Phase I therapeutic testing of viral-vectored vaccines that shift CD8+ T cell immunodominance to conserved regions of HIV-1

将 CD8 T 细胞免疫优势转移至 HIV-1 保守区域的病毒载体疫苗的 I 期治疗测试

• 批准号: 9322698
• 负责人: Nilu Goonetilleke
• 金额: $ 101.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322698
• 关键词: American; Antigens; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cell physiology; Cells; Clinical Trials; Combined Modality Therapy; Consensus; Development; Drug usage; Economics; Epidemic; Epitopes; Frequencies; Generations; Genetic Transcription; Goals; Grant; HIV; HIV Infections; HIV Seronegativity; HIV vaccine; HIV-1; Health Care Costs; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunology; Immunotherapy; In Vitro; Income; Individual; Interphase Cell; Interruption; Length; Life; Measures; Modified Vaccinia Virus Ankara; Mosaicism; National Institute of Allergy and Infectious Disease; One-Step dentin bonding system; Participant; Pharmaceutical Preparations; Phase; Proteins; Protocols documentation; Regimen; Reporting; Research Personnel; Safety; Standardization; Stigmatization; T cell response; T-Lymphocyte; Testing; Therapeutic; Translations; Universities; Ursidae Family; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Vector; Virus; aging population; antiretroviral therapy; arm; base; cytotoxic; design; experience; immunogenic; improved; innovation; killings; lymph nodes; novel; novel vaccines; response; success; therapeutic evaluation; vaccine evaluation; vaccine trial; vector; vector vaccine; virology

1.2 million Americans are currently infected with human immunodeficiency virus-1 (HIV). The advent of combination antiretroviral therapy (cART) successfully contains viral proliferation, preserving CD4+ T cell counts and prolonging life. However, HIV infection is still associated with significant stigmatization, and life-long cART treatment, in an ageing population, bears significant societal health costs. ‘HIV cure’ is defined as therapies to take HIV infected individuals off life-long cART. Cure would not only have societal and economic benefits but would also be a critical advance in ending the global HIV epidemic. The challenge for HIV curative strategies is that long-lived resting cells, principally CD4+ T cells, harbor replication-competent virus which can stochastically reactivate. The result is that, for most people, interruption of cART results in HIV rebound within weeks. Curative strategies for HIV largely involve combination therapies, drugs to drive reactivation of HIV and immune-based therapies to detect and clear the reactivated cells. In this study, we propose a first-in-human trial of a novel vaccine regimen which aims to elicit an arm of our immune response, called CD8+ T cells. CD8+ T cells are very effective at detecting virus infected cells. The vaccine regimen called, ChAdOx1.tHIVconsv5–MVA.tHIVconsv3 was developed by our collaborator at the University of Oxford. A previous iteration of this vaccine induced very high CD8+ T cells against HIV. The key features of this vaccine is that it shifts the T cell response to conserved HIV regions that limit the ability of HIV to evade the immune response. In this study, HIV infected durably suppressed participants will be sequentially vaccinated with ChAdOx1.tHIVconsv5 and MVA.tHIVconsv3. We will thoroughly characterize the safety profile of these vaccines. We will also use standardized assays to measure the level of T cells induced by vaccination and investigate whether vaccination has any impact on very low levels of HIV in our participants. Exploratory studies will examine whether we can detect vaccine-induced T cells that target HIV in lymph nodes and also whether checkpoint inhibitor molecules can be used in concert with vaccination to maximize T cell function. The first vaccine study will be followed by a second related study. The second study builds on the first, by examining whether mosaic vaccines (vaccines designed to increase coverage of HIV) can further improve on the conserved immunogen design of ChAdOx1.tHIVconsv5–MVA.tHIVconsv3.

目前有120万美国人感染了人类免疫缺陷病毒-1 （HIV）。的出现