Plant-derived vaccines against hepatitis C Cooperative *

植物源性丙型肝炎疫苗合作社*

• 批准号: 6988567
• 负责人: Charles Joel Arntzen
• 金额: $ 70万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988567
• 关键词: Plant; derived; vaccines; against; hepatitis

DESCRIPTION (provided by applicant): Research in immunology and virology has made enormous progress toward the design of an effective vaccine to prevent Hepatitis C infection, but multidisciplinary efforts are needed to move these designs to the ultimate manufacture of a cost-effective vaccine for global immunization. This proposed Cooperative Research Center (CRC) will critically evaluate a new means to biomanufacture HCV antigens known to induce specific immune responses to HCV - identified through human clinical studies, and predicted to be important in viral clearance - and evaluate responses to these antigens in appropriate in vitro and in vivo model systems. One of the co-Directors of this CRC has lead Chiron's discovery of recombinant antigens from HCV; the evaluation of his currently available suite of proteins in clinical trials indicates that a prophylactic and immunotherapeutic vaccine is feasible. Unfortunately, at least from the standpoint of manufacturing for public health markets, the optimal vaccine should consist of a "cocktail" of multiple antigens to elicit both antibody-mediated and T cell-mediated immune responses. The likely need for two separate protein expression systems to produce this vaccine, one limited by low yields, raises obstacles to commercial development - especially for global use. To overcome these production constraints, this CRC proposes to rapidly utilization current understanding of the properties of important vaccine components to develop and validate a new biomanufacturing system for multiple HCV antigens. A unique feature of this proposed CRC will be the use of green plants as versatile, highly cost-effective production system for recombinant proteins. The research proposed is an interactive partnership that draws upon Chiron's vaccine development expertise to critically evaluate HCV candidate vaccines produced by an academic team that has pioneered the use of plant biotechnology for subunit vaccine manufacture for more than a decade. PROJECT 1: Plant- Derived Envelope Glycoprotein E1/E2 Vaccine for HCV (Mason, H.) PROJECT 1 DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major worldwide agent of acute and chronic hepatitis, with over 3% of the world's population infected and at risk for liver cirrhosis and cancer, and a US cost burden of $1 billion per year. Studies showed that vaccine development should target both antibody and T-cell mediated immunity. Recombinant envelope glycoproteins gpE1 and gpE2 are the leading vaccine candidates for antibody-mediated protection, showing protection in chimpanzee. However, gpE1/gpE2 is currently produced in cultured mammalian cells, with a limited capacity for scale-up to achieve global immunization. Alternatively, production of gpE1/gpE2 in plant systems has the potential for vast scale-up. We hypothesize that: 1) HCV gpE1/gpE2 vaccine can be produced in a plant system in a form that is equivalent to the mammalian cell product used for injection; 2) HCV gpE1/gpE2 vaccine can be scaled up to a commercially competitive level using a leaf or a grain seed-based expression system; and 3) Plant-derived HCV gpE1/gpE2 can stimulate antibody responses when orally delivered by ingestion of minimally processed plant tissue. The specific aims of this proposal will address these questions by using plant-optimized gpE1/gpE2 genes expressed in plants to assess the potential to assemble immunogenic gpE1/gpE2 heterodimers. We will examine tobacco leaf and corn seed expression systems and evaluate gpE1/gpE2 accumulation and quality to select the optimal system. M. Houghton at Chiron Corporation leads their HCV vaccine effort and will direct Project 3 of this HCV Research Center, which will purify gpE1/gpE2 from plant sources and test its immunogenic capacity in animal models. We will furthermore test the potential for use of orally delivered plant-derived gpE1/gpE2 vaccine, with the aim to develop a convenient and economical vaccine for the developing world. If successful, these studies will greatly enhance the capacity to produce an injectable vaccine for HCV, while also offering the possibility to improve worldwide immunization coverage with an oral vaccine.

描述（由申请人提供）：免疫学和病毒学研究在设计预防丙型肝炎感染的有效疫苗方面取得了巨大进展，但需要多学科的努力将这些设计转移到全球免疫的成本效益疫苗的最终制造中。这个拟议的合作研究中心（CRC）将严格评估一种新的生物制造HCV抗原的方法，这种抗原已知可以诱导对HCV的特异性免疫反应-通过人体临床研究确定，并预测在病毒清除中很重要-并在适当的体外和体内模型系统中评估对这些抗原的反应。该CRC的共同主任之一领导了Chiron从HCV中发现重组抗原;他目前在临床试验中可用的蛋白质套件的评估表明，预防性和免疫性疫苗是可行的。不幸的是，至少从制造公共卫生市场的角度来看，最佳疫苗应该由多种抗原的“鸡尾酒”组成，以引发抗体介导的和T细胞介导的免疫应答。生产这种疫苗可能需要两个独立的蛋白质表达系统，其中一个受到产量低的限制，这给商业开发带来了障碍-特别是全球使用。为了克服这些生产限制，本CRC建议快速利用当前对重要疫苗组分性质的理解，开发和验证用于多种HCV抗原的新生物制造系统。该建议的CRC的一个独特特征是使用绿色植物作为重组蛋白的通用、高成本效益的生产系统。这项研究是一种互动的伙伴关系，利用Chiron的疫苗开发专业知识，对一个学术团队生产的HCV候选疫苗进行严格评估，该学术团队十多年来一直率先使用植物生物技术进行亚单位疫苗生产。 项目1：HCV的植物源包膜糖蛋白E1/E2疫苗（Mason，H.） 项目1描述（由申请人提供）：丙型肝炎病毒（HCV）是全球急性和慢性肝炎的主要病原体，世界上超过3%的人口受到感染并处于肝硬化和癌症的风险中，美国每年的成本负担为10亿美元。 研究表明，疫苗开发应针对抗体和T细胞介导的免疫。 重组包膜糖蛋白gpE 1和gpE 2是用于抗体介导的保护的主要疫苗候选物，在黑猩猩中显示出保护作用。 然而，gpE 1/gpE 2目前在培养的哺乳动物细胞中产生，具有有限的扩大规模以实现全面免疫的能力。 或者，在植物系统中生产gpE 1/gpE 2具有大规模扩大的潜力。 我们假设：1）HCV gpE 1/gpE 2疫苗可以在植物系统中以与用于注射的哺乳动物细胞产品等同的形式生产; 2）HCV gpE 1/gpE 2疫苗可以使用基于叶或谷物种子的表达系统按比例放大至商业竞争水平;和3）植物来源的HCV gpE 1/gpE 2当通过摄取最低限度加工的植物组织口服递送时可以刺激抗体应答。 本提案的具体目标将通过使用植物中表达的植物优化的gpE 1/gpE 2基因来评估组装免疫原性gpE 1/gpE 2异二聚体的潜力来解决这些问题。 我们将研究烟草叶片和玉米种子表达系统，并评估gpE 1/gpE 2积累和质量，以选择最佳系统。 M.凯龙公司的霍顿领导他们的HCV疫苗工作，并将指导该HCV研究中心的项目3，该项目将从植物来源纯化gpE 1/gpE 2，并在动物模型中测试其免疫原性能力。 我们将进一步测试口服植物源gpE 1/gpE 2疫苗的潜力，目的是为发展中国家开发一种方便和经济的疫苗。 如果成功，这些研究将大大提高生产HCV注射疫苗的能力，同时也为提高口服疫苗的全球免疫覆盖率提供了可能性。