DEVELOPMENT OF HEPATITIS C VIRUS-LIKE PARTICLES AS CANDIDATE HCV VACCINE

开发丙型肝炎病毒样颗粒作为候选 HCV 疫苗

• 批准号: 7957879
• 负责人: Krishna K Murthy
• 金额: $ 20.69万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957879
• 关键词: Adjuvant; Animals; CD8B1 gene; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Epidemic; Funding; Grant; HCV Vaccine; Hepatitis C virus; Immune response; Immunity; Immunization; Infection; Infection prevention; Infectious hepatitides; Insecta; Institution; Interleukin-2; Lymphocyte; Modeling; Mus; Pan Genus; Papio; Peripheral; Primates; Recombinants; Research; Research Personnel; Resources; Source; Structural Protein; T-Lymphocyte; Time; United States National Institutes of Health; Vaccinated; Vaccines; Viral; Viremia; Virion; Virus-like particle; falls; immunogenicity; intrahepatic; response; vaccine efficacy; viral RNA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. At the present time, no vaccines to prevent infection with HCV are available and the epidemic continues unabated worldwide. The objectives of this study are to develop a candidate HCV vaccine consisting of HCV-like particles and to evaluate the immunogenicity of the vaccine in the chimpanzee model. Four HCV na¿ve chimpanzees were immunized with HCV-VLP vaccine formulated with adjuvants and immunostimulatory complexes. The vaccinated animals have been challenged with infectious HCV to determine the efficacy of the vaccine preventing infection. Recombinant hepatitis C virus (HCV)-like particles (HCV-LPs) containing HCV structural proteins (core, E1, and #2) produced in insect cells resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice and baboons. Here, we present evidence on the immunogenicity and induction of protective immunity by HCV-LPs in chimpanzees. Chimpanzees (two in each group), were immunized with HCV-LPs or HCV-LPs plus AS01B adjuvant. After immunizations, all animals developed an HCV-specific immune response including IFN-¿+, IL-2+, CD4+, and CD8+ T cell and proliferative lymphocyte responses against core, E1, and #2. Upon challenge with an infectious HCV inoculum, one chimpanzee developed transient viremia with low HCV RNA titers (103 to 104 copies per ml) in the third and fourth weeks after the challenge. The three other chimpanzees became infected with higher levels of viremia (104 to 105) copies per ml), but their viral levels became unquantifiable (103 copies per ml) 10 weeks after the challenge. After the HCV challenge, all four chimpanzees demonstrated a significant increase in peripheral and intrahepatic T cell and proliferative responses against the HCV structural proteins. These T cell and proliferative responses coincided with the fall in HCV RNA levels. four na¿ve chimpanzees were infected with the same HCV inoculum, and three developed persistent infection with higher viremia in the range of 105 to 106 copies per ml. Our study suggests that HCV-LP immunization induces HCV-specific cellular immune responses that can control HCV challenge in the chimpanzee model.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 目前，还没有预防丙型肝炎病毒感染的疫苗，并且该流行病在全球范围内继续有增无减。本研究的目的是开发一种由丙型肝炎病毒样颗粒组成的候选丙型肝炎疫苗，并评估该疫苗在黑猩猩中的免疫原性。四种 HCV na¿使用由佐剂和免疫刺激复合物配制的 HCV-VLP 疫苗对 5 只黑猩猩进行免疫接种，并用传染性 HCV 攻击接种疫苗的动物，以确定疫苗预防感染的功效。 昆虫细胞中产生的含有 HCV 结构蛋白（核心、E1 和 #2）的重组丙型肝炎病毒 (HCV) 样颗粒 (HCV-LP) 与假定的 HCV 病毒颗粒相似，能够诱导强烈而广泛的体液和细胞免疫反应在这里，我们提供了黑猩猩（每组两只）中 HCV-LP 的免疫原性和诱导保护性免疫的证据。用HCV-LP或HCV-LP加AS01B佐剂进行免疫接种后，所有动物均产生包括IFN-¿的HCV特异性免疫反应。 +、IL-2+、CD4+ 和 CD8+ T 细胞和增殖淋巴细胞针对核心、E1 和 #2 的反应 在受到感染性 HCV 接种物攻击后，一只黑猩猩出现了短暂的病毒血症，HCV RNA 滴度较低（每份 103 至 104 个拷贝）。 ml）在攻击后的第三周和第四周，其他三只黑猩猩感染了更高水平的病毒血症（每人104至105）。 ml），但在 HCV 攻击后 10 周，它们的病毒水平变得无法量化（103 个拷贝/ml），所有四只黑猩猩的外周和肝内 T 细胞以及针对 HCV 结构蛋白的增殖反应均显着增加。细胞和增殖反应与 HCV RNA 水平下降同时发生。 5 只黑猩猩感染了相同的 HCV 接种物，其中 3 只出现了持续性感染，病毒血症水平高达 105 至 106 拷贝/毫升。我们的研究表明，HCV-LP 免疫可诱导 HCV 特异性细胞免疫反应，从而控制 HCV 攻击。黑猩猩模型。