MUCOSAL IMMUNE RESPONSE TO LIVE ATTENUATED SIV VACCINE

对 SIV 减毒活疫苗的粘膜免疫反应

• 批准号: 6336244
• 负责人: MARIAN R NEUTRA
• 金额: $ 44.86万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336244
• 关键词: AIDS vaccines; Macaca mulatta; active immunization; attenuated microorganism; biopsy; cytotoxic T lymphocyte; drug administration routes; genome; human immunodeficiency virus 1; immunocytochemistry; immunoglobulin A; immunoglobulin G; immunoglobulin M; immunomodulators; live vaccine; monoclonal antibody; mucosa; mucosal immunity; vaccine development; virulence; virus genetics

Mucosal immune effector mechanisms-secretory antibodies and mucosal cellular responses-could enhanced immune protection against HIV by intercepting virus at mucosal surfaces and reducing this effective "challenge dose" at mucosal portals of entry. The purpose of this project is to develop immunization protocols using a live, highly-attenuated SIV vaccine candidate, that could enhance local mucosal immune responses and shorten the time required for development of immune protection against mucosal challenge. Aim 1 is to define effective mucosal immunization protocols. First, SIVmac239delta4 will be inoculated via rectum or vagina with or without a mucosal adjuvant; local immune responses will be compared to those in systemically-inoculated monkeys. Then, systemic prime/mucosal boost strategies will be tested, including live SIVmac239delta4 given IV, followed by live or inactivated SIVmac239delta4 or oligomeric envelope protein (with adjuvant) administered nasally, rectally and/or vaginally. Anti-SIV IgA, IgM and IgG antibodies in serum and secretions, and anti-SIV T cells in blood will be monitored over time. Aim II is to compare levels of SIVmac239delta4 in the mucosal after mucosal versus systemic inoculation of SIVmac239delta4, and to evaluate possible effects of attenuated SIV infection on mucosal immune function. Viral genome and antigens will be localized in rectal biopsies and correlated with the immune responses observed in Aim I. Antigen-presenting cells, IgA, IgM and IgG producing cells and T cell subsets in mucosal lymphoid follicles and lamina propria will be quantitated, and mucosal responses to test antigens evaluated. Aim III is to test the capacity of SIVmac239delta4 to protect against mucosal challenge with virulent SIV. Monkeys immunized using the optimal SIVmac239delta4 prime/boost protocol identified in Aim I will be challenged at 2 time points (in parallel with systemically-inoculated monkeys in Project III) to compare the time required for development of immune protection against mucosal challenge with that seen after systemic inoculation alone. These studies will guide future investigations of the utility of live, attenuated SIV/HIV vaccines for mucosal immune protection.

粘膜免疫效应机制 - 分泌抗体和粘膜 细胞反应 - 基于通过 在粘膜表面拦截病毒并降低这种有效的 粘膜入境门户的“挑战剂量”。这个项目的目的 是使用实时，高度衰减的SIV制定免疫协议 疫苗候选者，可以增强局部粘膜免疫反应和 缩短开发免疫保护所需的时间 粘膜挑战。 目的1是定义有效的粘膜免疫方案。第一的， SIVMAC239DELTA4将通过直肠或阴道接种，有或没有 粘膜佐剂；将局部免疫反应与 全身接种的猴子。然后，全身质量/粘膜提升 将测试策略，包括IVE的实时SIVMAC239DELTA4 IV， 其次是活或灭活的SIVMAC239DELTA4或低聚信封 蛋白质（佐剂）通过直肠和/或阴道施用。 血清和分泌中的抗SIV IgA，IgM和IgG抗体以及抗SIV 随着时间的流逝，血液中的T细胞将受到监测。 AIM II是比较水平 粘膜与全身性后的粘膜中的sivmac239delta4 接种SIVMAC239DELTA4，并评估 粘膜免疫功能的SIV感染减弱。病毒基因组和 抗原将定位在直肠活检中，并与 在AIM I中观察到的免疫反应。抗原呈递细胞IgA，IgM和 粘膜淋巴卵泡中的IgG产生细胞和T细胞亚群，并 将定量固有薄片，并对测试抗原的粘膜反应 评估。 AIM III是测试SIVMAC239DELTA4保护的能力 反对有毒SIV的粘膜挑战。猴子使用 AIM中确定的最佳SIVMAC239DELTA4 PRIME/BOOST协议我将是 在2个时间点挑战（与全身接种 项目III中的猴子）比较开发的时间 免疫保护侵害粘膜挑战，全身性挑战 仅接种。这些研究将指导未来的调查 实用，粘膜免疫的SIV/HIV疫苗的效用 保护。