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Development of an effective genital herpes vaccine

开发有效的生殖器疱疹疫苗

基本信息

批准号：
7897851
负责人：
WILLIAM P HALFORD
金额：
$ 24.98万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
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：
2009-07-22 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897851
关键词：
Age Animals Antigens Attenuated Biology Cavia Chickenpox Childhood 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

项目摘要

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(申请人提供)：30年来，人们一直在寻找一种有效的疫苗来预防由单纯疱疹病毒2型(HSV-2)引起的生殖器疱疹。大多数研究集中在开发非复制型HSV-2疫苗制剂，如糖蛋白D亚单位或复制缺陷HSV-2病毒。这些做法值得考虑。然而，目前尚不清楚非复制型HSV-2疫苗能否引发人们所寻求的针对生殖器疱疹的终身免疫类型。在没有有效疫苗的情况下，每过去一年，就会有1000到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：复制的活HSV-2疫苗毒株可能更有效。我们在控制人类人群中的病毒疾病方面取得的大部分成功都是基于活的、复制的病毒。活牛痘病毒(最初的疫苗)被用来结束天花流行。脊髓灰质炎、腮腺炎、麻疹、风疹和水痘可以通过儿童疫苗预防，这种疫苗含有自然界中出现的可复制的活病毒，但其致病潜力已减弱。这是我们最成功的疫苗接种方式，但由于其控制生殖器疱疹的潜力尚未得到充分考虑。这在很大程度上是因为人们错误地认为活的HSV-2疫苗毒株是危险的。P.I.S发表的研究和初步数据表明，基因工程与目前的单纯疱疹病毒生物学知识相结合，可以用于生产安全且具有免疫原性的活的、可复制的单纯疱疹病毒1型和2型病毒疫苗。从原理上讲，HSV的减毒很容易实现，因为75个HSV基因中有30个不是病毒复制所必需的。其中许多基因，如ICP0基因，是HSV抵抗宿主免疫反应抑制所必需的。P.I.已经与干扰素敏感的HSV-1 ICP0病毒合作了10年。ICP0基因的破坏使HSV-1和HSV-2对干扰素-1/2的抑制高度敏感，在动物中是无毒的，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，对致死攻击具有1000倍的LD50剂量的HSV-1(McKrae株)或HSV-2(MS株)。同样，HSV-2 ICP0病毒在免疫部位复制的小鼠对HSV-2 MS的致死性攻击具有免疫力。目前还没有做出系统的努力来开发活的和适当减毒的HSV-2病毒，这种病毒可能会在免疫部位建立隐性感染。P.I.S的数据表明，单纯疱疹病毒1型或2型S只有在宿主发生病毒复制时才能实现完全的免疫原性。如果这一假设是正确的，那么复制的活HSV疫苗毒株可能比迄今为止认为的任何非复制HSV疫苗株具有更强的保护作用。需要两年的R21资金来验证这一假设，并开始开发HSV-2 ICP0病毒，如果HSV-2活疫苗株被证明在保护小鼠、豚鼠、兔子和仓鼠免受生殖器疱疹方面是安全有效的，这种病毒以后可能会用于人类临床试验。公共卫生相关性：干扰素敏感的单纯疱疹病毒2型(HSV-2)ICP0病毒被建议作为一种活的、复制的HSV-2疫苗株。这种活的HSV-2疫苗毒株可能能够防止生殖器疱疹的传播，生殖器疱疹目前正困扰着全球约5000万人。这里提出的工作将检验一个假设，即活的、复制的HSV-2 ICP0-病毒相对于非复制的HSV-2疫苗提供了对外源HSV-2感染的更好的保护，而HSV-2疫苗30年来一直是研究的重点。预计从这些研究中将出现一种新的活的HSV-2 ICP0疫苗株，从而保证进入人类临床试验。