New Approaches to Schistosome vaccine antigen discovery

简介（由申请人提供）：全世界有超过2亿人感染血吸虫病。目前只有一种对抗这种感染的有效药物正在生产中。目前还没有疫苗。开发血吸虫病疫苗的研究是防止耐药寄生虫传播的最佳长期防御措施，并将使大规模药物治疗规划更加有效和具有成本效益。疫苗是可行的，因为人类会产生部分天然免疫力，使用辐射减毒的幼虫可以在实验动物中实现70-90%的保护。尽管在确定血吸虫候选疫苗方面已经做出了重大努力，但世界卫生组织试验的最有希望的抗原在独立测试中未能提供规定的最低40%的保护。这种不良的疗效可能是由于许多原因造成的，但突出表明需要新的方法来鉴定和测试血吸虫疫苗候选抗原。

DESCRIPTION (provided by applicant): Schistosomiasis infects more than 200 million people worldwide. Only one effective drug against this infection is currently in production. No vaccine currently exists. Research toward development of a vaccine against schistosomiasis is the best long-term defense against propagation of drug-resistant parasites and will permit more efficient and cost-effective mass drug treatment programs. A vaccine is feasible because partial natural immunity develops in humans, and 70-90% protection can be achieved in experimental animals using radiation attenuated larvae. Although significant effort has been made toward identifying schistosome vaccine candidates, the most promising antigens trialed by World Health Organization failed to provide the stipulated minimum of 40% protection in independent tests. This poor efficacy may have occurred because for a number of reasons, but highlight the need for novel approaches to identify and test schistosome vaccine candidate antigens. Our long-term goal is to develop an effective schistosome vaccine for humans. This proposal aims to identify molecules expressed during early migratory phases of infection. Our central hypothesis is that larval secretory and/or surface proteins are essential for successful parasite invasion and survival and are principal targets of immune elimination. This derives from our own and others observations that skin-and lung-stage larvae are most vulnerable to host immune attack. To evaluate the hypothesis, we will pursue the following Specific Aims: 1) To generate and fractionate larval parasite preparations. We shall derive secretory and surface membrane preparations corresponding to skin- and lung-stage schistosomes, and fractionate them by 2D electrophoresis or MudPIT technologies. 2) To identify and characterize larval proteins with vaccine potential. We shall select gel spots or liquid chromatography (LC) fractions for analysis by mass spectrometry to link protein to encoding DNA by database searching. 3) To validate isolated larval antigens as potential vaccine candidates. We shall express larval antigens as recombinant proteins. These or coding sequences formulated in a DNA construct will be used to immunize mice to generate antibodies that will be used to probe native protein preparations and to localize the parasite tissue of origin. Immunized mice will also be challenged to assess protective potential of vaccine candidates. In this, the first systematic study of larval antigens as vaccine candidates, we expect to identify several novel antigens that could be incorporated into a multivalent vaccine. Partial identification of the larval proteome will also help to better define host-parasite interaction in schistosomiasis. An effective vaccine could transform control programs for schistosomiasis by reducing the costs of repeated treatment, and the risk of developing drug resistance.