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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 该项目的总体目标是确定能够显著增强基于MVA的病毒载体的艾滋病疫苗的免疫原性的策略。我们之前开发并鉴定了一种基于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)，该疫苗表达一致的HIV C亚型Gag和环境抗原(MVA4-HIV)。在MHC不同的猕猴种群中，这种基因工程疫苗被证明与未经修改的父母对照疫苗相比，诱导了显著更高的HIV特异性CD8和CD4T细胞反应水平，以及高达25倍的HIV包膜特异性抗体效价。最近，我们在恒河猴身上完成了一项研究，该研究表明，MVA4-HIV疫苗引起的HIV特异性抗体反应可以通过一种免疫方案进一步增强，该免疫方案包括联合给予TLR-9激动剂，而不是TLR-7/8激动剂作为疫苗佐剂。 在另一项对表达SIV而不是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的方法来表征SIVmac239感染后CTL逃逸突变病毒在淋巴组织和粘膜组织中的外观、动态和解剖扩散。我们的结果表明，在SIV感染急性期，CTL逃逸突变体的主要来源是淋巴结，而不是外周血单个核细胞或直肠粘膜，这表明淋巴是病毒复制的主要解剖部位和/或CTL压力在选择SIV逃逸突变体时最有效的组织。