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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目的总体目标是确定策略，通过该策略，可以显着增强来自MVA病毒载体的艾滋病疫苗的免疫原性。 我们先前开发并表征了基于MVA的HIV疫苗（其中四个内源性痘病毒免疫逃避基因已被删除），其表达共有HIV亚型C Gag和Env抗原（MVA4-HIV）。 在MHC不同的恒河猴群体中，与未修饰的亲本对照疫苗相比，这种基因工程疫苗显示出显著更高水平的HIV特异性CD 8和CD 4 T细胞应答以及高达25倍的HIV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引起的HIV特异性抗体应答4-HIV疫苗可以通过包括共施用TLR-9激动剂而不是TLR-7/8激动剂作为疫苗佐剂的免疫方案来进一步增强。 在用表达SIV而不是HIV抗原的基于MVA的疫苗免疫的猕猴的另一项研究中，我们采用深度焦磷酸测序方法来表征SIVmac 239感染后淋巴组织与粘膜组织中CTL逃逸突变病毒的外观、动力学和解剖学传播。 我们的研究结果表明，淋巴结，而不是外周血单核细胞或直肠粘膜，代表CTL逃逸突变体的主要来源，在急性期的SIV感染，这表明淋巴结的主要解剖部位的病毒复制和/或组织中的CTL压力是最有效的选择SIV逃逸变种。