Cotton Rat: Animal Model Predictive of Clinical Responses to HSV Vaccines

描述（由申请人提供）：生殖器疱疹是全球最流行的性传播感染之一，并与大量发病率相关。生殖器疱疹作为一种公共卫生威胁的影响被放大，因为它与艾滋病毒的流行病学协同作用。流行病学研究一致表明，HSV感染增加了HIV传播和获得的风险。原发性HSV感染、临床复发和高沉默再激活率的日益增加的患病率助长了HSV和HIV的传播，并突出了对新的预防策略的迫切需要。HSV疫苗的开发一直是难以捉摸的，然而，最有希望的结果是在两项试验中获得的HSV-2糖蛋白D（gD）亚单位疫苗开发的葛兰素史克（GSK），其中疫苗提供了部分保护的妇女谁是血清阴性的HSV-1和HSV-2在基线，但未能保护男性或保护HSV-1血清阳性的妇女。为了解决现有模型的局限性和不足，我们建立了生殖器疱疹的雌性（阴道）和雄性（阴茎皮肤破裂）棉鼠模型。我们还建立了口腔和眼部HSV- 1感染模型，从而提供了比较HSV-1血清阳性和HSV-1未感染动物的疫苗应答的机会。棉鼠的其他优势包括可获得研究体液和细胞粘膜和全身免疫反应的试剂。本I期STTR的总体目标是通过比较GSK gD亚单位疫苗在雄性和雌性棉鼠中的有效性，确定棉鼠是否可提供预测疫苗临床应答的模型。我们假设疫苗将在HSV-初治女性中提供比男性更大的保护，并且在HSV-1初治女性中提供比HSV-1血清阳性女性更大的保护，从而概括了人类临床试验中发生的情况。我们将比较疫苗对原发感染和疾病的影响，临床和亚临床复发率，粘膜和全身体液和细胞免疫应答。获得的结果将提供深入了解性别特异性反应的机制，并为未来的研究建立框架，以评估下一代疫苗以及其他预防策略。 公共卫生相关性：生殖器疱疹是世界上最普遍的性传播感染之一，并与大量的发病率。流行病学研究一致表明，HSV感染增加了HIV传播和获得的风险。HSV疫苗的开发一直难以捉摸，然而，最有希望的结果是在两项试验中获得的糖蛋白D（gD）亚单位疫苗开发的葛兰素史克（GSK），其中疫苗提供了部分保护的妇女谁是血清阴性的HSV-1和HSV-2在基线，但未能保护男性或保护HSV-1血清阳性的妇女。为了解决现有模型的局限性和不足，我们建立了生殖器疱疹的雌性（阴道）和雄性（阴茎皮肤破裂）棉鼠模型。本STTR申请的I期研究旨在比较GSK gD-2-明矾单磷酰脂质A（MPL）疫苗在雌性和雄性棉鼠中的有效性。

DESCRIPTION (provided by applicant): Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is associated with substantial morbidity. The impact of genital herpes as a public health threat is amplified because of its epidemiologic synergy with HIV. Epidemiological studies consistently demonstrate that HSV infection increases the risk of HIV transmission and acquisition. The increasing prevalence of primary HSV infection, clinical recurrences and high rates of silent reactivation fuel the spread of both HSV and HIV and highlight the urgent need for novel prevention strategies. HSV vaccine development has been elusive, however, the most promising results were obtained in two trials with a HSV-2 glycoprotein D (gD) subunit vaccine developed by GlaxoSmithKline (GSK) in which the vaccine provided partial protection for women who were seronegative for both HSV-1 and HSV-2 at baseline, but failed to protect men or to protect HSV-1 seropositive women. To address the limitations and inadequacies of the current models, we established female (vaginal) and male (disrupted penile skin) cotton rat models of genital herpes. We have also established models of oral and ocular HSV- 1 infection, thus providing the opportunity to compare vaccine responses in HSV-1 seropositive and HSV-1 naive animals. Additional advantages of the cotton rat include the availability of reagents to study humoral and cellular mucosal and systemic immune responses. The overall goal of this Phase I STTR is to determine if the cotton rat provides a model predictive of clinical responses to vaccines by comparing the efficacy of the GSK gD subunit vaccine in male and female cotton rats. We hypothesize that the vaccine will provide greater protection in HSV-naive females compared to males and in HSV-1 naove compared to HSV-1 seropositive females, thus recapitulating what happened in the human clinical trials. We will compare the impact of the vaccine on primary infection and disease, rates of clinical and subclinical recurrences, and mucosal and systemic humoral and cellular immune responses. Results obtained will provide insights into the mechanisms underlying gender specific responses and establish the framework for future studies to evaluate next generation vaccines as well as other prevention strategies. PUBLIC HEALTH RELEVANCE: Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is associated with substantial morbidity. Epidemiological studies consistently demonstrate that HSV infection increases the risk of HIV transmission and acquisition. HSV vaccine development has been elusive, however, the most promising results were obtained in two trials with a glycoprotein D (gD) subunit vaccine developed by GlaxoSmithKline (GSK) in which the vaccine provided partial protection for women who were seronegative for both HSV-1 and HSV-2 at baseline, but failed to protect men or to protect HSV-1 seropositive women. To address the limitations and inadequacies of the current models, we established female (vaginal) and male (disrupted penile skin) cotton rat models of genital herpes. The goal of Phase 1 of this STTR application is to compare the efficacy of the GSK gD-2-Alum monophosphoryl lipid A (MPL) vaccine in female and male cotton rats.