Cervicovaginal Vaccine Delivery by Novel Pod Intravaginal Rings for Therapeutic Immunization Against HSV-2

项目概要/摘要 单纯疱疹病毒2型（HSV-2）是最常见的性传播病原体之一， 导致全球每年新增2千万例感染。HSV-2生殖器感染是导致生殖器感染的主要原因。 生殖器溃疡疾病，并增加获得其他性传播疾病的可能性， 艾滋病。HSV-2感染可能导致免疫功能正常的患者出现自限性疼痛性病变， 但在免疫受损人群和暴露于以下物质的新生儿中， 产道中的病毒HSV-2感染个体中经常发生无症状的脱落事件， 使得传播的可能性更大HSV特异性T细胞和抗体分泌细胞位于上皮部位， 先前的HSV感染和再激活后从生殖器上皮清除病毒。提升这个本地 通过治疗性免疫以快速控制HSV-2脱落的免疫应答是合乎逻辑的疫苗策略。 全身注射的治疗性HSV-2疫苗已显示出减少病毒脱落和 复发率在临床试验中，但需要改善。我们建议直接粘膜刺激 生殖器驻留的HSV特异性免疫细胞将导致优于系统性加强的疫苗效力。 最近，通过阴道内注射将重组HIV抗原和佐剂延长递送至阴道， 环（IVR）导致的局部抗体反应的发展超过了那些实现的全身 次免疫作为一种治疗性疫苗接种方法的概念验证测试，我们将使用一种新的pod-IVR 递送平台以将HSV免疫原/佐剂递送至阴道粘膜，定量对HSV免疫原/佐剂的加强作用。 生殖道驻留、疫苗抗原特异性B和T细胞群，并测试疫苗的效力 预防HSV-2复发和病毒脱落。我们的长期目标是了解如何 增强生殖道驻留免疫细胞的功能，以增强对HSV-2脱落的免疫控制。我们 中心假设是将治疗性疫苗抗原直接递送至生殖器上皮将促进 生殖道驻留的HSV特异性T和B细胞，并增加对HSV-2脱落的控制。我们的目标是 这些研究是为了验证这样一种概念，即通过一种新的荚状阴道环递送的治疗性疫苗将 强烈增强生殖器驻留T和B细胞应答，并将证明有效控制病毒脱落， 复发性疾病本提案的具体目的是：目的1：测试重组HSV-1的直接递送。 2 gD+gB/ CpG佐剂通过pod-IVR对女性生殖道进行治疗性免疫接种， 目的2：测试女性生殖道pod-IVR免疫对HSV-2的保护效力， HSV-2复发性疾病和病毒脱落。这项工作意义重大，因为了解如何最好地 加强预先存在的生殖器驻留的HSV特异性免疫细胞对于提高免疫治疗的疗效至关重要。 治疗性疫苗以减少HSV-2传播。

PROJECT SUMMARY/ABSTRACT Herpes simplex virus type 2 (HSV-2) is one of the most common sexually transmitted pathogens and is responsible for 20 million new infections each year worldwide. HSV-2 genital infection is a leading cause of genital ulcer disease and increases the likelihood of acquiring other sexually transmitted diseases including HIV. HSV-2 infection may result in the development of self-limiting painful lesions in immune competent individuals but is a cause of severe morbidity in immune compromised populations and newborns exposed to virus in the birth canal. Asymptomatic shedding episodes occur frequently in HSV-2 infected individuals which makes transmission more likely. HSV-specific T cells and antibody secreting cells reside at epithelial sites of previous HSV infection and clear virus from the genital epithelium after reactivation. Boosting this local immune response by therapeutic immunization to rapidly control HSV-2 shedding is a logical vaccine strategy. Systemically-injected therapeutic HSV-2 vaccines have shown promise in reducing virus shedding and recurrent lesion rates in clinical trials but need to be improved. We propose that direct mucosal stimulation of genital resident, HSV-specific immune cells will result in improved vaccine efficacy over systemic boosting. Recently, prolonged delivery of recombinant HIV antigen and adjuvant to the vagina through an intravaginal ring (IVR) resulted in development of local antibody responses that exceeded those achieved by systemic immunization. As a proof-of-concept test of a therapeutic vaccination approach, we will use a novel pod-IVR delivery platform to deliver HSV immunogen/adjuvant to the vaginal mucosa, quantify the boosting effect on the genital-tract resident, vaccine antigen-specific B and T cell populations, and test the efficacy of the vaccine in protection against HSV-2 recurrent disease and virus shedding. Our long-term goal is to understand how to boost the function of genital tract-resident immune cells to enhance immune control of HSV-2 shedding. Our central hypothesis is that direct delivery of therapeutic vaccine antigen to the genital epithelium will boost genital tract-resident, HSV-specific T and B cells and increase control of HSV-2 shedding. Our objective in these studies is to test the concept that a therapeutic vaccine delivered by a novel pod-intravaginal ring will strongly boost genital-resident T and B cell responses and will prove effective in controlling virus shedding and recurrent disease. The Specific aims of this proposal are: Aim 1: Test direct delivery of recombinant HSV- 2 gD+gB/ CpG adjuvant to the female genital tract by pod-IVRs for therapeutic immunization against HSV-2; and Aim 2: Test protective efficacy of pod-IVR immunization of the female genital tract against HSV-2 recurrent disease and virus shedding. This work is significant because understanding how best to boost pre-existing genital-resident HSV-specific immune cells will be critical for improving the efficacy of therapeutic vaccines to reduce HSV-2 transmission.