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)：在过去的几年里，我们开发了两种新的、非传统的疫苗策略，产生了对SIV抗原的强大粘膜免疫力。这两种疫苗策略是基于人乳头瘤病毒递送SIV-cDNA，称为HPV-SIV，以及基于HEK293-细胞分泌免疫原性伴侣-gp96-Ig-SIV-肽复合体，称为gp96-Lg-SIV。疫苗通过不同的途径接种，通过不同的分子和细胞机制产生粘膜免疫反应。不同的分子机制意味着激活不同的转录和信号通路，并可能对阴道SIV攻击产生不同程度的保护。将两种疫苗激活的途径与对SIV挑战的免疫反应和对疾病的保护相关联，将提供信息，如有必要，如何最好地结合两种疫苗策略，以有效预防SIV疾病。假设1：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，进而通过不同的转录和信号通路不同地激活粘膜免疫的各个组成部分。粘膜中的不同免疫反应将转化为对SIV阴道攻击的不同程度的保护。假设2：联合接种HPV-SIV和gp96-LG-SIV疫苗将通过结合不同转录和信号通路的激活，从而产生全面的粘膜免疫，从而增强抵抗阴道SIV攻击的能力，从而在产生粘膜免疫方面发挥协同作用。1.用HPV-SIV和gp96-LG-SIV免疫恒河猴，并系统地测定其在阴道、引流淋巴结和系统中的免疫应答、转录谱和信号通路。2.用SIV经阴道攻击幼猴和接种过SIV的猕猴，并在病毒血症前的日食期间测定对病毒的免疫应答和病毒免疫应答。3.确定两种疫苗单独和联合使用对SIV感染的保护作用及其与粘液屏障功能、免疫应答、转录和蛋白质组学的关系。 公共卫生相关性：这项应用将研究两种创新的SIV疫苗，它们已知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分析来分析生殖道中的疫苗活性，并与保护免受阴道SIV攻击有关。这两种疫苗的结合提供了在粘膜中全面激活免疫的潜力，从而增强了对SIV感染的抵抗力。