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.

项目概要 HIV 感染者的慢性 HBV (CHB) 感染导致慢性肝硬化的可能性是其他人的六倍，结束 阶段性肝病和肝细胞癌的发生率高于免疫疗法阴性人群。 提高 HIV 阴性慢性乙型肝炎 (CHB) 患者的 HBV 特异性免疫力可以降低这种风险 但由于持续免疫，HIV感染者的疫苗免疫原性显着受损 因此，乙肝疫苗即使在免疫环境下也非常有效。 为了解决这个问题，我们开发了一种能够诱导强效的新型疫苗平台。 即使在免疫缺陷个体中，乙型肝炎病毒抗原（HBsAg、HBcAg）也会与抗原融合。 模式识别受体 CD180/RP105（抗人 CD180）特异性抗体 (Ab)。 在小鼠和恒河猴中的结果表明，我们的 CD180 疫苗平台可诱导强大的多功能 T 细胞反应和抗体超过传统重组蛋白疫苗诱导的水平。 通过激活 Ag 特异性 B 细胞（包括未成熟 B 细胞）使其变得高效，从而实现显着效力 即使在免疫缺陷的情况下，Ag 呈递细胞 (APC) 和基于 CD180 的疫苗也能保留免疫原性效力 通过规避传统的抗原呈递途径，我们建议我们的小鼠缺乏成熟的 B 细胞。 HBV-αCD180疫苗将克服现有乙肝疫苗的局限性并诱导强乙肝特异性 我们将在临床前研究这一假设。 艾滋病 SIV 猕猴模型我们的目标是 1) 确定最佳免疫方案以诱导强效免疫。 慢性 SIV 感染恒河猴中 HBV 特异性抗体以及 CD4+ 和 CD8+ T 细胞反应 接受抗逆转录病毒药物治疗以及 2) 确定联合使用检查点抑制剂是否可以增强疗效 主要 CD180scAb-HBV 疫苗方案在 ART 治疗的 SIV 感染恒河猴中的免疫原性 如果成功，这项工作将支持 HBV-αCD180 疫苗平台的进一步开发。 HIV感染者慢性乙型肝炎的免疫治疗。