An Orally Delivered Booster Vaccine Candidate for Hepatitis B

描述(申请人提供)：有3.5亿慢性乙肝病毒感染者，他们有很高的肝硬变和肝癌风险，每年导致约100万人死亡。这是一个令人震惊的速度，因为市场上已经有20多年的安全有效的疫苗了。高昂的生产、分销和管理成本限制了这种疫苗在发展中国家的使用。就诊的不便和对注射的恐惧限制了全球范围内的合规。NIH的目标是开发新的疫苗和交付技术，以实现更全面的疫苗接种覆盖。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，并在提高遵从性的同时降低生产、分配和交付的成本。该项目最初的重点是为高危人群和反应差的人提供乙肝强化治疗。以植物为基础的生产系统有可能实现理想的口服疫苗的目标。这些在动物试验中显示出巨大的希望，包括植物产生的乙肝抗原在人类临床试验中引发免疫反应的能力。然而，由于抗原的低表达和工艺的限制，这项技术的发展受到了实际的限制。在第一阶段，乙肝抗原水平增加了30多倍，并建立了保持抗原完整性的加工方法。这种改进的材料能够在口服给小鼠时引起强大的免疫反应。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)高表达系的优化和鉴定，2)提供可口和稳定形式的产物的加工方法，以及3)在小鼠中的免疫反应，使其引起与注射疫苗类似的保护反应。第二阶段AIMS的成功完成将导致临床试验和与人类健康合作伙伴的商业化道路。

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.