Novel oral delivery system for subunit vaccine against ETEC

项目总结/摘要 口服疫苗有可能使生活质量得到革命性的改善， 发展中国家由于这些疫苗可以由社区卫生工作者管理， 没有受过训练的医务人员，可以在短时间内接种疫苗的人数， 时间周期急剧增加，而每个患者的成本显著降低。口服 疫苗还避免了被污染的注射器和针头的危险，这是一个严重的威胁， 艾滋病毒和肝炎发病率高的地区。口服疫苗广泛使用的一个障碍是， 传染病的一个重要原因是，大多数疫苗在通过严酷的酸性环境时都会被破坏。 它们在胃的环境中被蛋白水解酶降解。这个目标 一个研究项目是开发一种新的口服疫苗输送系统， 蛋白质在通过胃和肠腔时被消化。该疫苗针对 肠毒素E.大肠杆菌（ETEC），这是南亚幼儿死亡的主要原因 撒哈拉以南非洲。ETEC感染也是游客腹泻的主要原因， 前往发展中国家的军事人员。没有疫苗被许可用于 预防ETEC。该SBIR研究项目的第一阶段旨在保护ETEC疫苗 微珠中的蛋白质保持密封，直到它们与壁直接接触 小肠的一部分只有这样，包封的蛋白质才能从载体中释放出来。作为 结果，疫苗蛋白被保护免受蛋白酶的破坏，直到它们被紧密地结合在一起。 靠近派尔集合淋巴结的M细胞这应该会大大提高 疫苗将被M细胞吸收并传递给粘膜免疫细胞。建立 为了验证该系统的概念，我们将追求三个具体目标：1）优化性能 a）它们对包封的蛋白抗原的保护， 蛋白酶和B）抗原在与刷状缘酶接触时的释放; 2）负载 具有确定量的所选ETEC抗原和确定的佐剂的微珠; 和3）测试加载的微珠在小鼠中诱导免疫应答的能力， 通过强饲法施用。该输送系统的一个重要特征是，它基于 马铃薯淀粉的天然分解产物。这就提出了一种可能性， 以适度的成本扩大规模，并可为广泛免疫提供一个可行的选择， 在资源贫乏的社区。

Project Summary/Abstract Oral vaccines have the potential to make a revolutionary improvement in the quality of life in developing countries. Since these vaccines can be administered by community health workers who are not trained medical personnel, the number of people who can be immunized in a short period of time is drastically increased while the cost per patient is significantly lowered. Oral vaccines also avoid the danger of contaminated syringes and needles which is a serious threat in areas with high rates of HIV and hepatitis. One obstacle to the wider use of oral vaccines against infectious diseases is that most vaccines are destroyed as they pass through the harsh acidic environment of the stomach where they are degraded by proteolytic enzymes. The goal of this research project is to develop a new delivery system for oral vaccines that protects the vaccine proteins as they pass through the stomach and the lumen of the intestine. This vaccine targets enterotoxogenic E. coli (ETEC), a major cause of death in young children living in South Asia and Sub-Saharan Africa. ETEC infections are also the major cause of diarrhea in tourists and military personnel travelling to the developing world. No vaccine has been licensed for the prevention of ETEC. This Phase I SBIR research project is designed to shield the ETEC vaccine proteins within microbeads that remain sealed until they come into direct contact with the wall of the small intestine. Only then are the encapsulated proteins released from the carriers. As a result, the vaccine proteins are shielded from destruction by proteases until they are in close proximity to the M cells of the Peyer’s patches. This should greatly improve the odds that a vaccine will be taken up by the M cells and be passed on to mucosal immune cells. To establish proof of concept of this system, we will pursue three specific aims: 1) Optimize the performance of the microbeads in terms of a) their protection of encapsulated protein antigens from proteases and b) the release of the antigens upon contact with brush border enzymes; 2) Load the microbeads with defined amounts of selected ETEC antigens and an established adjuvant; and 3) Test the ability of the loaded microbeads to induce immune responses in mice when administered by gavage. An important feature of the delivery system is that it is based on a natural breakdown product of potato starch. This raises the possibility that the system can be scaled up at modest cost and that it can provide a feasible option for widespread immunization in resource-poor communities.