Polymorphism in the Bordetella pertussis Virulence Factors P.69/Pertactin and Pertussis Toxin in The Netherlands: Temporal Trends and Evidence for Vaccine-Driven Evolution

Abstract

The Bordetella pertussis proteins P.69 (also designated pertactin) and pertussis toxin are important virulence factors and have been shown to confer protective immunity in animals and humans. Both proteins are used in the new generation of acellular pertussis vaccines (ACVs), and it is therefore important to study the degree of antigenic variation in these proteins. Sequence analysis of the genes for P.69 and the pertussis toxin S1 subunit, using strains collected from Dutch patients in the period 1949 to 1996, revealed three P.69 and three S1 variants which show differences in amino acid sequence. Polymorphism in P.69 was confined to a region comprised of repeats and located proximal to the RGD motif involved in adherence to host tissues. Variation in S1 was observed in two regions previously identified as T-cell epitopes. P.69 and S1 variants, identical to those included in the Dutch whole-cell pertussis vaccine (WCV), were found in 100% of the strains from the 1950s, the period when the WCV was introduced in The Netherlands. However, nonvaccine types of P.69 and S1 gradually replaced the vaccine types in later years and were found in ∼90% strains from 1990 to 1996. These results suggest that vaccination has selected for strains which are antigenically distinct from vaccine strains. Analysis of strains from vaccinated and nonvaccinated individuals indicated that the WCV protects better against strains with the vaccine type P.69 than against strains with non-vaccine types (P = 0.024). ACVs contain P.69 and S1 types which are found in only 10% of recent Dutch B. pertussis isolates, implying that they do not have an optimal composition. Our findings cast a new light on the reemergence of pertussis in highly vaccinated populations and may have major implications for the long-term efficacy of both WCVs and ACVs.

Bordetella pertussis in infants hospitalized for acute respiratory symptoms remains a concern

“…The "universal" indicator for characterizing the molecular features of B. pertussis is the catalytic subunit S1. Four S1 subunit variants have been described: S1-A (ptxA1), S1-B (ptxA2), S1-D (ptxA3), and S1-E (ptxA4) [2,4,6,16,18,19]. Culture and molecular data allowed us to identify strains that express the S1-A variant, whereas pertussis vaccine contains the S1-B variant [4].…”

“…To obtain gene molecular sequence data, the pertussis toxin S1 subunit (ptxA), pertussis toxin promoter (ptxP) and pertactin (prn) sequences were analyzed for two B. pertussis clinical isolates. The used primers are those described previously [2,18,19].…”

“…Pertussis resurgence in Europe has been attributed to an incomplete immunization program or to genetic changes in Bordetella pertussis (B. pertussis). [2] The currently used acellular pertussis vaccine contains the pertactin gene variant prn1 and the pertussis toxin-B S1 subunit [3,4]. Molecular changes in these two genes over the past years suggest that the antigenic divergence may make pertussis vaccination less effective than before [5,6].…”

Genotypic and phenotypic characterization of Bordetella pertussis strains used in different vaccine formulations in Latin America

“…Moreover, the reported shift in the antigenic characteristics of Bord. pertussis circulating strains (Mooi et al 1998;Hozbor et al 2009) makes such surveillance crucial to evaluate the Keywords disease, pertussis, proteomic, re-emergence, vaccine strains. 1365-2672.2012.05299.x Abstract Aim: To characterize Bordetella pertussis vaccine strains in comparison with current circulating bacteria.…”

The virulence factors of Bordetella pertussis: a matter of control

“…Recent data from The Netherlands reported a dramatic increase in the incidence of pertussis in that country in 1996, despite high levels of immunisation [259]. An extensive study has traced the problem to the changing population structure of B. pertussis itself [260]. The antigenic variation of the protective antigens pertactin and the S1 subunit of PT was analysed using circulating clinical isolates collected over a long period.…”