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.

项目摘要/摘要 在急性感染的患者中，宿主T细胞对HBV的反应是剧烈而多特异的，他们清除了 该病毒，但它是虚弱的，更狭窄地专注于那些长期感染的人。 因此，尽管人类免疫响应能够消除感染，但通常无法 这样做。治疗性免疫抑制诱导足以控制病毒的免疫响应是一个 不幸的是，目前的HBV疫苗可能是治疗慢性丙型肝炎的可能的新方法 尽管它引起了强烈的中和抗体反应 阻止感染的，当前的疫苗不会引起 感染后消除病毒。向前迈出的重要一步是开发免疫治疗 影响CD8细胞免疫学和有效抗体的方法。 正在开发的VLV技术创新能够诱导强大的抗体 响应以及多特异性CD8 T细胞响应，以满足HBV的需求 免疫疗法。我们以前已经发现，反向工程平台的改进版本 会产生包含VSV-G的“病毒状蔬菜”（VLV），但没有其他病毒结构蛋白是安全的， 在遗传上稳定并且缺乏小鼠的神经病毒。采用这种进化的VLV矢量设计为 表达HBV中表面包膜糖蛋白（MHB），我们发现它诱导了CD8 T细胞 小鼠的反应在大小和特异性方面的特异性更大，与其他人获得的反应更广泛 免疫策略，包括重组蛋白和DNA。促进促进免疫增强 幼稚的小鼠的CD8 T细胞反应，该方案在转基因中诱导HBV特异性CD8 T细胞 CHB感染的小鼠模型。我们采用合理设计和设计了一种VLV疫苗 包括HBV基因组的多种抗原，并表明该多药疫苗可诱导CD8- 单个免疫抑制中的特定T细胞。我们进一步设计了这些多蛋白要分泌。我们 现在将检验以下假设，即未分泌的VLV-Multi-Antigen构造的分泌版本 不仅会驱动出色的细胞介导的和抗体免疫史，而且还会增加宽度 与单个抗原MHB抗原构建体相比，这些反应的大小。到 评估我们的假设，我们将执行三个具体目标。首先，我们将表征免疫 对正常小鼠中VLV-multi-antigen载体的反应。其次，我们将开发并优化一个主要 促进策略以增强对这些向量的免疫反应。最后，我们将建立 II期发展的里程碑。提案研究很重要，因为有效的疗法 治愈慢性HBV的疫苗对预防HBV相关会产生重大影响 慢性肝病。