No innocent bystanders: pertussis vaccination and evolutionary parallelisms between Bordetella parapertussis and...

Pathogens adapting to the human host and to vaccination-induced immunity may follow parallel evolutionary paths. Bordetella parapertussis (Bpp) contributes significantly to the burden of whooping cough (pertussis) and shares vaccine antigens with Bordetella pertussis (Bp); both pathogens are phylogenetically related and ecological competitors. Bp vaccine antigen-coding genes have accumulated variation, including pertactin (PRN) disruptions, after the introduction of acellular vaccines in the 1990s. We aimed to evaluate evolutionary parallelisms in Bpp, even though pertussis vaccines were designed against Bp. We sequenced 242 Bpp isolates collected in France, the USA and Spain between 1937 and 2019, spanning pre-vaccine and two vaccines eras. We investigated the temporal evolution of Bpp sublineages using a Bayesian approach based on whole-genome SNPs and performed comparative genomic analyses focusing on antigen and virulence gene loci. The most recent common ancestor of all sequenced Bpp isolates was estimated around the year 1877, making it one of the youngest human pathogens, and the Bpp evolutionary rate we estimated (2.12×10^-7 substitutions per site per year) was remarkably similar to the one previously reported for Bp (2.24×10^-7). PRN antigen deficiency in Bpp was driven by 18 disruptive mutations, including deletion prn:ΔG-1895 estimated to have occurred around 1998 and observed in 73.8 % (149/202) of post-2007 Bpp isolates. In addition, we detected two early (year ~1900) mutations in the bvgA-fhaB intergenic region, which controls multiple virulence factors including the filamentous haemagglutinin antigen. Gene clusters for pertussis toxin and fimbriae showed a surprising lack of gene decay. Our findings suggest early adaptation of Bpp to humans through modulation of the bvgAS regulon, and a rapid adaptation through the loss of PRN expression, representing a late evolutionary parallelism concomitant with acellular vaccination against whooping cough.