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

项目摘要/摘要 单纯疱疹病毒2型是最常见的性传播病原体之一， 每年造成全球2000万新感染病例。HSV-2生殖器感染是导致 生殖器溃疡疾病，并增加感染其他性传播疾病的可能性，包括 爱滋病毒。HSV-2感染可能导致免疫功能自限性疼痛损害的发展 但它是免疫功能受损人群和新生儿严重发病的原因 产道中的病毒。HSV-2感染者经常发生无症状脱皮发作， 使传播的可能性更大。单纯疱疹病毒特异性T细胞和抗体分泌细胞驻留在上皮处 既往HSV感染并清除病毒后生殖器上皮细胞重新激活。提升这一地方性 通过治疗性免疫进行免疫应答以快速控制HSV-2的脱落是一种合理的疫苗策略。 系统注射的治疗性HSV-2疫苗在减少病毒脱落和 临床试验中的复发皮损率，但需要提高。我们认为直接的粘膜刺激 生殖器常驻、单纯疱疹病毒特异性免疫细胞将导致疫苗效力的提高，而不是全身免疫。 最近，通过阴道内延长重组艾滋病毒抗原和佐剂的阴道递送 环状病毒(IVR)导致的局部抗体反应超过了全身抗体反应 免疫接种。作为治疗性疫苗接种方法的概念验证测试，我们将使用一种新的Pod-IVR 将HSV免疫原/佐剂输送到阴道粘膜的递送平台，量化对 生殖道居民，疫苗抗原特异的B和T细胞群，并测试疫苗的效力 用于预防HSV-2复发疾病和病毒脱落。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输送到生殖器上皮细胞将促进 驻留在生殖道的、HSV特异性的T和B细胞，并加强对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种概念，即通过新型豆荚阴道环送送的治疗性疫苗将 强烈促进生殖器驻留的T和B细胞反应，将被证明在控制病毒脱落和 复发性疾病。这项建议的具体目标是：目标1：检测直接递送重组HSV- 2 Gd+Gb/CpG佐剂经Pod-IVRs免疫女性生殖道用于治疗性免疫 以及目标2：测试女性生殖道POD-IVR免疫的保护效果 HSV-2反复发病和病毒脱落。这项工作意义重大，因为了解如何最好地 增强预先存在的生殖器常驻单纯疱疹病毒特异性免疫细胞将是提高治疗效果的关键 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.