Mechanisms of mucosal protection by HPV-SIV and gp96-lg-SIV vaccines

HPV-SIV 和 gp96-lg-SIV 疫苗的粘膜保护机制

• 批准号: 8193660
• 负责人: ECKHARD R PODACK
• 金额: $ 200万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193660
• 关键词: Mechanisms; mucosal; protection; HPV; SIV

DESCRIPTION (provided by applicant): During the last several years we have developed two novel, unconventional vaccine strategies generating powerful mucosal immunity to SIV antigens. The two vaccine strategies are based on human papilloma virus delivering SIV-cDNAs, designated HPV-SIV, and on HEK293-cells secreting immunogenic chaperone-gp96- Ig-SIV-peptide-complexes, designated gp96-lg-SIV. The vaccines are administered by different routes and generate mucosal immune responses by different molecular and cellular mechanisms. Different molecular mechanisms imply activation of different transcriptional and signaling pathways and may generate different degrees of protection against vaginal SIV challenge. Correlating the pathways activated by the two vaccines with immune response to SIV challenge and protection from disease will provide the information how best to combine the two vaccine strategies, if necessary, for effective protection from SIV disease. Hypothesis 1: Mucosal immunity generated by HPV-SIV and gp96-lg SIV activate different molecular and cellular mechanisms which, in turn, differentially activate the various components of mucosal immunity through different transcriptional and signaling pathways. Differential immune responses in the mucosa will translate to different degrees of protection from vaginal challenge with SIV. Hypothesis 2: Combination of HPV-SIV and gp96-lg-SIV vaccination will synergize in generating mucosal immunity by combining the activation of different transcriptional and signaling pathways thereby generating comprehensive mucosal immunity with increased power to resist vaginal SIV challenge. These hypotheses will be tested in the following specific alms: 1. Vaccinate Rhesus macaques with HPV-SIV and with gp96-lg-SIV and determine the immune response, transcriptional profiles and signaling pathways in the vagina, draining lymph nodes and systemically. 2. Challenge naive and vaccinated macaques with SIV by the vaginal route and determine immune response to the virus and viral responses to immunity during the eclipse period prior to viremia. 3. Determine the effectiveness of the two vaccines singly and in combination in SIV protection SIV infection and correlate with mucus barrier function, immune responses, transcriptional and proteomic profiles. PUBLIC HEALTH RELEVANCE: This application will study two innovative SIV vaccines that are known to generate immune responses at mucosal sites including the female genital tract. Vaccine activity in the genital tract will be analyzed by genomic and proteomic analysis in addition to immunological assays and correlated with protection from vaginal SIV challenge. The combination of the two vaccines offers the potential of comprehensive immune activation in the mucosa providing enhanced resistance to SIV infection.

描述（由申请人提供）：在过去的几年中，我们开发了两种新颖的，非常规的疫苗策略，产生了对SIV抗原的强大粘膜免疫。这两种疫苗策略基于人类乳头状瘤病毒，该病毒提供了SIV-CDNA，指定为HPV-SIV，以及HEK293细胞，分泌免疫原性的GP96- Ig-Ig-SIV肽肽 - 指定为GP96-LG-SIV。疫苗通过不同的路线施用，并通过不同的分子和细胞机制产生粘膜免疫反应。不同的分子机制暗示着不同转录和信号通路的激活，并且可能会产生不同程度的针对阴道SIV挑战的保护程度。将两种疫苗激活的途径与对SIV挑战的免疫反应和疾病的免疫反应相关联，将提供如何最好地结合两种疫苗策略（如有必要），以有效保护SIV疾病。假设1：由HPV-SIV和GP96-LG SIV产生的粘膜免疫激活不同的分子和细胞机制，这反过来又通过不同的转录和信号传导途径差异地激活了粘膜免疫的各种成分。粘膜中的差异免疫反应将转化为与SIV阴道挑战不同程度的保护程度。假设2：HPV-SIV和GP96-LG-SIV疫苗接种的组合将通过结合不同转录和信号通路的激活来产生粘膜免疫，从而产生综合粘膜免疫，从而增加抗阴道SIV挑战的能力。这些假设将在以下特定施舍中进行测试：1。用HPV-SIV和GP96-LG-SIV疫苗接种猕猴，并确定阴道中的免疫反应，转录曲线和信号通路，并在系统上排出淋巴结和系统地排出淋巴结。 2。挑战通过阴道途径幼稚和接种SIV的猕猴，并在病毒血症之前的日食中确定对病毒的免疫反应以及对免疫的病毒反应。 3。单独确定两种疫苗的有效性以及SIV保护SIV感染中的有效性，并与粘液屏障功能，免疫反应，转录和蛋白质组织特征相关。 公共卫生相关性：该应用将研究两种创新的SIV疫苗，这些疫苗已知可以在包括女性生殖道在内的粘膜部位产生免疫反应。除了免疫学分析外，还将通过基因组和蛋白质组学分析来分析生殖道中的疫苗活性，并与阴道SIV挑战的保护相关。两种疫苗的结合提供了粘膜中综合免疫激活的潜力，从而增强了对SIV感染的抗性。