Are acellular vaccines driving the rise of pertactin-deficient Bordetella pertussis

项目摘要 百日咳杆菌是引起“百日咳”的呼吸道病原体， 每年有2 400万例疫苗可预防的疾病，导致超过20万人死亡 每年。重要的是，在疫苗覆盖率高的国家，百日咳的发病率在2008年至2009年期间呈上升趋势。 上升，并已被CDC和NIH确认为优先（再）出现的传染性病原体 高度关注。无细胞百日咳疫苗所赋予的有缺陷的免疫力已经高度 与百日咳复发有关虽然无细胞疫苗是合理的， 有效预防严重疾病，产生的免疫力迅速减弱， 预防B的无症状定植或传播。百日咳从接种疫苗的宿主到易感宿主 新生儿这些疫苗不是杀死或减毒的细菌，而是由3-5个免疫原性的 蛋白质，特别是perceptin，一种细菌自身转运蛋白，现在在85%的人中被破坏或缺失， 在美国传播的菌株。细菌适应疫苗驱动的压力， 怀疑已经选择了pertactin缺陷菌株，这可能使细菌逃避 宿主免疫力直接针对performin。在美国， 国家被视为确证性证据，但几乎没有强有力的实验证据来支持或 反驳这个假设。更重要的是，没有明确的实验证据， 如何应对，让疾病预防控制中心和国家卫生研究院发起研讨会和小组，试图解决， 了解问题并考虑可能的解决方案。令人兴奋的是，我们开发了一种新型鼠标， 自然感染的模型，让我们第一次，直接解决疫苗驱动的选择， 疫苗抗原的损失，并在这里提出了初步数据测量减少， 从无粘附素的支气管败血波氏杆菌鼻孔的定植和细菌脱落， B的近亲。自然感染老鼠的百日咳该模型在 接种疫苗的小鼠产生的初步数据表明，pertactin缺陷型菌株具有 与野生型B相比，在定殖和从接种宿主脱落方面具有优势。 支气管炎这些数据与预期一致， 在未接种疫苗的宿主中降低适应性，但在接种疫苗的宿主中增加适应性。因此，我们打算 使用我们创新的小鼠模型，彻底研究percusn缺乏的作用和影响， 使用代表性的同基因B。百日咳菌株。这些实验将提供第一个 直接证据支持或反驳疫苗驱动的B进化的有争议的解释。 百日咳，从而告知非常不同的反应，观察到的发病率上升， 在疫苗覆盖面广的国家中流行的百日咳杆菌粘附素缺乏型菌株的流行率。

PROJECT SUMMARY Bordetella pertussis, the respiratory pathogen responsible for “whooping cough,” causes an estimated 24 million cases of vaccine-preventable illness per year, resulting in an excess of 200,000 deaths annually. Importantly, the incidence of whooping cough in nations with high vaccine coverage is on the rise and has been recognized by both the CDC and NIH as a priority (re)emerging infectious pathogen of high concern. The flawed immunity conferred by acellular pertussis vaccines has been highly implicated in the re-emergence of whooping cough. Although acellular vaccines are reasonably effective in preventing severe disease, resultant immunity quickly wanes, and does not effectively prevent asymptomatic colonization or transmission of B. pertussis from vaccinated hosts to susceptible newborns. Rather than killed or attenuated bacteria, these vaccines are composed of 3-5 immunogenic proteins, notably, pertactin, a bacterial autotransporter that is now disrupted or absent in 85% of circulating strains in the United States. Bacterial adaptation in response to vaccine-driven pressure is suspected to have selected for pertactin-deficient strains, which may enable the bacterium to evade host immunity directed against pertactin. The high prevalence of pertactin deficient strains in the United States is taken as confirmatory evidence, but there is little robust experimental evidence to support or refute this hypothesis. More importantly, without clear experimental evidence, there is no consensus on how to respond, leaving the CDC and NIH to launch workshops and panels to try to tackle and understand the problem and consider possible solutions. Excitingly, we have developed a novel mouse model of natural infection that allows us, for the first time, to directly address vaccine driven selection for the loss of vaccine antigens, and here present preliminary data measuring the reduction in colonization and bacterial shedding from the nares of pertactin-deficient Bordetella bronchiseptica, a close ancestral relative of B. pertussis that naturally infects mice. Application of this model in vaccinated mice has generated preliminary data indicating that pertactin-deficient strains have an advantage in colonization and shedding from vaccinated hosts in comparison with wildtype B. bronchiseptica. These data are consistent with the expectation that pertactin deficiency measurably reduces fitness in unvaccinated hosts but increases fitness in vaccinated hosts. Therefore, we intend to employ our innovative mouse model to thoroughly investigate the role and effect of pertactin deficiency using representative isogenic B. pertussis strains. Together these experiments will provide the first direct evidence to either support or refute the controversial explanation of vaccine-driven evolution of B. pertussis, and thereby inform very different responses to the observed rise in incidence of disease and prevalence of circulating pertactin-deficient strains in countries with wide vaccine coverage.