Immunization to Reduce Genital and Neonatal Herpes

免疫接种可减少生殖器和新生儿疱疹

• 批准号: 7788638
• 负责人: Nigel Bourne
• 金额: $ 20.4万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788638
• 关键词: Accounting; Adjuvant; Animals; Antibodies; Antigens; Antiviral Agents; Belief; Cavia; Clinical; Clinical Research; Clinical Trials; Controlled Clinical Trials; DNA; DNA Vaccines; Development; Disease; Doctor of Philosophy; Emulsions; Evaluation; Exposure to; Female; Frequencies; Future; Genital system; Glycoproteins; Health; Herpes Simplex Virus Vaccines; Human; Human Herpesvirus 2; Immune response; Immunity; Immunization; Incidence; Infection; Infection prevention; Latent Virus; Latent virus infection phase; Letters; MF59; Measures; Modeling; Mucous Membrane; Mus; Neonatal; Oils; Pathogenesis; Pharmacotherapy; Proteins; Recurrence; Recurrent disease; Reporting; Research Design; Risk; Role; Sensory Ganglia; Simplexvirus; Site; Surface; System; Treatment Protocols; Vaccinated; Vaccine Clinical Trial; Vaccines; Virus; Virus Diseases; Virus Replication; Virus Shedding; Water; Woman; aluminum sulfate; chiron vaccine; genital herpes; genital infection; genital secretion; glycoprotein D-herpes simplex virus type 2; improved; latent infection; monophosphoryl lipid A; mouse model; pathogen; preclinical evaluation; prevent; reactivation from latency; research study; response; transmission process; trend; vaccine efficacy

DESCRIPTION (provided by applicant): The control of genital herpes will require widespread use of effective vaccines. However, if herpes simplex virus (HSV) vaccines do not achieve sterilizing immunity (prevent virus replication at the entry site) the virus will establish latency, rendering the host potentially contagious during reactivation, and allowing continued transmission. While animal studies with a variety of vaccines show that immunization does not prevent virus replication in the genital mucosa following high titer challenge, a HSV type 2 glycoprotein D vaccine protected 39-46% of seronegative women against infection in a recent clinical Trial. Since much of the spread of genital herpes occurs during periods of asymptomatic shedding when relatively little virus is present, we believe that the protection resulted because immunization increased the virus inoculum required to infect the genital mucosa. In Aim 1 we will explore this hypothesis by determining the effect of immunization with the clinical study vaccine on the virus inoculum required to infect the genital mucosa in a mouse model. In Aim 2 we will again use the threshold of infection to measure efficacy and determine whether DNA prime glycoprotein boost improves protection compared to DNA or glycoprotein only immunization. These studies are relevant because an effective vaccine will need to induce T helper type 1 (Th1) responses in addition to antibody and DNA vaccine priming with protein boosting has been shown to increase Th1 responses compared to protein only immunization. While a vaccine that increases the threshold of infection will reduce the incidence of transmission, it will not provide universal protection. In Aim 3 we will use conditions that overcome protection from infection to examine the impact of immunization on the magnitude of latent infection and recurrent disease (both clinical recurrences and virus shedding into the genital tract). These studies will provide new information about the risks of transmission from immunized hosts who become infected. Taken together, the studies in this proposal will yield new information about the capacity of HSV vaccines to reduce the spread of genital herpes. These study designs may become standard for preclinical evaluation of HSV vaccines.

描述（由申请人提供）：生殖器疱疹的控制将需要广泛使用有效的疫苗。但是，如果单纯疱疹病毒（HSV）疫苗无法实现灭菌免疫（预防入口部位的病毒复制），则病毒将建立潜伏期，从而在重新激活期间可能会传播宿主并允许继续传播。虽然各种疫苗的动物研究表明，在高滴度挑战之后，免疫不能阻止生殖器粘膜中的病毒复制，但在最近的一项临床试验中，HSV 2型糖蛋白D疫苗D疫苗可保护39-46％的塞隆女性免受感染。 由于生殖器疱疹的大部分传播发生在相对较少的病毒时无症状脱落时期发生，因此我们认为，由于免疫增加了感染生殖器粘膜所需的病毒，因此产生了保护。在AIM 1中，我们将通过确定用临床研究疫苗免疫对接种物质的接种物的影响来探讨这一假设，以感染小鼠模型中的生殖器粘膜。在AIM 2中，我们将再次使用感染阈值来测量功效，并确定与仅DNA或仅糖蛋白免疫相比，DNA Prime糖蛋白是否可以提高保护。这些研究很重要，因为除了仅蛋白质促进抗体和DNA疫苗启动外，还需要有效的疫苗诱导T辅助1型（TH1）反应，与仅蛋白质免疫相比，促进蛋白质的促进作用可以增加TH1反应。 尽管增加感染阈值的疫苗将减少传播的发生率，但它不会提供普遍的保护。在AIM 3中，我们将使用克服免受感染保护的条件来检查免疫对潜在感染和复发性疾病（临床复发和病毒脱落到生殖道）的影响的影响。这些研究将提供有关受感染的免疫宿主传播风险的新信息。综上所述，该提案中的研究将产生有关HSV疫苗减少生殖器疱疹传播的能力的新信息。这些研究设计可能成为HSV疫苗临床前评估的标准。