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Improving Vaccine Safety and Efficacy to Control Primary HSV-1 Infections

提高疫苗安全性和有效性以控制原发性 HSV-1 感染

基本信息

批准号：
7945290
负责人：
David J Davido
金额：
$ 20.93万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7945290
关键词：
Acute Address Alanine Antiviral Agents Attenuated Cells Cornea Corneal Diseases Defective Viruses Disease Dose Effectiveness Engineering Epitopes Eye Infections Eye diseases Eyelid structure Genes Goals Herpes Simplex Infections Herpesvirus 1 Immune response Immunization Immunologics Individual Infection Interferons Laboratories Life Mediating Monitor Mus Mutation Nervous system structure Pain Phosphorylation Phosphorylation Site Prophylactic treatment Proteins Recurrence Research Ribonucleases SS DNA BP Safety Severities Simplexvirus Spleen T cell response T-Lymphocyte Testing Tissues Transactivation United States Vaccination Vaccines Viral Genes Viral Proteins Virion Virulence Virulent Virus Virus Replication Vision Work base cytokine disease diagnosis gene repression immunogenic immunogenicity improved insight lymph nodes mouse model mutant prevent prophylactic prototype recombinant virus relating to nervous system response vaccine development vaccine efficacy vaccine safety

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus 1 (HSV-1) causes painful, sight-threatening infections of the eyelid and cornea. HSV- 1 infects more than half of individuals in the United States, and 300,000 new cases of HSV-1-induced eye disease are diagnosed each year. No vaccine to reduce or prevent HSV-mediated corneal infection and blinding disease currently exists. The long-term objective of our research is to develop a prophylactic vaccine that limits the acquisition and spread of HSV-1-mediated ocular infections. An effective prophylactic vaccine against HSV-1 must be safe and highly immunogenic. Previous and preliminary studies indicate that 1) mutation of phosphorylation cluster III on ICP0 creates a markedly neuroattenuated virus (Phos3) that is immunogenic and effectively prevents corneal disease in mice; 2) mutation of ICP8 creates a replication-defective virus that is immunogenic and represents a safe, live virus-based vaccine strategy; and 3) mutation of vhs enhances the immunogenicity and efficacy of a replication-defective virus. We therefore hypothesize that HSV-1 bearing mutations in phosphorylation cluster III of ICP0 can be further modified to optimize its safety and effectiveness in protecting against eye disease caused by HSV-1 by additional deletion of ICP8 and vhs. We will use an established mouse model of acute corneal infection to determine whether these multigenic alterations to HSV-1 result in a safe and optimally effective vaccine strain for reducing HSV-1-mediated corneal disease, and to determine the immunologic basis of protection. In Specific Aim 1, two new recombinant viruses will be generated, specifically to test whether ICP8 can be deleted from Phos3 without compromising its capacity to stimulate protective immune responses after immunization, and whether deletion of vhs increases the immunogenicity of the ICP8-Phos3 virus. These viruses will be used to immunize mice and will be compared with the parental Phos3 for their capacity to prophylactically protect mice against HSV-1 corneal infection. In Specific Aim 2, the magnitude and type of HSV-specific T cell responses will be determined in the lymph nodes and spleen after immunization with optimal and suboptimal vaccines, and in the cornea after HSV-1 challenge. Cytokine profiles in the cornea will be determined, and potential reactivity to a pathogenic epitope in gK will be monitored. The viral genes we have chosen to inactivate normally allow HSV-1 to replicate and/or evade the immune response of the host; thus, inactivating at least two of these genes is expected to maintain the effectiveness of this HSV-1 vaccine prototype while improving its safety. In-depth analyses of T cell responses to vaccination and challenge will provide insight into mechanisms underlying vaccine-mediated protection. PUBLIC HEALTH RELEVANCE: Herpes simplex virus 1 (HSV-1) causes painful infections of the eyelid and cornea that can threaten sight. HSV-1 infects more than half of individuals in the United States, and 300,000 new cases of HSV-1-induced eye disease are diagnosed each year. Our goal is to develop a vaccine that can be used as prophylaxis to prevent the debilitating consequences of primary and recurrent HSV-1 infections of the eye.

描述（由申请人提供）：单纯疱疹病毒1型（HSV-1）引起眼睑和角膜疼痛、威胁视力的感染。HSV- 1感染了美国一半以上的人，每年诊断出30万例HSV-1诱导的眼病新病例。目前还没有疫苗来减少或预防HSV介导的角膜感染和致盲性疾病。我们研究的长期目标是开发一种预防性疫苗，限制HSV-1介导的眼部感染的获得和传播。有效的HSV-1预防性疫苗必须是安全和高免疫原性的。先前和初步的研究表明，1）ICP 0上磷酸化簇III的突变产生了具有免疫原性并有效预防小鼠角膜疾病的显著神经减毒病毒（Phos 3）; 2）ICP 8的突变产生了具有免疫原性并代表安全的基于活病毒的疫苗策略的复制缺陷型病毒;和3）VHS的突变增强复制缺陷型病毒的免疫原性和效力。因此，我们假设可以进一步修饰ICP 0磷酸化簇III中携带突变的HSV-1，以通过额外缺失ICP 8和vhs来优化其在预防HSV-1引起的眼病中的安全性和有效性。我们将使用已建立的急性角膜感染小鼠模型来确定这些HSV-1的多基因改变是否会导致安全且最佳有效的疫苗株用于减少HSV-1介导的角膜疾病，并确定保护的免疫学基础。在具体目标1中，将产生两种新的重组病毒，专门用于测试ICP 8是否可以从Phos 3中删除而不损害其在免疫后刺激保护性免疫应答的能力，以及vhs的删除是否会增加ICP 8-Phos 3病毒的免疫原性。这些病毒将用于免疫小鼠，并将与亲本Phos 3比较其免疫保护小鼠免受HSV-1角膜感染的能力。在特定目标2中，将在用最佳和次佳疫苗免疫后的淋巴结和脾脏中以及在HSV-1攻击后的角膜中确定HSV特异性T细胞应答的幅度和类型。将测定角膜中的细胞因子谱，并监测对gK中致病性表位的潜在反应性。我们选择的病毒基因通常允许HSV-1复制和/或逃避宿主的免疫应答;因此，灭活这些基因中的至少两个有望保持这种HSV-1疫苗原型的有效性，同时提高其安全性。深入分析T细胞对疫苗接种和攻击的反应将深入了解疫苗介导的保护机制。公共卫生相关性：单纯疱疹病毒1型（HSV-1）引起眼睑和角膜的疼痛感染，可威胁视力。HSV-1感染了美国一半以上的人，每年诊断出30万例HSV-1诱导的眼病新病例。我们的目标是开发一种疫苗，可用于预防原发性和复发性HSV-1眼部感染的衰弱后果。