CD180 targeted immunotherapeutic for chronic HBV in HIV infected patients

CD180靶向免疫疗法治疗HIV感染者的慢性乙型肝炎

• 批准号: 9913651
• 负责人: Deborah H. Fuller
• 金额: $ 90.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-18 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913651
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animals; Anti-Retroviral Agents; Antibodies; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Apoptosis; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cessation of life; Chronic; Chronic Hepatitis B; Cirrhosis; DNA Vaccines; Dendritic Cells; Development; Dose; Exhibits; Face; Fc domain; Formulation; Frequencies; Geography; HIV; HIV Seronegativity; Health; Hepatitis B Antigens; Hepatitis B Core Antigen; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B Virus; Human; IgG1; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Immunity; Immunization; Immunocompromised Host; Immunodeficient Mouse; Immunoglobulin Variable Region; Immunotherapeutic agent; Immunotherapy; Impairment; Individual; Infection; Interruption; Lead; Light; Liver diseases; Macaca; Macaca mulatta; Malignant Neoplasms; Malignant neoplasm of liver; Mature B-Lymphocyte; Mediating; Memory; Modeling; Mus; Patients; Pattern recognition receptor; Pharmacotherapy; Population; Prevalence; Primary carcinoma of the liver cells; Proteins; Recombinant Proteins; Regimen; Regulatory T-Lymphocyte; Risk; Route; SIV; SLEB2 gene; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Vaccination; Vaccines; Viral Antigens; Viral Load result; Work; anti-PD1 antibodies; base; checkpoint receptors; co-infection; exhaustion; experimental study; immune checkpoint; immunogenic; immunogenicity; improved; novel vaccines; pre-clinical; response; therapeutic vaccine; transmission process; vaccine immunotherapy

PROJECT SUMMARY Chronic HBV (CHB) infection in HIV infected patients is six times more likely to lead to chronic cirrhosis, end stage liver disease and hepatocellular carcinomas than the HIV negative population. Immunotherapies that improve HBV-specific immunity in HIV-negative patients with chronic hepatitis B (CHB) could reduce this risk but vaccine immunogenicity in HIV infected patients is significantly compromised due to persistent immune dysfunction in this population. As a result, HBV vaccines that are highly effective even in the setting of immune dysfunction are needed. To address this, we developed a novel vaccine platform capable of inducing strong immune responses even in immunodeficient individuals. HBV antigens (HBsAg, HBcAg) are fused to an antibody (Ab) specific for the pattern recognition receptor CD180/RP105 (anti-human CD180). Our preliminary results in mice and rhesus macaques show that our CD180 vaccine platform induces robust, polyfunctional T cell responses and antibody that exceed levels induced by traditional recombinant protein vaccines. This remarkable potency is achieved by activating Ag-specific B cells including immature B cells to become efficient Ag presenting cells (APCs) and CD180-based vaccines retain immunogenic potency even in immunodeficient mice lacking mature B cells. By circumventing traditional antigen presentation pathways, we propose that our HBV-αCD180 vaccine will overcome limitations of current HBV vaccines and induce strong HBV specific immune responses in immunodeficient HIV infected patients. We will investigate this hypothesis in a preclinical SIV macaque model for AIDS. Our aims will 1) determine the optimum immunization regimen to induce strong HBV specific antibody and CD4+ and CD8+ T cell responses in chronically SIV infected rhesus macaques receiving antiretroviral drug therapy and 2) Determine if co-administration of a checkpoint inhibtor enhances the immunogenicity of the lead CD180scAb-HBV vaccine regimen in ART treated SIV infected rhesus macaques. If successful, this work will support further development of the HBV-αCD180 vaccine platform for immunotherapy of chronic HBV in HIV infected patients.

项目总结 HIV感染者慢性乙肝(CHB)感染导致慢性肝硬变的可能性是后者的六倍 分期肝病和肝细胞癌的人群比HIV阴性人群。免疫疗法 提高HIV阴性慢性乙型肝炎(CHB)患者的乙肝病毒特异性免疫可降低这一风险 但是，由于持续免疫，艾滋病毒感染者的疫苗免疫原性显著降低。 这一人群中的功能障碍。因此，即使在免疫设置中也是高效的乙肝疫苗 功能障碍是必要的。为了解决这个问题，我们开发了一种新的疫苗平台，能够诱导强烈的 即使在免疫缺陷的个体中也有免疫反应。将乙肝病毒抗原(乙肝表面抗原、乙肝核心抗原)与 模式识别受体CD180/RP105(抗人CD180)的特异性抗体。我们的预赛 在小鼠和猕猴身上的结果表明，我们的CD180疫苗平台诱导了强大的、多功能的T细胞 超过传统重组蛋白疫苗诱导的细胞反应和抗体水平。这 通过激活抗原特异的B细胞，包括未成熟的B细胞，使其变得有效，从而实现了非凡的效力 抗原提呈细胞(APC)和基于CD180的疫苗即使在免疫缺陷的情况下也保持免疫原性 缺乏成熟B细胞的小鼠。通过绕过传统的抗原呈递途径，我们提出了我们的 HBVCD180HBVCD180疫苗将克服现有α疫苗的局限性，诱导出强烈的HBV特异性 免疫缺陷的HIV感染者的免疫反应。我们将在临床前研究这一假设 艾滋病的SIV猕猴模型。我们的目标是：1)确定最佳免疫方案，以诱导更强的 慢性SIV感染恒河猴的乙肝病毒特异性抗体和CD4+、CD8+T细胞反应 接受抗逆转录病毒药物治疗和2)确定联合使用检查点抑制物是否增强 先导CD180scAb-乙肝疫苗方案治疗SIV感染恒河猴的免疫原性研究 猕猴。如果成功，这项工作将支持α-CD180CD180疫苗平台的进一步开发 HIV感染者慢性乙肝的免疫治疗。