An Orally Delivered Booster Vaccine Candidate for Hepatitis B

描述（由申请人提供）：全球有3.5亿慢性乙型肝炎病毒感染者，他们有肝硬化和肝癌的高风险，每年约有100万人死亡。这是一个惊人的速度，因为市场上已经有一种安全有效的疫苗20多年了。生产、分销和管理的高成本限制了这种疫苗在发展中国家的使用。诊所就诊的不便和对注射的恐惧限制了全世界的依从性。美国国立卫生研究院的目标是开发新的疫苗和递送技术，使疫苗接种覆盖率更高。这项研究的长期目标是开发一种在环境温度下安全、有效和稳定的口服疫苗，并降低生产、分销和交付成本，同时提高依从性。这个项目最初的重点是为高危人群和反应不良者提供乙肝强化治疗。基于植物的生产系统有可能达到理想口服疫苗的目标。这些在动物试验中显示出巨大的希望，包括在人体临床试验中植物产生的乙型肝炎抗原引起免疫反应的能力。然而，由于抗原低表达和加工限制所施加的实际限制，该技术的发展受到限制。在第一阶段，乙肝抗原水平增加了30多倍，并建立了保留抗原完整性的加工方法。这种改进的材料能够引起强大的免疫反应，当口服给老鼠。在第二阶段，研究的重点是优化和表征可以商业化的最终产品。这包括1)高表达系的优化和表征，2)提供美味和稳定产品形式的加工方法，以及3)小鼠免疫反应，使其产生与注射疫苗相当的保护反应。二期目标的成功完成将导致临床试验，并与人类健康合作伙伴走上商业化道路。

DESCRIPTION (provided by applicant): There are 350 million people chronically infected with hepatitis B virus who have a high risk for cirrhosis of the liver and liver cancer resulting in approximately a million deaths annually. This is an alarming rate as there has been a safe and efficacious vaccine on the market for more than twenty years. High costs of production, distribution and administration have limited use of this vaccine in developing nations. The inconvenience of clinic visits and fear of injections restrict compliance worldwide. It is an NIH goal to develop new vaccines and delivery technologies that allow more complete vaccination coverage. The long-term objective of this research is to develop an oral vaccine that is safe, effective and stable at ambient temperatures, as well as reducing costs of production, distribution and delivery while boosting compliance. The initial focus of this project is for hepatitis B booster treatments for at-risk individuals and poor responders. Plant-based production systems have the potential to meet the goals of the ideal oral vaccine. These have shown great promise in animal trials including the ability of a plant-produced hepatitis B antigen to elicit an immune response in a human clinical trial. However, development of this technology has been limited because of the practical limitations imposed by low expression of the antigen and processing constraints. In Phase I, hepatitis B antigen levels were increased by more than 30-fold and processing methods were established that retained the antigen integrity. This improved material was able to elicit a robust immune response when orally fed to mice. In Phase II, the research is focused on optimizing and characterizing a final product that can be commercialized. This includes 1) optimization and characterization of a high expressing line, 2) a processing method that provides a palatable and stable form of the product, and 3) an immune response in mice so that it elicits a comparable protective response as that of the injected vaccine. Successful completion of Phase II aims will lead to a clinical trial and to a commercialization path with a human health partner.