Vaccine-driven evolution of Bordetella pertussis: changes in population structure and strain fitness

Abstract

Whooping cough or pertussis is a highly contagious disease of the respiratory tract, caused by Bordetella pertussis. In The Netherlands mass vaccination against B. pertussis was introduced in 1953 and was very effective in reducing the pertussis incidence and mortality. Although vaccination was initially very effective, the pertussis incidence increased remarkably after 1996 in The Netherlands. Epidemics have been reported in 1996, 1999 and 2001, while in the intermittent years the incidence did not return to levels observed previous to 1996. The goal of this thesis was to find an explanation for the re-emergence of B. pertussis in countries with highly vaccinated populations, in particular The Netherlands. The re-emergence of pertussis might be explained by changes in surveillance and diagnostic criteria, changes in vaccine quality or a decrease in vaccine coverage. However, for The Netherlands these possibilities have been excluded. Waning vaccine-induced immunity and strain adaptations are other possible explanations. Indeed, we observed that the introduction of vaccination affected the B. pertussis population significantly. Notable changes were observed in the population structure of Dutch B. pertussis strains in 2 periods: the 1960s, a decade after the introduction of vaccination and in the 1990s, the period, when pertussis re-emerged in The Netherlands. IS1002-based fingerprint typing showed a change in fingerprint types a decade after the introduction of vaccination. Fingerprint types from the prevaccination period disappeared, while novel fingerprint types emerged. We hypothesized that antigenic divergence between vaccine strains and circulating strains may be the underlying cause of the changes observed with IS1002 fingerprint typing. To address this hypothesis, we studied polymorphism in genes coding for surface proteins. In the 1960s the only mismatch we detected between the vaccine strains and circulating strains was with respect to pertussis toxin subunit 1 (PtxS1). Although we observed divergence between vaccine strains and clinical isolates, suggesting that vaccination selected for strains that were less affected by vaccine-induced immunity, vaccination remained very effective, since mortality decreased 114-fold in the late 1960s compared to the prevaccination period. The second period showing changes in the population structure was observed in the 1990s. In this period we observed divergence between vaccine strains and clinical isolates in the surface associated proteins pertactin (Prn) and tracheal colonization factor (TcfA). Polymorphism was not restricted to genes coding for surface proteins, but was also observed in regulatory genes, such as the promoter region for pertussis toxin, ptxP. The alleles of Prn, TcfA and ptxP, found in the vaccine strains, were replaced by novel variants in the 1990s. Further, animal studies indicate that vaccination has shifted the competitive balance between strains, resulting in expansion of strains that are less affected by vaccine-induced immunity. The data presented in this thesis provide an explanation for the re-emergence of pertussis and a better understanding of how pathogens evolve after the introduction of vaccines