An Orally Delivered Hepatitis B Vaccine

描述(申请人提供)：乙肝是一个主要的全球健康问题。约有3.5亿慢性感染者有患肝硬变和肝癌的高风险，每年导致近100万人死亡。目前的疫苗年市场规模为10亿美元。然而，这些非肠道注射疫苗的生产、分销和管理成本高昂，限制了它们在发展中国家的使用。此外，诊所就诊的不便和对注射的恐惧限制了发达国家的遵从性。这项研究的长期目标是开发一种在常温下有效和稳定的口服疫苗，降低生产、分配和交付的成本，并提高依从性。我们实验室已经使用玉米来表达病毒和细菌疾病的稳定制剂中的抗原，这些制剂在大型农场动物试验和人类临床试验中口服。候选疫苗耐受性良好，可引发体液和粘膜免疫反应，并在测试中获得保护。在次级粘膜部位观察到的反应，表明这些疫苗对性传播疾病的适用性。它们还可以诱导乳源性反应，这意味着有可能产生被动免疫。这项研究的目标是为高危人群和反应不佳的人提供乙肝强化治疗，但也可能适用于初级免疫。这项技术也应该适用于其他疾病。对候选乙肝疫苗的初步研究表明，该疫苗在玉米中表达，并能够在小鼠身上引发抗体反应。本研究有四个目的。首先，将1毫克剂量的疫苗免疫原表达在易于给药的10克颗粒材料中。这是一个比报道的其他植物系统更集中的数量级。三分之一的目标水平已经实现。提高表达的策略包括导入适合蛋白质积累的种质，增加基因剂量，开发新的转基因株系，包括改进的种子启动子、多拷贝表达单位和用于亚细胞靶向的替代信号。第二个目标是评估佐剂提高免疫反应效率的可能性。第三个目标是确定一种加工方法，在不降解抗原的情况下产生可口的产品。第四个目的是证明该产品作为口服增强剂在小鼠身上的安全性和体液和粘膜免疫原性。完成第一阶段的目标将导致第二阶段的临床试验提案。这将使该产品进入与人类健康合作伙伴的商业化道路。 公共卫生相关性--项目叙述：该项目与公共卫生的相关性在于，它可以产生一种稳定、廉价和口服的乙肝疫苗。这种疫苗可用于高危人群和目前无法获得疫苗的发展中地区。这项研究也可能为以类似方式接种其他疫苗铺平道路。

DESCRIPTION (provided by applicant): Hepatitis B is a major global health problem. About 350 million chronically infected people are at high risk for cirrhosis of the liver and liver cancer, resulting in appoximately a million deaths annually. Current vaccines command a $1 billion annual market. However, high costs of production, distribution and administration for these parenterally delivered vaccines limit their use in developing nations. Also, inconvenience of clinic visits and fear of injections restrict compliance in developed nations. The long-term objective of this research is to develop an oral vaccine that is effective and stable at ambient temperatures, reducing costs of production, distribution and delivery, and boosting compliance. Maize has been used in our lab to express antigens in stable formulations for viral and bacterial diseases that were orally delivered in large farm animal trials and human clinical trials. Vaccine candidates were well-tolerated, elicited humoral and mucosal immune responses and where tested conferred protection. Responses observed at secondary mucosal sites, indicate the applicability of these vaccines for sexually transmitted diseases. They can also induce a lactogenic response, implying potential for passive immunity. This research targets hepatitis B booster treatments for at risk individuals and poor responders, but may also be suitable for primary immunizations. The technology should be applicable to other diseases as well. Preliminary research with hepatitis B vaccines candidates has demonstrated expression in maize and the ability to elicit an antibody response in mice. This research has four aims. Firstly, to express a 1 mg dose of vaccine immunogen in an easily administered 10 g amount of grain material. This is an order of magnitude more concentrated than reported with other plant systems. Levels at one third the target have already been achieved. Strategies to increase expression include introgression into germplasm suited to protein accumulation, increasing gene dosage, and developing new transgenic lines incorporating an improved seed promoter, a multicopy expression unit and alternative signals for subcellular targeting. The second aim is to evaluate the potential for an adjuvant to increase the efficiency of the immune response. The third aim is to identify a processing method to yield a palatable product without degrading the antigen. The fourth aim is to demonstrate safety, and humoral and mucosal immunogenicity of the product as an oral booster in mice. Completion of phase I aims will lead to a phase II proposal for a clinical trial. This will allow the product to enter a commercialization path with a human health partner. PUBLIC HEALTH RELEVANCE - PROJECT NARRATIVE: The relevance of this project to public health is that it can lead to a stable, inexpensive and orally delivered vaccine for hepatitis B. Such a vaccine can be used for at-risk individuals and in developing areas where the current vaccine is unavailable. This research may also pave the way for other vaccines to be administered in a similar fashion.