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

描述（由申请人提供）：生殖器疱疹是世界范围内最普遍的性传播感染之一，发病率很高。生殖器疱疹作为一种公共卫生威胁的影响因其与艾滋病毒的流行病学协同作用而被放大。流行病学研究一致表明，单纯疱疹病毒感染增加了艾滋病毒传播和获得的风险。原发性HSV感染的日益流行、临床复发和高沉默再激活率加剧了HSV和HIV的传播，并突出了迫切需要新的预防策略。HSV疫苗的开发一直难以实现，然而，葛兰素史克（GSK）开发的HSV-2糖蛋白D （gD）亚单位疫苗在两项试验中获得了最有希望的结果，该疫苗对基线时HSV-1和HSV-2血清均阴性的女性提供部分保护，但未能保护男性或HSV-1血清阳性的女性。为了解决现有模型的局限性和不足，我们建立了雌性（阴道）和雄性（阴茎皮肤受损）棉花大鼠生殖器疱疹模型。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幼稚动物的疫苗反应的机会。棉花大鼠的其他优点包括可用的试剂来研究体液和细胞粘膜和全身免疫反应。该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花大鼠中的效果，确定棉花大鼠是否提供了预测疫苗临床反应的模型。我们假设，与男性相比，该疫苗将为单纯疱疹病毒感染的女性提供更大的保护，与单纯疱疹病毒1血清阳性的女性相比，单纯疱疹病毒1血清阳性的女性提供更大的保护，从而概括了在人体临床试验中发生的情况。我们将比较疫苗对原发性感染和疾病的影响，临床和亚临床复发率，以及粘膜和全身体液和细胞免疫反应。获得的结果将有助于深入了解具体性别反应的机制，并为今后的研究建立框架，以评价下一代疫苗和其他预防战略。

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.