Antibody mediated protective immunity against cholera

7.项目总结 霍乱弧菌在47个国家流行，导致300万霍乱病例和10万人死亡 每年一次。此外，霍乱弧菌还会引起大规模的疾病流行。然而，在口服霍乱的同时 疫苗(OCVS)正越来越多地被用于预防霍乱流行，目前还没有 有系统地努力在占全球霍乱负担95%以上的流行地区使用疫苗。 对广泛实施疫苗接种作为一项公共卫生战略犹豫不决的一个原因是，目前 霍乱疫苗有很大的免疫学局限性。例如，最近对一名被杀的OCV的审判 孟加拉国显示出37%的保护效果。相比之下，自然感染霍乱弧菌提供了 对再次感染的保护率超过90%。造成这种情况的一个潜在原因是自然感染，而且可能 减毒但不灭活的OCVS，对体内表达的蛋白产生抗体反应，这些蛋白 有助于长期保护。这得到了我们的初步数据的支持，该数据表明，尽管诱导 感染和接种霍乱弧菌后的类似杀弧性抗体反应 对新的蛋白质抗原产生反应，这种抗原不太可能由杀死的口腔霍乱诱导 疫苗。 在这项建议中，我们将通过比较感染和感染后的霍乱弧菌抗原谱系来测试这一点。 使用我们团队最近开发的霍乱弧菌抗原微阵列进行疫苗接种。到时候我们会的 确定对任何抗原的反应是否与预防霍乱有关。最后，我们会 以此知识为基础，确定霍乱保护性抗体的功能。这些研究的结果 将提高我们对霍乱期间宿主和病原体相互作用的了解，从而产生更好的免疫学 疫苗保护的相关性，以及改进霍乱疫苗和其他潜在疫苗的影响战略 粘膜感染。

7. PROJECT SUMMARY Vibrio cholerae is endemic in 47 countries and causes 3 million cases of cholera and 100,000 deaths annually. In addition, V. cholerae also causes large epidemics of disease. However, while oral cholera vaccines (OCVs) are increasingly being used to prevent cholera epidemics, there has not yet been a systematic effort to use vaccines in endemic areas which account for over 95% of the global cholera burden. One reason for the hesitancy to widely implement vaccination as a public health strategy is that current cholera vaccines have significant immunologic limitations. For example, a recent trial of a killed OCV in Bangladesh demonstrated a 37% protective efficacy. In contrast, natural infection with V. cholerae provides over 90% protection against re-infection. One potential reason for this is that natural infection, and potentially live-attenuated but not killed OCVs, generate antibody responses to in vivo expressed proteins which contribute to long term protection. This is supported by our preliminary data which shows that despite induction of comparable vibriocidal antibody responses following infection and vaccination, V. cholerae infection generates responses to novel protein antigens, which are not likely to be induced by killed oral cholera vaccines. In this proposal, we will test this by comparing the V. cholerae-antigen repertoire following infection and vaccination using a V. cholerae-antigen microarray which our team has recently developed. We will then determine whether responses to any antigens are associated with protection against cholera. Finally, we will build on this knowledge to identify the function of protective antibodies to cholera. The results of these studies will improve our understanding of host-pathogen interactions during cholera, result in better immunologic correlates of vaccine protection, and impact strategies for improving vaccines for cholera and potentially other mucosal infections.