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.
Bordetella pertussis, the human specific etiologic agent of whooping cough, has reemerged as a pathogen of high concern with increased incidence following the implementation of acellular pertussis vaccines. Recently, up to 85% of circulating B. pertussis strains in the United States have been found to be deficient in pertactin, a putative autotransporter and one of the 3-5 antigens included in all acellular vaccines. We propose the following study using our novel mouse model of infection to provide the first direct evidence to either support or refute the highly speculated role of vaccine-driven selective pressure on pertactin-deficient B. pertussis, and the role of pertactin in infection of both vaccinated and unvaccinated hosts.
