Durable HIV Vaccine Targeting Mucosal Epithelium

针对粘膜上皮的耐用 HIV 疫苗

• 批准号: 10548066
• 负责人: Marie-Claire Elisabeth Gauduin
• 金额: $ 98.99万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548066
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animals; Antibodies; Antigen Presentation; Antigens; Antiviral Response; Attenuated; Attenuated Vaccines; Biopsy; Cells; Clinical Trials; Cross-Priming; Cytomegalovirus; Data; Daughter; Development; Dose; Epithelial; Epithelial Cells; Female; Genome; HIV; HIV Infections; HIV vaccine; Histologic; Human; Immune Targeting; Immune response; Immune system; Immunization; ImmunoPET; Infection; Infection Control; Lentivirus; Lentivirus Vector; Macaca; Macaca mulatta; Manuscripts; Measures; Modeling; Modification; Monkeys; Mucosal Immune Responses; Mucous Membrane; Pathogenicity; Penetration; Phase; Positron-Emission Tomography; Preparation; Production; Proliferating; Proteins; Recurrence; Resolution; Risk Reduction; SIV; Safety; Site; Solid; Source; Stimulus; Stratum Basale; System; T cell response; T-Lymphocyte; Testing; Time; Tissues; Translating; Translations; Vaccinated; Vaccination; Vaccine Antigen; Vaccinee; Vaccines; Vagina; Viral; Viral Antigens; Viral Vector; Virus; Virus Replication; base; chronic infection; clinical efficacy; draining lymph node; efficacy study; epidermal stem cell; epithelial stem cell; follow-up; improved; in vivo; infection risk; involucrin; keratinocyte differentiation; lymphoid organ; mucosal site; mutant; novel vaccines; offspring; pathogen; preclinical trial; prevent; promoter; rectal; reproductive; reproductive tract; response; time use; transmission process; vaccination strategy; vaccine delivery; vaccine platform; vaccine strategy; vector vaccine; viral transmission

Abstract The impressive amount of data generated by experimental HIV/SIV vaccines has led to the realization that protection will most likely requires 2 levels of barriers, the initial one at the mucosal port of entry and if breached, a second set of systemic defenses. The capacity of humoral and cellular immune responses in mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound impact on the ability of a vaccinated host to resist infection, even in the case when virus progresses beyond the port of entry, allowing the systemic response more time to control or eradicate the incoming pathogen. We hypothesized that there are two necessary features for a successful vaccine: 1) A prolonged if not life-long stimulation of the immune system with viral antigens to maintain “alert” immune responses; and 2) a targeted immune response at the site of primary replication of HIV. A vaccine approach that simultaneously addresses these two issues would have the potential to achieve solid, long-term active protection. To fulfill these requirements, we have developed an original strategy to successfully deliver a vaccine to mucosal sites that provide antigen stimuli at recurrent intervals and elicit protective mucosal immune responses. Our strategy leverages epithelial stem cells as permanent but non-expressing source of viral antigen while their differentiated offspring express and present antigen to the local immune system, along the reproductive cycle. Using a single cycle SIV (SIVsc) approach, which has been shown to be safe compared to traditional attenuated vaccines, we have cloned the SIVsc genome under the control of the involucrin promoter (pINV- SIVsc), a terminally differentiated keratinocyte specific promoter. When administered, the vaccine targets and transduces basal epithelial stem cells from vaginal tissues. These then proliferate and differentiate into mature epithelial cells, triggering SIV antigen expression via the promoter and leading to both direct and cross priming. For this project, we propose: 1) To confirm and further improve the efficacy and safety profile of the pINV-SIVsc vaccine in female macaques; 2) To visualize and optimize vaccine delivery, and investigate the mechanisms of action underlying protection; and, 3) Using our best optimized vaccine strategy, demonstrate protection from virus acquisition and/or viral replication in vivo and determine the correlates of protection or control against repeated low-dose vaginal challenges with heterologous SIV.

摘要