Small mutations allow B. pertussis to persist and resurge in the face of intensive vaccination
The Gram-negative bacterium Bordetella pertussis is the causative agent of whooping cough or pertussis, a highly contagious disease of the human respiratory tract. Less severe forms of pertussis are caused by Bordetella parapertussis and Bordetella bronchiseptica. Despite high vaccination coverage since the 1950s, pertussis has resurged and has become one of the most prevalent vaccine-preventable diseases worldwide. In the Netherlands, the infection frequency has been estimated to be 9% per year for the age category >9 years. Since 1996, a dramatic increase in pertussis notifications has been observed and we proposed that both waning immunity and pathogen adaptation have contributed to this phenomenon. Allelic variation has been found in virulence-associated genes that are included in the currently used acellular vaccines; ptxA, prn and fim3. Differences in these genes are mainly caused by single nucleotide polymorphisms and may effect immune recognition and hence strain fitness. Moreover, in the 1990s, ptxP3 strains emerged that were associated with increased Ptx production and interestingly, the emergence of the ptxP3 strain is closely related with the increased pertussis notifications in the Netherlands. In this study, we investigated how more than 60 years of intensive vaccination has affected the Dutch B. pertussis population by combining data from phylogeny, genomics and temporal trends in strain frequencies. We have studied Dutch B. pertussis clinical isolates isolated from 1949-2010. Our results showed that the Dutch B. pertussis population has undergone as least four selective sweeps that were associated with small mutations in virulence-associated genes and phylogenetic analysis revealed a stepwise adaptation in which these mutations accumulated. Genomic analysis did not reveal a role for gene acquisition in adaptation. Our results suggest that the B. pertussis gene repertoire is already well adapted to its current niche and required only fine tuning to persist in the face of intensive vaccination.