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

Pathogens adapting to the human host and to vaccination-induced immunity may follow parallel evolutionary paths. <i>Bordetella parapertussis</i> (<i>Bpp</i>) contributes significantly to the burden of whooping cough (pertussis) and shares vaccine antigens with <i>Bordetella pertussis (Bp)</i>; both pathogens are phylogenetically related and ecological competitors. <i>Bp</i> 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 <i>Bpp</i>, even though pertussis vaccines were designed against <i>Bp</i>. We sequenced 242 <i>Bpp</i> 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 <i>Bpp</i> 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 <i>Bpp</i> isolates was estimated around the year 1877, making it one of the youngest human pathogens, and the <i>Bpp</i> evolutionary rate we estimated (2.12×10^-7 substitutions per site per year) was remarkably similar to the one previously reported for <i>Bp</i> (2.24×10^-7). PRN antigen deficiency in <i>Bpp</i> was driven by 18 disruptive mutations, including deletion <i>prn</i>:ΔG-1895 estimated to have occurred around 1998 and observed in 73.8 % (149/202) of post-2007 <i>Bpp</i> isolates. In addition, we detected two early (year ~1900) mutations in the <i>bvg</i>A-<i>fhaB</i> 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 <i>Bpp</i> to humans through modulation of the <i>bvgAS</i> regulon, and a rapid adaptation through the loss of PRN expression, representing a late evolutionary parallelism concomitant with acellular vaccination against whooping cough.