MUCOSALLY DELIVERED DNA/MVA VACCINES IN A SHIV MODEL

在 SHIV 模型中粘膜递送 DNA/MVA 疫苗

• 批准号: 6374311
• 负责人: Thomas C. VanCott
• 金额: $ 34万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374311
• 关键词: AIDS vaccines; Macaca mulatta; active immunization; cytokine; cytotoxic T lymphocyte; helper T lymphocyte; immunoglobulin A; immunomodulators; laboratory mouse; mucosal immunity; simian immunodeficiency virus; vaccine development; vector vaccine

Recent reports have identified the presence of HIV-1 gp160 specific IgA, but not IgG, responses in the female genital tract of highly exposed commercial sex workers as well as HIV-1 discordant couples. Similarly, a subset of rhesus macaques vaginally exposed to pathogenic SHIV-89.6PD, but who have remained SHIV PBMC virus co-culture negative with no clinical disease progression nor loss of CD4 T cells, developed a potent IgA response localized to the genital tract. Binding specificities of the vaginal IgA were unique and included a neutralizing epitope in gp41 as well as epitopes exposed uniquely on the gp120-CD4 complex. Furthermore, the macaque CVL IgA responses were capable of neutralizing SHIV-89.6PD infection of cultures of dendritic cells and T cells in vivo. Prime-boost immunization regimens using combinations of DNA and MVA vaccines have recently been demonstrated to be particularly potent at inducing both cellular and humoral immunity. We propose to mucosally administer DNA and MVA encoding HIV-1 env antigens and SIV gag/pol antigens in a prime-boost immunization regimen alone or in combination with boosting by a soluble oligomeric gp140 protein. The basic hypothesis of this proposal is that the induction of potent HIV envelope-specific vaginal IgA, together in combination with circulating as well as local lymph node T helper and CTL responses, will provide protection against vaginal pathogenic SHIV-89.6PD challenge. The aims of this proposal are: (i) optimize adjuvant formulations of DNA vaccines encoding HIV-1 envelope and SIV gag/pol antigens for mucosal delivery; (ii) evaluate systemic and mucosal ummunogenicity of mucosally administered combinations of DNA, MVA and ogp140 in rhesus macaques and protection from vaginal challenge with pathogenic SHIV-89.6PD; (iii) determine whether co-administration of DNA encoding chemokine or cytokine molecular adjuvants enhances immunogenicity and degree of protection from vaginal pathogenic SHIV challenge; and (iv) correlate vaccine-induced immune responses with in-vivo protection from vaginal SHIV challenge and determine for the non-protected monkeys whether pre-existing immunity augments or modulates subsequent post challenge SHIV immunity. The ability of vaccination to influence vaginal transmission of pathogenic SHIV-89.6PD will be evaluated and correlated with mucosal and system immunogenicity parameters. By relating these results to challenge studies, insight may be gained into correlates of protection at mucosal surfaces.

最近的报道已经确定了HIV-1 GP160特异性IgA的存在，但不是IgG，在女性生殖器中的反应是高度暴露的商业性工作者以及HIV-1不一致的夫妇的存在。 同样，恒河猕猴的一部分阴道暴露于致病性SHIV-89.6PD上，但仍保持SHIV PBMC病毒共培养共培养为阴性，没有临床疾病进展或CD4 T细胞的损失，并产生了一种有效的IgA反应，该反应局部局部生殖器。 阴道IgA的结合特异性是独一无二的，包括GP41中中和表位，以及在GP120-CD4复合物上唯一暴露的表位。 此外，猕猴CVL IgA反应能够中和体内树突状细胞和T细胞培养物的SHIV-89.6PD感染。 最近证明，使用DNA和MVA疫苗的组合使用促进型免疫治疗方案在诱导细胞和体液免疫方面特别有效。 我们建议单独使用原始促进免疫治疗方案中的HIV-1 ENV抗原和SIV GAG/POL抗原的DNA和MVA单独使用DNA和MVA。 该提议的基本假设是，有效的HIV包膜特异性阴道IGA的诱导以及循环以及局部淋巴结T辅助器和CTL反应的结合，将提供防止阴道致病性SHIV-89.6pd挑战的保护。 该提案的目的是：（i）优化编码HIV-1包膜和SIV GAG/POL抗原的DNA疫苗的辅助制剂，以递送粘膜； （ii）评估恒河猕猴中DNA，MVA和OGP140的粘膜组合的全身性和粘膜umumunogenity，并通过致病性Shiv-89.6pd的阴道挑战进行保护； （iii）确定编码趋化因子或细胞因子分子佐剂的DNA是否会增强免疫原性和保护程度，以免受阴道致病性SHIV挑战的影响； （iv）将疫苗诱导的免疫反应与阴道SHIV挑战的维护保护相关联，并确定非保护的猴子是否会增加免疫力增加或调节随后的后后挑战SHIV免疫。 疫苗接种影响致病性SHIV-89.6PD阴道传播的能力将与粘膜和系统免疫原性参数进行评估并相关。 通过将这些结果与挑战研究联系起来，可以将洞察力纳入粘膜表面的保护相关性。