A Mucosal Vaccine for HSV-2

描述(申请人提供)：大约每5个美国人中就有1人感染单纯疱疹病毒2型(HSV-2)。单纯疱疹病毒2型的局部生殖器感染导致疼痛的复发性生殖器损害，而播散性感染可涉及多个内脏器官和致死性脑炎。利用第一阶段资金，我们开发了一种新的异种免疫方案，由糖蛋白D(GD)DNA疫苗和脂质体包裹的gD加强免疫组成。该方案可诱导强健的血清免疫球蛋白抗原特异性抗体、粘膜免疫球蛋白和分泌型免疫球蛋白A，以及以辅助性T细胞1型(Th1)为主的免疫反应。用该方案免疫的小鼠在感染100倍致死量的病毒后获得保护，免受疾病侵袭。使用较高的DNA预备量可使80%的免疫小鼠产生灭菌免疫。我们正在申请第二阶段的资金，以补充和延长这些研究，为临床前的安全性测试做准备。申请的资金将用于进一步鉴定新型HSV-2疫苗诱导的免疫介体。资金还将用于评估疫苗组件的商业供应商并建立质量控制参数。组件的剂量将进一步优化，为人体使用和毒性测试做准备。将使用豚鼠在第二个动物模型中展示疫苗的效力，并测试疫苗防止潜伏病毒建立和/或重新激活的能力。这些实验的最终结果将是建立一种新型的HSV-2疫苗。公共卫生相关性：这种疫苗显然会对每年花费在与HSV-2相关的直接医疗费用上的超过16亿美元产生影响。公共卫生服务(PHS)已经认识到由单纯疱疹病毒引起的重大公共卫生问题。PHS出版物《2010年健康人》已将性传播疾病列为国家优先事项，旨在减少感染人乳头瘤病毒和HSV-2的成年人数量。

DESCRIPTION (provided by applicant): Approximately 1 out of every 5 Americans is infected with herpes simplex virus type 2 (HSV-2). Localized genital infection by HSV-2 results in painful recurring genital lesions while disseminated infection can involve multiple visceral organs and lethal encephalitis. Using Phase 1 funding we have developed a new heterologous immunization protocol composed of a glycoprotein D (gD) DNA vaccine followed by a liposome-encapsulated gD boost. This protocol induces robust serum IgG antigen-specific antibodies, mucosal IgG and secretory IgA and a T helper type 1 (Th1)-biased immune response. Mice immunized with this protocol are protected from disease after infection with 100 times the lethal dose of virus. Use of a higher priming dose of DNA revealed sterilizing immunity in 80% of immunized mice. We are requesting Phase 2 funding to complement and extend the studies in preparation for preclinical safety testing. The requested funding will be used to further characterize immune mediators induced by the novel HSV-2 vaccine. Funding will also be used to evaluate commercial suppliers of vaccine components and establish quality control parameters. Dosing of components will be further optimized in preparation for human use and toxicity testing. Guinea pigs will be used to demonstrate efficacy of the vaccine in a second animal model and to test the ability of the vaccine to prevent establishment of latency and/or reactivation of latent virus. The end result of these experiments will be the establishment of a novel vaccine for HSV-2. PUBLIC HEALTH RELEVANCE: This vaccine would clearly have an impact on the greater than $1.6 billion spent annually on direct medical costs associated with HSV-2. The Public Health Service (PHS) has recognized the significant public health issues caused by herpes simplex virus. The PHS publication, "Healthy People 2010", has set sexually transmitted diseases as a national priority with a goal to reduce the number of adults infected with human papilloma virus and HSV-2.