Development of an effective genital herpes vaccine

开发有效的生殖器疱疹疫苗

• 批准号: 7739363
• 负责人: WILLIAM P HALFORD
• 金额: $ 25.46万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739363
• 关键词: Age; Animals; Antigens; Attenuated; Biology; Cavia; Chickenpox; Childhood; Classification; Clinical Trials; Contracts; Data; Development; Disease; Dose; Epidemic; Exhibits; Eye; Female; Figs - dietary; Funding; Genes; Genetic Engineering; Glycoproteins; Hamsters; Herpes Simplex Virus Vaccines; Herpes encephalitis; Herpesvirus 1; Human; Human Herpesvirus 2; Immune; Immune response; Immune system; Immunity; Immunization; Infection; Interferons; Knowledge; Left; Lethal Dose 50; Life; Measles; Modality; Modeling; Mumps; Mus; Mutation; Nature; Oryctolagus cuniculus; Poliomyelitis; Population; Proteins; Publishing; Recovery; Relative (related person); Repression; Research; Rubella; Simplexvirus; Site; Smallpox; Testing; Time; Vaccination; Vaccines; Vaccinia virus; Viral; Viral Vaccines; Virus; Virus Diseases; Virus Shedding; Work; attenuation; base; genital herpes; immunogenic; in vivo; prevent; public health relevance; research study; success

DESCRIPTION (provided by applicant): For 30 years, an effective vaccine has been sought to prevent genital herpes caused by herpes simplex virus 2 (HSV-2). Most of the research has focused on the development of non-replicating HSV-2 vaccine agents such as the glycoprotein D subunit or replication-defective HSV-2 viruses. Such approaches merit consideration. However, it is unclear that non-replicating HSV-2 vaccines elicit the type of life-long immunity against genital herpes that is sought. For each year that elapses without an effective vaccine, another 10 to 20 million people contract HSV-2 infections. Given the scope of the problem, perhaps it is time to consider a second possibility: a live, replicating HSV-2 vaccine strain may be more effective. Most of our successes in controlling viral disease in the human population have been based upon live, replicating viruses. Live vaccinia virus (the original vaccine) was used to end smallpox epidemics. Poliomyelitis, mumps, measles, rubella, and chickenpox are prevented with childhood vaccines that contain live, replicating viruses that occur in nature, but are attenuated in their disease-causing potential. This, our most successful vaccination modality, has not been adequately considered for its potential to control genital herpes. In large part, this is due to the misconception that a live HSV-2 vaccine strain would be dangerous. The P.I.'s published studies and preliminary data establish that genetic engineering combined with current knowledge of HSV biology may be applied to derive live, replicating HSV-1 and HSV-2 viral vaccines that are safe and immunogenic. In principle, attenuation of HSV is readily achieved because ~30 of 75 HSV genes are not essential for viral replication. Many of these genes, such as the ICP0 gene, are required for HSV to resist repression by the host immune response. The P.I. has worked with interferon-sensitive HSV-1 ICP0- viruses for 10 years. Disruption of the ICP0 gene renders HSV-1 and HSV-2 hypersensitive to repression by interferon-1/2, avirulent in animals, and yet these viruses may serve as powerful immunogens. Mice immunized with a live, replicating HSV-1 ICP0- virus are immune to lethal challenge with 1000 times the LD50 dose of HSV-1 (McKrae strain) or HSV-2 (MS strain). Likewise, mice in which an HSV-2 ICP0- virus replicates at the site of immunization are immune to lethal challenge with HSV-2 MS. A systematic effort has not been made to develop a live and appropriately attenuated HSV-2 virus that may establish an inapparent infection at the site of immunization. The P.I.'s data indicate that HSV-1 or HSV-2's full immunogenic potential is only realized when viral replication occurs in the host. If this hypothesis is correct, then live, replicating HSV vaccine strains may be far more protective than any non-replicating HSV vaccine considered to date. Two years of R21 funding is requested to test this hypothesis, and to begin developing HSV-2 ICP0- viruses that may later be used in human clinical trials if a live HSV-2 vaccine strain proves to be safe and effective in protecting mice, guinea pigs, rabbits, and hamsters against genital herpes. PUBLIC HEALTH RELEVANCE: Interferon-sensitive herpes simplex virus-2 (HSV-2) ICP0- viruses are proposed as a live, replicating HSV-2 vaccine strain. Such live HSV-2 vaccine strains may be capable of preventing the spread of genital herpes, a disease that currently afflicts ~50 million people worldwide. The work proposed herein will test a hypothesis that live, replicating HSV-2 ICP0- viruses provide superior protection against exogenous HSV-2 infections relative to non-replicating HSV-2 vaccines that have been the focus of research for 30 years. It is anticipated that a new live HSV-2 ICP0- vaccine strain will emerge from these studies that warrants advancement to human clinical trials.

描述（由申请人提供）：30 年来，人们一直在寻找有效的疫苗来预防由单纯疱疹病毒 2 (HSV-2) 引起的生殖器疱疹。大多数研究都集中在非复制型 HSV-2 疫苗制剂的开发上，例如糖蛋白 D 亚基或复制缺陷型 HSV-2 病毒。这些方法值得考虑。然而，目前尚不清楚非复制型 HSV-2 疫苗是否能产生所寻求的针对生殖器疱疹的终身免疫力。如果没有有效的疫苗，每年就会有 10 至 2000 万人感染 HSV-2。考虑到问题的范围，也许是时候考虑第二种可能性了：活的、可复制的 HSV-2 疫苗株可能更有效。我们在控制人类病毒性疾病方面取得的大部分成功都是基于活的、可复制的病毒。活痘苗病毒（最初的疫苗）被用来结束天花流行。儿童疫苗可预防脊髓灰质炎、腮腺炎、麻疹、风疹和水痘，这些疫苗含有自然界中存在的活复制病毒，但其致病潜力被减弱。这是我们最成功的疫苗接种方式，但尚未充分考虑其控制生殖器疱疹的潜力。这在很大程度上是由于人们错误地认为 HSV-2 活疫苗株是危险的。 P.I. 发表的研究和初步数据表明，基因工程与现有的 HSV 生物学知识相结合可用于衍生安全且具有免疫原性的活的、可复制的 HSV-1 和 HSV-2 病毒疫苗。原则上，HSV 减毒很容易实现，因为 75 个 HSV 基因中约有 30 个对于病毒复制不是必需的。其中许多基因，例如 ICP0 基因，是 HSV 抵抗宿主免疫反应抑制所必需的。 P.I.从事干扰素敏感 HSV-1 ICP0- 病毒研究已有 10 年。 ICP0 基因的破坏使得 HSV-1 和 HSV-2 对干扰素 1/2 的抑制高度敏感，在动物中无毒力，但这些病毒可能作为强大的免疫原。用活的、复制的HSV-1 ICP0-病毒免疫的小鼠对1000倍LD50剂量的HSV-1（McKrae株）或HSV-2（MS株）的致命攻击免疫。同样，HSV-2 ICP0-病毒在免疫位点复制的小鼠对HSV-2 MS的致命攻击免疫。尚未进行系统性的努力来开发可在免疫部位建立隐性感染的活的且适当减毒的 HSV-2 病毒。 P.I.的数据表明，HSV-1或HSV-2的全部免疫原性潜力只有当病毒在宿主体内发生复制时才能实现。如果这个假设是正确的，那么活的、复制型 HSV 疫苗株可能比迄今为止认为的任何非复制型 HSV 疫苗更具保护性。需要两年的 R21 资金来检验这一假设，并开始开发 HSV-2 ICP0-病毒，如果 HSV-2 活疫苗株被证明能够安全有效地保护小鼠、豚鼠、兔子和仓鼠免受生殖器疱疹侵害，这些病毒随后可用于人体临床试验。公共卫生相关性：干扰素敏感型单纯疱疹病毒 2 (HSV-2) ICP0- 病毒被提议作为活的复制型 HSV-2 疫苗株。这种 HSV-2 活疫苗株可能能够预防生殖器疱疹的传播，这种疾病目前困扰着全世界约 5000 万人。本文提出的工作将检验一个假设，即相对于非复制型 HSV-2 疫苗，活的复制型 HSV-2 ICP0 病毒可提供针对外源性 HSV-2 感染的卓越保护，非复制型 HSV-2 疫苗已成为 30 年来研究的焦点。预计这些研究中将出现一种新的 HSV-2 ICP0-活疫苗株，并有利于进入人体临床试验。