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

无细胞疫苗是否会导致缺乏百日咳博德特氏菌的增加

基本信息

批准号：
10364771
负责人：
Eric T Harvill
金额：
$ 18.88万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-04 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364771
关键词：
Acellular Vaccines Address Animals Antigens Attenuated Automobile Driving Bacteria Bacterial Adhesins Biological Biological Assay Bordetella Bordetella bronchiseptica Bordetella pertussis Centers for Disease Control and Prevention (U.S.)Cessation of life Child Complex Consensus Costs and Benefits Country Data Disease Dose Educational workshop Etiology Evolution Flushing Grant Growth High Prevalence Human Immune response Immunity In Situ Incidence Infant Infection Investigation Lung Measurable Measures Modeling Mus Newborn Infant Pathogenesis Pathology Pertussis Pertussis Vaccine Prevalence Process Proteins Pulmonary Pathology Respiratory System Role Symptoms System Time United States United States National Institutes of Health Vaccinated Vaccination Vaccine Antigen Vaccines co-infection cost expectation experimental study fitness immunogenic in vivo innovation mouse model mutant novel pathogen pertactin pressure prevent respiratory pathogen response transmission process unvaccinated vaccine-induced immunity

项目摘要

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.

项目摘要造成“百日咳”的呼吸道病原体Bordetella buttussis导致估计每年有2400万例疫苗可预防疾病，导致超过200,000例死亡重要的是。重要的是，在疫苗覆盖率高的国家中百日咳的事件在 CDC和NIH崛起并已被认为是优先（RE）新兴的感染性病原体高度关注。 acelaculular百日咳疫苗赋予的有缺陷的免疫力已高度在咳嗽的重新出现时实施。尽管大疫苗是合理的有效预防严重疾病，导致的免疫力迅速减弱，并且没有有效的预防疫苗接种宿主的百日咳无症状的定殖或传播到易感性新生儿。这些疫苗不是杀死或减毒细菌，而是由3-5个免疫原性组成蛋白质，尤其是肌肉蛋白，一种细菌自动转移蛋白，现在在85％中被破坏或不存在在美国循环菌株。响应疫苗驱动的压力的细菌适应为怀疑已选择去肌蛋白质缺陷菌株，这可能使细菌逃避宿主免疫针对发生性交。联合伴奏毒素不足菌株的高流行率国家被视为确认证据，但几乎没有强大的实验证据可以支持或驳斥这一假设。更重要的是，如果没有明确的实验证据，就没有达成共识如何做出响应，离开疾病预防控制中心和NIH进行研讨会和面板，以尝试解决和了解问题并考虑可能的解决方案。令人兴奋的是，我们已经开发了一种新颖的鼠标自然感染模型，这使我们首次可以直接解决疫苗驱动选择对于疫苗抗原的丧失，此处介绍了测量降低的初步数据从伴发色素缺乏的Bordetella支气管炎的鼻菌和细菌脱落，A 自然感染小鼠的百日咳B.百日咳的亲密亲戚。在此模型中应用接种疫苗的小鼠已经产生了初步数据，表明缺乏性菌株具有与Wildtype相比，接种宿主的定植和脱落的优势。支气管肽。这些数据与期望痛觉缺乏的期望是一致的降低了未接种宿主的健身，但增加了接种宿主的适应性。因此，我们打算员工我们创新的鼠标模型，以彻底研究心肌蛋白质缺乏的作用和效果使用代表百日咳B.百日咳菌株。这些实验将共同提供第一个直接证据支持或反驳B.疫苗驱动的进化的有争议的解释。百日咳，从而告知对观察到的事件增加和疫苗覆盖范围广泛的国家中循环性心肌缺乏菌株的患病率。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modeling Immune Evasion and Vaccine Limitations by Targeted Nasopharyngeal Bordetella pertussis Inoculation in Mice.

DOI：
10.3201/eid2708.203566
发表时间：
2021-08
期刊：
Emerging infectious diseases
影响因子：
11.8
作者：
Soumana IH;Linz B;Dewan KK;Sarr D;Gestal MC;Howard LK;Caulfield AD;Rada B;Harvill ET
通讯作者：
Harvill ET

Probing Immune-Mediated Clearance of Acute Middle Ear Infection in Mice.

DOI：
10.3389/fcimb.2021.815627
发表时间：
2021
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
Dewan KK;Sedney C;Caulfield AD;Su Y;Ma L;Blas-Machado U;Harvill ET
通讯作者：
Harvill ET

The Neonatal Immune System and Respiratory Pathogens.

DOI：
10.3390/microorganisms11061597
发表时间：
2023-06-16
期刊：
Microorganisms
影响因子：
4.5
作者：
Sedney CJ;Harvill ET
通讯作者：
Harvill ET

Modeling the catarrhal stage of Bordetella pertussis upper respiratory tract infections in mice.

模拟小鼠百日咳博德特氏菌上呼吸道感染的卡他期。

DOI：
10.1242/dmm.049266
发表时间：
2022-05-01
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
Soumana IH;Dewan KK;Linz B;Rivera I;Ma L;Howard LK;Caulfield AD;Sedney CJ;Blas-Machado U;Sebo P;Harvill ET
通讯作者：
Harvill ET

Evolution and Conservation of Bordetella Intracellular Survival in Eukaryotic Host Cells.