Plant-Derived hepatitis B Vaccine from Biomanufacturing System to Clinical Trial

植物源乙型肝炎疫苗从生物制造体系到临床试验

• 批准号: 7686304
• 负责人: Robert G. Britt
• 金额: $ 64.27万
• 依托单位: QUANTUM TUBERS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686304
• 关键词: AIDS/HIV problem; Address; Adjuvant; Adult; Antibodies; Antibody Formation; Antigens; Applications Grants; Award; Biological Response Modifier Therapy; Biomanufacturing; Biomass; Businesses; Cessation of life; Child; Clinical Trials; Cold Chains; Combined Vaccines; Computers; Containment; Controlled Environment; Data; Deglutition; Developing Countries; Development; Discipline; Documentation; Dosage Forms; Dose; Double-Blind Method; Drug Formulations; Drug Industry; Economic Models; Economics; Effectiveness; Engineering; Environment; Evaluation; Farming environment; Food Chain; Genes; Genetic Engineering; Genome; Goals; Government Agencies; Growth; Health; Hepatitis B; Hepatitis B Antigens; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B Virus; Human; Immune response; Immunity; Immunization; Individual; Infection; Ingestion; Laboratories; Lead; Licensing; Life; Liquid substance; Marketing; Measurable; Measures; Methods; Modeling; Mucosal Immune Responses; Mus; Needles; Nose; Oral; Oral cavity; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Placebo Control; Plant Leaves; Plants; Population; Potato; Pre-Clinical Model; Process; Production; Proteins; Recombinants; Refrigeration; Regulation; Research; Running; Safety; Scheme; Serum; Site; Small Business Innovation Research Grant; System; Technology; Testing; Time; Transgenic Organisms; Vaccination; Vaccine Production; Vaccines; Validation; base; commercialization; cost; design; discount; dosage; human subject; hypodermic needle; immunogenicity; in vivo; mucosal site; next generation; oral vaccine; pathogen; plant genetics; prevent; programs; prototype; public health relevance; quantum; research and development; scale up; vaccine delivery; volunteer

DESCRIPTION (provided by applicant): The ability of plants to be used as factories for the production of biopharmaceuticals has the potential to dramatically cut costs of production of many current biotherapeutics and will encourage development of new drugs and vaccines that can be genetically inserted into the genome of certain plants. Production via plants by growing biomass from plants that are genetically engineered to carry a specific biopharma product will allow for a fast and cost-effective multiplication of drugs that can be delivered to consumers at a substantial discount, and will allow numerous other advantages from current production methods. A significant roadblock to the production of plant-made-pharmaceuticals is the fact that plant materials containing a pharmaceutical gene could escape into the wild and genetically contaminate the food chain. To prevent escape of transgenic materials strict regulations have been put into effect by government agencies as a matter of oversight. In fact, it is not actually possible, nor is it practical to grow a crop of pharmaceutical plants in a farm production field, consequently, the need to produce pharmaceutical crops in fully controlled containment facilities that accommodate zero-tolerance regulations are now a necessity for entry into the plant biomanufacturing business and a biomanufacturing system to address these problems is a focus of this SBIR. In the current application we provide an example of a plant-made-pharmaceutical (recombinant hepatitis B vaccine) that we propose to take all the way from large scale controlled containment growth, secondary processing to provide stable shelf life and a human clinical trial in healthy adult volunteers. The award of the Phase I SBIR allowed us to establish the biomanufacturing baseline for measuring the antigen production levels of several HBsAg varieties of potato, for selection for highest antigen yield and increased production levels of the plant biomass. The plant production system being tested was developed by the SBIR Company, Quantum Tubers Corporation, and provides up to six crops per year in a computer controlled, modular system designed for biomanufacturing of potato plants. The QT Biomanufacturing System can provide as much as 36:1 production advantage over a seasonal greenhouse of the same size, and will provide exact and reproducible growing conditions to increase recombinant hepatitis B vaccine production in a GMP manufacturing environment. The Phase II SBIR application necessarily combines the logical path of progression for documentation of the QT Biomanufacturing System technology combined with the production of hepatitis B vaccine-bearing potatoes, verification of their vaccination potential through a Phase I Clinical Trial of the hepatitis B vaccine produced from the transgenic potato plant, and then the secondary processing of the raw biomass into a stable oral dose. The specific aims of the Phase II SBIR are : A) To quantify the economic production parameters providing for a best growing time vs. yield scenario for growing plant-derived hepatitis B vaccine using the QT Biomanufacturing System. B) To evaluate the safety, tolerability, and immunogenicity of orally delivered HBsAg that is formulated as an expressed protein in transgenic potato tubers (HBV-EPV) administered with a mucosal adjuvant to healthy adult subjects who have evidence of immunity to hepatitis B derived from previous immunization with licensed recombinant hepatitis B vaccine. C) To determine through R&D the most effective secondary processing system for potato leaf and tuber biomass to provide for the formulation of a shelf-stable, oral dosage of (HBsAg) hepatitis B vaccine and to evaluate in a preclinical model the in vivo immunogenicity of the processed material. The completion of this SBIR will bring together a combined set of technologies that will conclude years of research from multiple scientific disciplines that will now culminate in a next-generation set of technologies providing an alternative biotherapeutics production system for the pharmaceuticals industry. This SBIR will validate a new and market-changing technology that will accelerate production, lower delivered costs, provide a safer product, and bring vaccines and other biotherapeutics to the consumer. PUBLIC HEALTH RELEVANCE: More than 2 billion of the global population have been infected with hepatitis B virus estimated to cause 500,000 to 700,000 deaths each year worldwide. Plant-derived hepatitis B vaccine from potatoes grown in controlled environment biomanufacturing facilities will provide for orally administered vaccines that can be manufactured as large quantities of shelf-stable, non-refrigerated, oral vaccines that can dramatically lower global deaths and infections from the hepatitis B virus because of affordability of the vaccination. Our production system would revolutionize worldwide vaccine delivery along with other health programs where biotherapeutics could be employed. Oral vaccination would eliminate many of the problems associated with the current needle delivery method for vaccines including refrigeration ('cold chain" requirements,) storage & handling limitations for liquid vaccines along with the need for hypodermic needles that are regularly reused in third world countries resulting in the spread of hepatitis B and even HIV/AIDS from previously infected individuals. Oral vaccines are not only easier to administer than injected vaccines, allow for compliance in children and adults but they also stimulate both systemic and mucosal immune responses, whereas injected vaccines only lead to serum antibody production. Stimulating an immune response at the mucosal sites (such as the nose and mouth) is very desirable, because many pathogens enter the body at these sites. If an immune response occurs at the mucosal sites, pathogens can be prevented from even entering the body. The overall goals of this project are to document a biomanufacturing system, and to validate a vaccine produced by plants delivered to humans as part of a clinical trial, thus creating an integrated plant-derived vaccines delivery system for worldwide deployment.

描述（由申请人提供）：植物被用作生产生物药品的工厂的能力有可能大大降低许多当前生物治疗药物的生产成本，并将鼓励开发可以遗传地插入某些植物基因组的新药和疫苗。通过种植植物的生物量，通过基因工程的植物来携带特定的生物制药产品，将允许快速和具有成本效益的药物增殖，可以以很大的折扣交付给消费者，并且将从当前的生产方法中获得许多其他优势。植物制造药物的一个重要障碍是，含有药物基因的植物材料可能会逃逸到野外，并在基因上污染食物链。为了防止转基因材料的逃逸，政府机构已经实施了严格的监管规定。事实上，在农场生产领域种植药用植物作物实际上是不可能的，也不现实，因此，现在进入植物生物制造业务必须在完全控制的密闭设施中生产药用作物，以适应零容忍法规，而解决这些问题的生物制造系统是本SBIR的重点。在目前的申请中，我们提供了一个植物制造药物（重组乙型肝炎疫苗）的例子，我们建议从大规模控制的封闭生长，二次加工以提供稳定的保质期，以及在健康成年志愿者中进行人体临床试验。I期SBIR的授予使我们能够建立生物制造基线，用于测量几种HBsAg马铃薯品种的抗原生产水平，以选择最高的抗原产量和增加的植物生物量生产水平。正在测试的植物生产系统是由量子块茎公司的SBIR公司开发的，并在计算机控制的模块化系统中每年提供多达六种作物，该系统专为马铃薯植物的生物制造而设计。QT生物制造系统与相同规模的季节性温室相比，可提供高达36:1的生产优势，并将在GMP生产环境中提供精确和可重复的生长条件，以增加重组乙型肝炎疫苗的生产。二期SBIR申请必须结合QT生物制造系统技术的逻辑进展路径，结合生产携带乙肝疫苗的马铃薯，通过转基因马铃薯植物生产的乙肝疫苗的一期临床试验验证其疫苗接种潜力，然后将原料生物质二次加工成稳定的口服剂量。II期SBIR的具体目标是：A)量化经济生产参数，为使用QT生物制造系统种植植物源性乙型肝炎疫苗提供最佳生长时间和产量方案。B)评估口服HBsAg的安全性、耐受性和免疫原性，该HBsAg是转基因马铃薯块茎（HBV-EPV）中的表达蛋白，与粘膜佐剂一起给药给健康成人受试者，这些受试者有证据表明先前接种过许可的重组乙型肝炎疫苗对乙型肝炎具有免疫力。C)通过研发确定最有效的马铃薯叶和块茎生物质二次加工系统，以提供货架稳定的（HBsAg）口服乙肝疫苗的配方，并在临床前模型中评估加工材料的体内免疫原性。该SBIR的完成将汇集一系列综合技术，这些技术将结束多年来来自多个科学学科的研究，现在将最终形成下一代技术，为制药行业提供可替代的生物治疗生产系统。这项SBIR将验证一项改变市场的新技术，该技术将加速生产，降低交付成本，提供更安全的产品，并将疫苗和其他生物疗法带给消费者。公共卫生相关性：全球有20多亿人口感染了乙型肝炎病毒，估计每年在全世界造成50万至70万人死亡。从受控环境生物制造设施中种植的土豆中提取的植物源性乙型肝炎疫苗将提供口服疫苗，这些疫苗可以制造成大量货架稳定、非冷藏的口服疫苗，由于疫苗接种的可负担性，可以大大降低全球乙型肝炎病毒的死亡和感染。我们的生产系统将彻底改变全球疫苗的交付，以及其他可以使用生物疗法的健康项目。口服疫苗接种将消除与目前疫苗针头递送方法相关的许多问题，包括冷藏（“冷链”要求）、液体疫苗的储存和处理限制，以及第三世界国家经常重复使用皮下注射针头的需求，这些针头会导致乙型肝炎甚至艾滋病毒/艾滋病从以前感染的人那里传播。口服疫苗不仅比注射疫苗更容易接种，允许儿童和成人的依从性，而且还能刺激全身和粘膜免疫反应，而注射疫苗只导致血清抗体的产生。刺激粘膜部位（如鼻和口）的免疫反应是非常可取的，因为许多病原体从这些部位进入人体。如果在粘膜部位发生免疫反应，病原体甚至可以被阻止进入人体。该项目的总体目标是记录一个生物制造系统，并验证由植物生产的疫苗作为临床试验的一部分交付给人类，从而创建一个用于全球部署的综合植物衍生疫苗交付系统。