Preclinical Testing of an Adenoviral Vector based HSV-2 Vaccine

描述(由申请人提供)：这项建议将利用UW/FHCRC在HSV-2和细胞免疫学方面的专业知识，以及GenVec开发的最先进的腺病毒递送平台来开发基于HSV-2、腺病毒载体的疫苗。这一阶段的SBIR应用将产生并在临床前模型中测试这种疫苗的初始原型。SBIR第一阶段的具体目标是构建和测试两个腺病毒载体，每个载体都包含HSV-2病毒抗原UL-47和UL-19。这些抗原已被证明在自然感染HSV-2的人中引起普遍的CD4+和CD8+T细胞反应。在动物模型中，预计所提出的AdHSV-2疫苗将增加HSV-2特异性CD8+T细胞对UL-47和UL-19抗原的应答。在SBIR的第二阶段，我们计划将这些AdHSV-2疫苗带入IND阶段。这项工作的长期目标是进行临床试验，测试AdHSV-2疫苗是否减少HSV-2的获得和/或减少病毒重新激活，这是通过病毒脱落的频率和滴度以及减少复发发作的比率来衡量的。 公共卫生相关性：HSV-2疫情继续在世界各地传播，血清阳性率已攀升至30-50%。先前感染单纯疱疹病毒2型与感染艾滋病毒的风险增加之间存在很强的关联。减少将HSV-2传染给性伴侣的抗病毒治疗只取得了部分成功。目前还没有有效的HSV-2疫苗可用。越来越多的证据表明，HSV-2特异性CD8+T细胞在控制人类HSV-2感染的潜伏期和重新激活方面发挥着重要作用。伴随着对HSV-2免疫生物学的这些研究，最近在人类中证明了重组腺病毒载体诱导了高频率的HIV CD8+T细胞反应。这项建议将利用L.Corey博士和D.Koelle博士的实验室开发的HSV-2专业知识和细胞免疫学，以及GenVec开发的最先进的腺病毒递送平台来开发基于HSV-2、Ad5的疫苗。

DESCRIPTION (provided by applicant): This proposal will leverage the expertise in HSV-2 and cellular immunology developed at the UW/FHCRC with the state of the art adenovirus delivery platform developed by GenVec to develop an HSV-2, adenovirus vector based vaccine. This phase 1 SBIR application will generate and test in preclinical models initial prototypes of such a vaccine. The specific aims during phase I of the SBIR are to construct and test two adenovirus vectors each containing a HSV-2 viral antigen, UL-47 and UL-19. These antigens have been shown to cause prevalent in CD4+ and CD8+ T cell responses among humans with naturally acquired HSV-2. It is anticipated that the proposed AdHSV-2 vaccine will increase the HSV-2 specific CD8+ T cell responses to the UL-47 and UL-19 antigens in animal models. During phase II of this SBIR we plan to bring these AdHSV-2 vaccines to the IND stage. The long-term goal of this effort is to conduct clinical trials testing whether AdHSV-2 vaccines decrease acquisition of HSV-2 and/or decrease viral reactivation as measured by frequency and titer of viral shedding and lessened rate of recurrent episodes. PUBLIC HEALTH RELEVANCE: The HSV-2 epidemic has continued to spread throughout the world and seroprevalence rates have climbed to 30-50%. There is a strong association between antecedent HSV-2 infection and increased risk of HIV acquisition. Antiviral therapy to reduce transmission of HSV-2 to sexual partners is only partially successful. No effective HSV-2 vaccine is currently available. Evidence has accumulated on the importance that HSV-2 specific CD8+ T cells play in control of latency and reactivation of HSV-2 infections in humans. Concomitant with these studies of HSV-2 immunobiology has been the recent demonstration in humans that recombinant adenovirus vectors elicit high frequency of HIV CD8+ T cell responses. This proposal will leverage the expertise in HSV-2, and cellular immunology developed in the laboratories of Drs. L. Corey and D. Koelle with the state of the art adenovirus delivery platform developed by GenVec to develop an HSV-2, Ad5 based vaccine.