 关键词: AIDS Vaccines; Acute; Agonist; Anatomic Sites; Anatomy; Antibodies; Antibody Formation; Appearance; CD4 Positive T Lymphocytes; CD8B1 gene; Consensus; Engineering; Escape Mutant; Funding; Genes; Goals; Grant; HIV; HIV Antigens; HIV vaccine; Immune; Immunization; Infection; Lymphoid; Macaca; Macaca mulatta; Mucous Membrane; National Center for Research Resources; Peripheral Blood Mononuclear Cell; Phase; Population; Poxviridae; Primates; Principal Investigator; Regimen; Research; Research Infrastructure; Resources; SIV; Source; T cell response; Tissues; United States National Institutes of Health; Vaccine Adjuvant; Vaccines; Variant; Viral Vector; Virus; Virus Replication; base; cost; env Gene Products; gag Gene Products; immunogenicity; lymph nodes; pressure; rectal

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of this project is to identify strategies by which the immunogenicity of AIDS vaccines derived from MVA-based viral vectors can be significantly augmented. We previously developed and characterized an MVA-based HIV vaccine (from which four endogenous poxvirus immune-evasion genes have been deleted) that expresses consensus HIV subtype C Gag and Env antigens (MVA4-HIV). In MHC-disparate populations of rhesus macaques, this genetically engineered vaccine was shown to elicit significantly higher levels of HIV-specific CD8 and CD4 T cell responses and up to 25-fold higher titers of HIV envelope-specific antibodies, as compared to the unmodified parental control vaccine. Recently, we completed a study, in rhesus macaques, which demonstrated that the HIV-specific antibody responses elicited by the MVA4-HIV vaccine may be further augmented through an immunization regimen that includes co-administration of a TLR-9 agonist, but not a TLR-7/8 agonist, as a vaccine adjuvant. In another study of macaques immunized with MVA-based vaccines expressing SIV, rather than HIV, antigens, we took a deep pyrosequencing approach to characterize the appearance, dynamics and anatomic dissemination of CTL escape mutant viruses in lymphoid versus mucosal tissues following SIVmac239 infection. Our results indicate that lymph nodes, rather than peripheral blood mononuclear cells or rectal mucosa, represent the primary source of CTL escape mutants during the acute phase of SIV infection, suggesting that lymph nodes are the main anatomic sites of virus replication and/or the tissues in which CTL pressure is most effective in selecting SIV escape variants.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该项目的总体目标是确定可显着增强基于 MVA 的病毒载体的艾滋病疫苗的免疫原性的策略。 我们之前开发并表征了一种基于 MVA 的 HIV 疫苗（其中删除了四个内源性痘病毒免疫逃避基因），该疫苗表达共有的 HIV C 亚型 Gag 和 Env 抗原（MVA 4-HIV）。 在不同 MHC 的恒河猴群体中，与未经修饰的亲本对照疫苗相比，这种基因工程疫苗可引发显着更高水平的 HIV 特异性 CD8 和 CD4 T 细胞反应，以及高达 25 倍的 HIV 包膜特异性抗体滴度。 最近，我们在恒河猴中完成了一项研究，该研究表明，MVA 4-HIV 疫苗引发的 HIV 特异性抗体反应可以通过免疫方案进一步增强，该方案包括共同施用 TLR-9 激动剂（而非 TLR-7/8 激动剂）作为疫苗佐剂。 在另一项针对用表达 SIV（而非 HIV）抗原的 MVA 疫苗免疫的猕猴的研究中，我们采用深度焦磷酸测序方法来表征 SIVmac239 感染后淋巴组织与粘膜组织中 CTL 逃逸突变病毒的外观、动态和解剖学传播。 我们的结果表明，淋巴结，而不是外周血单核细胞或直肠粘膜，代表了SIV感染急性期CTL逃逸突变体的主要来源，这表明淋巴结是病毒复制的主要解剖部位和/或CTL压力在选择SIV逃逸变异体中最有效的组织。