An Orally Delivered Hepatitis B Vaccine

描述（由申请人提供）： B型肝炎是一个主要的全球性健康问题。约3.5亿慢性感染者处于肝硬化和肝癌的高风险中，每年导致约100万人死亡。目前的疫苗每年有10亿美元的市场。然而，这些胃肠外递送疫苗的生产、分配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，分配和交付成本，并提高依从性。玉米已在我们的实验室中用于在病毒和细菌疾病的稳定制剂中表达抗原，这些制剂在大型农场动物试验和人类临床试验中口服递送。候选疫苗耐受性良好，引起体液和粘膜免疫应答，并在测试时赋予保护作用。在次级粘膜部位观察到的反应表明这些疫苗适用于性传播疾病。它们还可以诱导催乳反应，这意味着潜在的被动免疫。 这项研究的目标是B型肝炎加强治疗的风险个人和穷人的反应，但也可能适用于初级免疫接种。这项技术也应该适用于其他疾病。对B型肝炎候选疫苗的初步研究已经证明了在玉米中的表达和在小鼠中引发抗体应答的能力。本研究有四个目的。首先，在易于施用的10 g量的颗粒材料中表达1 mg剂量的疫苗免疫原。这是一个数量级更集中的比报告与其他植物系统。已达到目标的三分之一。 增加表达的策略包括渐渗到适合蛋白质积累的种质中，增加基因剂量，以及开发新的转基因品系，其并入改进的种子启动子、多拷贝表达单元和用于亚细胞靶向的替代信号。第二个目的是评估佐剂提高免疫应答效率的潜力。 第三个目的是确定一种加工方法，以产生可口的产品，而不降解抗原。第四个目的是证明本品作为小鼠口服加强剂的安全性以及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建议。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，它可以导致一种稳定、廉价和口服的B型肝炎疫苗。这种疫苗可用于有风险的个人和目前疫苗不可用的发展中地区。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.