Antibody mediated protective immunity against cholera

7.项目摘要 霍乱弧菌在47个国家流行，造成300万例霍乱和10万人死亡 每年。此外，霍乱弧菌还引起大规模的疾病流行。然而，虽然口服霍乱 虽然疫苗（OCV）越来越多地被用于预防霍乱流行，但迄今为止还没有一种 在占全球霍乱负担95%以上的流行地区系统地努力使用疫苗。 在将疫苗接种作为一项公共卫生战略广泛实施方面犹豫不决的一个原因是， 霍乱疫苗具有明显的免疫局限性。例如，最近对一种被杀死的OCV的试验， 孟加拉国的保护效力为37%。相比之下，自然感染霍乱弧菌 90%以上的预防再次感染。一个潜在的原因是自然感染， 减毒活的但不杀死的OCV，产生对体内表达的蛋白质的抗体应答， 有助于长期保护。这是支持我们的初步数据表明，尽管诱导， 在感染和接种疫苗后，可比较的杀弧菌抗体应答，霍乱弧菌感染 产生对新蛋白抗原的反应，这不太可能由杀死的口服霍乱引起 疫苗。 在这个建议中，我们将通过比较感染后的霍乱弧菌抗原库来测试这一点， 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。然后我们将 确定对任何抗原的反应是否与预防霍乱有关。最后我们将 在此基础上，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-病原体相互作用的理解， 疫苗保护的相关因素，以及改进霍乱疫苗和其他潜在的 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.