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

• 批准号: 10040583
• 负责人: Gregg N. Milligan
• 金额: $ 24.94万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-25 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040583
• 关键词: Adjuvant; Animal Model; Antibody Response; Antigens; B-Lymphocytes; Birth; Cavia; Cells; Clinical Trials; Development; Disease; Epithelial; Epithelium; Event; Exposure to; Female; Genital system; 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

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.

项目总结/文摘