Enhancing Immunogenicity of VLV-Based Vaccines for Treatment of Chronic HBV

增强基于 VLV 的疫苗治疗慢性乙型肝炎的免疫原性

• 批准号: 9551368
• 负责人: Valerian Nakaar
• 金额: $ 22.47万
• 依托单位: CAROGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-05 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9551368
• 关键词: Acute; Address; Adopted; Affect; Animals; Antibodies; Antibody Response; Antigens; Antiviral Therapy; Attenuated; B-Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Capital; Cells; Cellular Immunity; Chronic; Chronic Hepatitis B; Cirrhosis; Communicable Diseases; Coupled; Data; Dependovirus; Development; Disease; Dose; Engineering; Genes; Glycoproteins; Goals; HIV; Health; Hepatitis B; Hepatitis B Antigens; Hepatitis B Core Antigen; Hepatitis B Therapy; Hepatitis B Vaccines; Hepatitis B Virus; Human; Human Papillomavirus; Immune response; Immune system; Immunity; Immunization; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Infection prevention; Liver; Liver diseases; Malaria; Malignant Neoplasms; Mediating; Modality; Mus; Patients; Phase; Phase I Clinical Trials; Polymerase; Polyproteins; Prevention; Primary carcinoma of the liver cells; Publications; Publishing; Recombinant DNA; Recombinant Proteins; Refractory; Regimen; Research; Risk; Safety; Series; Specificity; Surface; System; T cell response; T-Lymphocyte; Technology; Testing; Transgenic Mice; Treatment Efficacy; Vaccinated; Vaccine Design; Vaccine Therapy; Vaccines; Vesicle; Vesicular stomatitis Indiana virus; Viral Antigens; Viral Genome; Viral Structural Proteins; Viral Vaccines; Virus; Virus Diseases; Virus-like particle; base; chronic liver disease; clinical candidate; commercial application; commercialization; design; efficacy testing; immunogenic; immunogenicity; improved; infectious disease treatment; innovation; mouse model; neurovirulence; neutralizing antibody; novel strategies; novel vaccines; response; technological innovation; therapeutic immunization; therapeutic vaccine; treatment strategy; vaccine candidate; vaccine development; vector; vector vaccine

PROJECT SUMMARY/ABSTRACT The host T cell response to HBV is vigorous and multi-specific in acutely infected patients who clear the virus, but it is weak and more narrowly focused in those who become chronically infected. Therefore, although the human immune response is capable of eliminating the infection, it often fails to do so. Therapeutic immunization to induce an immune response sufficient to control the virus is a possible new approach for treating chronic hepatitis B. Unfortunately however the current HBV vaccine is not effective for therapeutic vaccination. Although it elicits a strong neutralizing antibody response that prevents infection, the current vaccine does not induce the potent CD8 T cell response needed to eliminate the virus after infection. An important step forward would be to develop immune therapy approaches that induce both CD8 cellular immunity and effective antibodies in vaccinated individuals. The VLV technological innovation under development is capable of inducing both a robust antibody responses as well as multi-specific CD8 T-cell responses addressing the need for HBV immunotherapy. We have previously found that an improved version of the reverse-engineered platform that generates “virus-like vesicles” (VLVs) containing VSV-G but no other viral structural proteins are safe, are genetically stable and lack neurovirulence in mice. Employing this evolved VLV vector engineered to express the HBV middle surface envelope glycoprotein (MHBs) we have found that it induces CD8 T cell responses in mice that were greater in magnitude and broader in specificity than those obtained with other immunization strategies, including recombinant protein and DNA. A prime-boost immunization enhanced CD8 T cell responses in naïve mice and that regimen induced HBV-specific CD8 T cells in a transgenic mouse model of CHB infection. We have rationally designed and engineered a VLV vaccine that encompasses multiple antigens of the HBV genome and show that this multimeric vaccine induces CD8- specific T cells in a single immunization. We have further engineered these polyproteins to be secreted. We will now test the hypothesis that the secreted versions of the non-secreted VLV-Multi-Antigen constructs will not only drive both a superior cell-mediated and antibody immunity but would also increase the breadth and magnitude of these responses when compared to a single antigen MHBs antigen construct. To evaluate our hypothesis, we will carry out three specific aims. First, we will characterize the immune response to the VLV-Multi-Antigen vectors in normal mice. Second, we will develop and optimize a prime- boost strategy in order to enhance the immune responses to these vectors. Finally, we will establish milestones for phase II development. The propose research is significant because an effective therapeutic vaccine that cures chronic HBV would have a substantial impact on the prevention of HBV-associated chronic liver diseases.

项目概要/摘要 在急性感染患者中，宿主 T 细胞对 HBV 的反应强烈且具有多特异性。 病毒，但它的强度较弱，并且更集中于那些慢性感染者。 因此，虽然人体免疫反应能够消除感染，但往往无法消除感染。 这样做。诱导足以控制病毒的免疫反应的治疗性免疫是一种 治疗慢性乙型肝炎的可能新方法。不幸的是，目前的乙型肝炎疫苗 对于治疗性疫苗接种无效。虽然它会引起强烈的中和抗体反应 预防感染，目前的疫苗不能诱导有效的 CD8 T 细胞反应 感染后消灭病毒。向前迈出的重要一步是开发免疫疗法 在接种疫苗的个体中诱导 CD8 细胞免疫和有效抗体的方法。 正在开发的 VLV 技术创新能够诱导产生强大的抗体 反应以及满足 HBV 需求的多特异性 CD8 T 细胞反应 免疫疗法。我们之前发现了一个改进版本的逆向工程平台 产生含有 VSV-G 的“病毒样囊泡”（VLV），但其他病毒结构蛋白都不安全， 在小鼠中遗传稳定且缺乏神经毒力。采用这种进化的 VLV 载体设计 表达 HBV 中表面包膜糖蛋白 (MHB)，我们发现它诱导 CD8 T 细胞 小鼠的反应比其他方法获得的反应幅度更大、特异性更广泛 免疫策略，包括重组蛋白和DNA。增强免疫增强 初始小鼠体内的 CD8 T 细胞反应以及该方案在转基因小鼠体内诱导了 HBV 特异性 CD8 T 细胞 CHB感染小鼠模型。我们合理设计和制造了VLV疫苗 包含 HBV 基因组的多种抗原，并表明这种多聚体疫苗可诱导 CD8- 单次免疫中的特异性 T 细胞。我们进一步设计了这些多蛋白以使其分泌。我们 现在将检验非分泌型 VLV-多抗原构建体的分泌型版本的假设 不仅会驱动卓越的细胞介导免疫和抗体免疫，而且还会增加免疫广度 以及与单一抗原 MHBs 抗原构建体相比时这些反应的强度。到 评估我们的假设，我们将实现三个具体目标。首先，我们要了解免疫的特征 正常小鼠对 VLV-多抗原载体的反应。其次，我们将开发和优化主要 加强策略以增强对这些载体的免疫反应。最后，我们将建立 第二阶段开发的里程碑。这项研究意义重大，因为有效的治疗方法 治愈慢性乙型肝炎的疫苗将对预防乙型肝炎相关疾病产生重大影响 慢性肝脏疾病。