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

项目概要/摘要 2 型单纯疱疹病毒 (HSV-2) 是最常见的性传播病原体之一， 全球每年有 2000 万新感染病例。 HSV-2 生殖器感染是导致以下疾病的主要原因 生殖器溃疡病并增加患其他性传播疾病的可能性，包括 艾滋病毒。 HSV-2 感染可能导致免疫功能正常的人出现自限性疼痛病变 个体，但也是免疫受损人群和暴露于病毒的新生儿中严重发病的一个原因 产道中的病毒。无症状排毒事件经常发生在 HSV-2 感染者中， 使传播更有可能。 HSV 特异性 T 细胞和抗体分泌细胞位于 以前感染过 HSV，并在重新激活后清除生殖器上皮中的病毒。推动这个地方 通过治疗性免疫来快速控制 HSV-2 脱落的免疫反应是一种合乎逻辑的疫苗策略。 全身注射治疗性 HSV-2 疫苗已显示出在减少病毒脱落和减少病毒传播方面的前景。 但临床试验中病变复发率有待提高。我们建议直接粘膜刺激 生殖器驻留的 HSV 特异性免疫细胞将比全身加强疫苗效果提高。 最近，通过阴道内延长将重组HIV抗原和佐剂递送至阴道 环（IVR）导致局部抗体反应的发展超过了全身抗体反应所实现的反应 免疫接种。作为治疗性疫苗接种方法的概念验证测试，我们将使用新型 pod-IVR 将HSV免疫原/佐剂递送至阴道粘膜的递送平台，量化对阴道粘膜的增强作用 生殖道驻留疫苗抗原特异性 B 和 T 细胞群，并测试疫苗的功效 预防 HSV-2 复发性疾病和病毒脱落。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，增强对 HSV-2 脱落的免疫控制。我们的 中心假设是，将治疗性疫苗抗原直接递送至生殖器上皮将增强 生殖道驻留的 HSV 特异性 T 和 B 细胞，并增强对 HSV-2 脱落的控制。我们的目标是 这些研究是为了测试这样一个概念：通过新型荚状阴道环递送的治疗性疫苗将 强烈促进生殖器驻留 T 和 B 细胞反应，并将被证明可有效控制病毒脱落和 疾病反复发作。该提案的具体目标是： 目标 1：测试重组 HSV-的直接递送 通过 pod-IVR 将 2 gD gB/ CpG 佐剂添加到女性生殖道，用于治疗性免疫 HSV-2；目标 2：测试 pod-IVR 免疫对女性生殖道的保护效果 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 增强已有的生殖器HSV特异性免疫细胞对于提高治疗效果至关重要 减少 HSV-2 传播的治疗性疫苗。

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.