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

• 批准号: 7708388
• 负责人: David J Davido
• 金额: $ 20.14万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708388
• 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-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; public health relevance; recombinant virus; relating to nervous system; response; vaccine development; vaccine efficacy; vaccine safety

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。在美国，超过一半的人感染了HSV-1，每年诊断出30万例HSV-1引起的眼病新病例。目前还没有疫苗可以减少或预防单纯疱疹病毒介导的角膜感染和致盲疾病。我们研究的长期目标是开发一种预防性疫苗，以限制hsv -1介导的眼部感染的获得和传播。针对1型单纯疱疹病毒的有效预防性疫苗必须是安全和高度免疫原性的。先前和初步的研究表明：1)ICP0磷酸化簇III的突变可产生一种明显的神经减毒病毒（Phos3），该病毒具有免疫原性，可有效预防小鼠角膜疾病；2) ICP8突变产生复制缺陷病毒，该病毒具有免疫原性，代表了一种安全的、基于活病毒的疫苗策略；3) VHS突变增强了复制缺陷病毒的免疫原性和免疫效力。因此，我们假设ICP0磷酸化簇III中携带HSV-1的突变可以通过进一步修饰ICP8和vhs的缺失来优化其保护HSV-1引起的眼病的安全性和有效性。我们将使用已建立的急性角膜感染小鼠模型来确定这些对HSV-1的多基因改变是否会产生一种安全且最有效的疫苗株，以减少HSV-1介导的角膜疾病，并确定保护的免疫学基础。在Specific Aim 1中，将生成两个新的重组病毒，专门测试从Phos3中删除ICP8是否可以在不影响其免疫后刺激保护性免疫反应的能力的情况下，以及删除vhs是否可以增加ICP8-Phos3病毒的免疫原性。这些病毒将用于小鼠免疫，并将与亲本pho3进行比较，以确定其预防小鼠感染HSV-1角膜感染的能力。在特异性目标2中，将确定最佳和次最佳疫苗免疫后淋巴结和脾脏以及HSV-1攻击后角膜中hsv特异性T细胞反应的大小和类型。将测定角膜中的细胞因子谱，并监测对gK致病性表位的潜在反应性。我们选择灭活的病毒基因通常允许HSV-1复制和/或逃避宿主的免疫反应；因此，至少灭活其中两个基因有望保持这种1型单纯疱疹病毒疫苗原型的有效性，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有助于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 （HSV-1）引起眼睑和角膜的疼痛感染，可能威胁视力。在美国，超过一半的人感染了1型单纯疱疹病毒，每年新诊断出30万例由1型单纯疱疹病毒引起的眼部疾病。我们的目标是开发一种疫苗，可以作为预防措施，防止眼部原发性和复发性单纯疱疹1型感染的衰弱后果。