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.

项目摘要 HIV感染者的慢性HBV（CHB）感染导致慢性肝硬化的可能性是HIV感染者的6倍， 期肝病和肝细胞癌的发病率高于HIV阴性人群。的免疫疗法 提高HIV阴性慢性B型肝炎（CH B）患者HBV特异性免疫力可降低这种风险 但由于持续免疫，HIV感染患者的疫苗免疫原性显著受损， 在这个人群中。因此，即使在免疫环境中也高度有效的HBV疫苗也是不可能的。 功能障碍是必要的。为了解决这一问题，我们开发了一种新的疫苗平台，能够诱导强 免疫反应，甚至在免疫缺陷的人。HBV抗原（HBsAg、HBcAg）融合到 模式识别受体CD 180/RP 105特异性抗体（Ab）（抗人CD 180）。我们的初步 在小鼠和恒河猴中的结果表明，我们的CD 180疫苗平台诱导了稳健的多功能T细胞， 细胞应答和抗体水平超过传统重组蛋白疫苗诱导的水平。这 通过激活Ag特异性B细胞（包括未成熟B细胞）使其变得有效， Ag呈递细胞（APC）和基于CD 180的疫苗即使在免疫缺陷的小鼠中也保留免疫原性效力。 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， HBV-α CD 180疫苗将克服现有HBV疫苗的局限性，诱导强的HBV特异性 免疫缺陷型HIV感染者的免疫应答。我们将在临床前研究中研究这一假设。 SIV猕猴艾滋病模型。我们的目标是：1）确定最佳免疫方案， 慢性SIV感染恒河猴的HBV特异性抗体及CD 4+和CD 8 + T细胞应答 接受抗逆转录病毒药物治疗和2）确定检查点阻断剂的联合给药是否增强 CD 180 scAb-HBV疫苗方案在ART治疗的SIV感染恒河猴中的免疫原性 猕猴如果成功，这项工作将支持HBV-α CD 180疫苗平台的进一步开发， HIV感染者慢性HBV免疫治疗