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

通过新型 Pod 阴道环输送宫颈阴道疫苗，用于 HSV-2 治疗性免疫

基本信息

批准号：
10171554
负责人：
Gregg N. Milligan
金额：
$ 19.65万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-25 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171554
关键词：
Adjuvant Animal Model Antibody Response Antigens B-Lymphocytes Birth Cavia Cells Clinical Trials Development Disease Epithelial Event Exposure to Female genitalia Genital Genitalia Goals HIV HIV Antigens Herpes Simplex Virus Vaccines Human Human Herpesvirus 2 Immune Immune response Immunity Immunization Immunocompetent Immunoglobulin-Secreting Cells Individual Infection Lesion Methods Modeling Morbidity - disease rate Mucous Membrane Newborn Infant Pain Phase I/II Clinical Trial Population Preventive vaccine Recombinants Recurrence Recurrent disease Risk Sexual Transmission Sexually Transmitted Diseases Simplexvirus Site Symptoms T memory cell T-Lymphocyte Testing Therapeutic Treatment Efficacy Ulcer Vaccine Antigen Vaccine Therapy Vaccines Vagina Vaginal Ring Virus Virus Latency Virus Shedding Work antigen-specific T cells cervicovaginal clinical development design efficacy testing experience genital herpes genital infection improved mathematical model novel pathogen protective efficacy reproductive tract response therapeutic candidate therapeutic immunization therapeutic vaccine transmission process vaccine delivery vaccine efficacy vaginal mucosa virus development

项目摘要

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.

项目摘要/摘要单纯疱疹2型（HSV-2）是最常见的性传播病原体之一，是每年在全球范围内负责2000万新感染。 HSV-2生殖器感染是生殖器溃疡疾病，增加了获得其他性传播疾病的可能性艾滋病病毒。 HSV-2感染可能导致免疫能力的自限性疼痛病变发展个人，但是由于免疫受损的人群和新生儿暴露于免疫发病率的原因出生管中的病毒。无症状的脱落发作经常发生在HSV-2感染的个体中使变速箱更有可能。 HSV特异性T细胞和抗体分泌细胞位于重生后，先前的HSV感染和生殖器上皮的清除病毒。加强这个本地治疗免疫对快速控制HSV-2脱落的免疫反应是一种逻辑疫苗策略。全身注射的治疗性HSV-2疫苗在减少病毒脱落和临床试验中的复发性病变率，但需要改善。我们建议直接粘膜刺激生殖器驻留，HSV特异性免疫细胞将使疫苗的功效提高，而疫苗的功效比全身性增强。最近，通过腔内长期递送重组HIV抗原和佐剂到阴道环（IVR）导致发展局部抗体反应，超过了全身性的抗体反应免疫。作为治疗疫苗接种方法的概念验证测试，我们将使用一种新颖的POD-IVR 输送平台将HSV免疫原/佐剂传递到阴道粘膜，量化对增强作用生殖器捕获疫苗抗原特异性B和T细胞种群，并测试疫苗的功效防止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居民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到生殖器上皮将增强生殖道居民，HSV特异性T和B细胞，并增加对HSV-2脱落的控制。我们的目标这些研究是为了检验以下概念：新型豆荚内环将提供的治疗疫苗将强烈提高生殖器居民T和B细胞反应，并将证明有效控制病毒脱落和复发性疾病。该提案的具体目的是：目标1：测试重组HSV-的直接交付 2 GD+GB/ CpG辅助对女性生殖道的辅助pod-ivrs用于治疗免疫 HSV-2;和目标2：测试女性生殖道免疫的保护性保护功效 HSV-2复发性疾病和病毒脱落。这项工作很重要，因为了解如何最好增强先前存在的生殖器居民HSV特异性免疫细胞对于提高提高功效至关重要治疗性疫苗可减少HSV-2传播。