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Analysis of Bordetella pertussis clinical isolates circulating in European countries during the period 1998-2012.

ABSTRACT: Despite more than 50 years of vaccination, pertussis is still an endemic disease, with regular epidemic outbreaks. With the exception of Poland, European countries have replaced whole-cell vaccines (WCVs) by acellular vaccines (ACVs) in the 1990s. Worldwide, antigenic divergence in vaccine antigens has been found between vaccine strains and circulating strains. In this work, 466 Bordetella pertussis isolates collected in the period 1998-2012 from 13 European countries were characterised by multi-locus antigen sequence typing (MAST) of the pertussis toxin promoter (ptxP) and of the genes coding for proteins used in the ACVs: pertussis toxin (Ptx), pertactin (Prn), type 2 fimbriae (Fim2) and type 3 fimbriae (Fim3). Isolates were further characterised by fimbrial serotyping, multi-locus variable-number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE). The results showed a very similar B. pertussis population for 12 countries using ACVs, while Poland, which uses a WCV, was quite distinct, suggesting that ACVs and WCVs select for different B. pertussis populations. This study forms a baseline for future studies on the effect of vaccination programmes on B. pertussis populations.

SUBMITTER: van Gent M

PROVIDER: S-EPMC4365279 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe objective of the study was to analyse the evolution of Bordetella pertussis population and the influence of herd immunity in different areas of the world where newborns and infants are highly vaccinated.MethodologyThe analysis was performed using DNA microarray on 15 isolates, PCR on 111 isolates as well as GS-FLX sequencing technology on 3 isolates and the B. pertussis reference strain, Tohama I.Principal findingsOur analyses demonstrate that the current circulating isolates are continuing to lose genetic material as compared to isolates circulating during the pre-vaccine era whatever the area of the world considered. The lost genetic material does not seem to be important for virulence. Our study confirms that the use of whole cell vaccines has led to the control of isolates that were similar to vaccine strains. GS-FLX sequencing technology shows that current isolates did not acquire any additional material when compared with vaccine strains or with isolates of the pre-vaccine era and that the sequenced strain Tohama I is not representative of the isolates. Furthermore, this technology allowed us to observe that the number of Insertion Sequence elements contained in the genome of the isolates is temporally increasing or varying between isolates.ConclusionsB. pertussis adaptation to humans is still in progress by losing genetic material via Insertion Sequence elements. Furthermore, recent isolates did not acquire any additional material when compared with vaccine strains or with isolates of the pre-vaccine era. Herd immunity, following intensive vaccination of infants and children with whole cell vaccines, has controlled isolates similar to the vaccine strains without modifying significantly the virulence of the isolates. With the replacement of whole cell vaccines by subunit vaccines, containing only few bacterial antigens targeting the virulence of the bacterium, one could hypothesize the circulation of isolates expressing less or modified vaccine antigens.

Project description:Resurgence of pertussis has been observed in many countries with high vaccination coverage and clonal expansion of certain Bordetella pertussis strains has been associated with recent epidemics in Europe. It is known that vaccinations have selected strains which are different from those used for vaccine production. However, little is known about the differences in genomic content of strains circulating before the vaccination was introduced. In this study, we compared the genomes of 39 vaccine strains and old clinical isolates collected from Finland (N=5), Poland (N=14), Serbia (N=10) and the UK (N=10). The analysis included genotyping, pulsed-field gel electrophoresis (PFGE) and comparative genomic hybridisation (CGH). Compared to the strain Tohama I, the European strains analyzed have lost three major regions of difference (RD3, 5 and 29). However, difference in frequency of the absent RDs 3, 5 or 29 was observed among the four countries. Of the strains with absent RD5, half had also a duplicated region in the genome. All four RDs (RD22, 23, 24 and 26) absent in Tohama I were present in majority of the tested strains. Results obtained from PFGE analysis correlated well with those of CGH. Recently a novel pertussis toxin promoter allele (ptxP3) was described. Strains with ptxP3 have replaced resident ptxP1 strains. When the recent strains (N=22) selected from the four countries were examined, the ptxP3 allele was found in all countries except Poland. Our result indicates that at least three clusters of B. pertussis circulated in Europe in pre-vaccine era and their genomes were distinct from that of the reference strain Tohama I. Although progressive gene loss occurs in B. pertussis population with time, difference in frequency of the lost genes were observed among the countries. The observed differences in genomic content might be vaccine-driven. The strains were serotyped for the fimbriae, genotyped with LightCycler RT-PCR for pertussis toxin subunit 1 (ptxA), pertussis toxin promoter (ptxP) (Kallonen et al 2011, unpublished data, submitted) and pertactin (prn). The vaccine and old strains were assigned to profiles according to the PFGE results. From every PFGE profile from all countries at least 1 strain was selected and tested for CGH. Altogether 29 strains were analysed with CGH from Poland, Serbia and the United Kingdom, 12, 7 and 10, respectively. In addition 5 old previously published Finnish strains were included in the analysis as well as the reference strain Tohama I (Heikkinen et al., 2007). The hybridisations were performed as previously described (Heikkinen et al., 2007). Microarray data analysis was performed with R/Bioconductor (R Development Core Team, 2008). Print-tip-loess normalization was performed with default parameters and the gains/losses were filtered with Limma package. The regions of difference (RDs) found in this study are presented with the nomenclature defined by Brinig et al. (2006). The RDs which were not described by Brinig et al are indicated by RDs and the consequent unused number.

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Analysis of Bordetella pertussis clinical isolates circulating in European countries during the period 1998-2012.

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