An Orally Delivered Hepatitis B Vaccine

描述（由申请人提供）：乙型肝炎是一个主要的全球健康问题。约3.5亿慢性感染者面临肝硬化和肝癌的高风险，每年导致约100万人死亡。目前的疫苗每年占有10亿美元的市场。然而，这些注射疫苗的生产、分销和管理的高成本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也限制了发达国家的依从性。这项研究的长期目标是开发一种在环境温度下有效和稳定的口服疫苗，降低生产、分销和交付成本，并提高依从性。在我们的实验室里，玉米被用来表达病毒和细菌疾病的抗原，这些抗原在大型农场动物试验和人体临床试验中被口服。候选疫苗耐受性良好，可引起体液和粘膜免疫反应，经测试可产生保护作用。在二次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。它们还能诱导生乳反应，这意味着潜在的被动免疫。本研究针对高危人群和不良应答者的乙肝强化治疗，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。对乙型肝炎候选疫苗的初步研究已证实在玉米中表达，并能在小鼠中引起抗体反应。这项研究有四个目的。首先，在易于施用的10克谷物材料中表达1毫克剂量的疫苗免疫原。这是一个数量级比报道的其他植物系统更集中。已经达到了目标的三分之一。提高表达的策略包括渗入适合蛋白质积累的种质，增加基因剂量，开发新的转基因系，包括改进的种子启动子，多拷贝表达单元和亚细胞靶向的替代信号。第二个目的是评估一种佐剂提高免疫反应效率的潜力。第三个目的是确定一种加工方法，以产生美味的产品而不降解抗原。第四个目的是证明该产品作为口服增强剂在小鼠中的安全性、体液和粘膜免疫原性。I期目标的完成将导致II期临床试验的建议。这将使该产品与人类健康合作伙伴一起进入商业化道路。

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.