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Bordetella pertussis strains with increased toxin production associated with pertussis resurgence.

ABSTRACT: Before childhood vaccination was introduced in the 1940s, pertussis was a major cause of infant death worldwide. Widespread vaccination of children succeeded in reducing illness and death. In the 1990s, a resurgence of pertussis was observed in a number of countries with highly vaccinated populations, and pertussis has become the most prevalent vaccine-preventable disease in industrialized countries. We present evidence that in the Netherlands the dramatic increase in pertussis is temporally associated with the emergence of Bordetella pertussis strains carrying a novel allele for the pertussis toxin promoter, which confers increased pertussis toxin (Ptx) production. Epidemiologic data suggest that these strains are more virulent in humans. We discuss changes in the ecology of B. pertussis that may have driven this adaptation. Our results underline the importance of Ptx in transmission, suggest that vaccination may select for increased virulence, and indicate ways to control pertussis more effectively.

SUBMITTER: Mooi FR

PROVIDER: S-EPMC2815961 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Bordetella pertussis strains with increased toxin production associated with pertussis resurgence.

Mooi Frits R FR van Loo Inge H M IH van Gent Marjolein M He Qiushui Q Bart Marieke J MJ Heuvelman Kees J KJ de Greeff Sabine C SC Diavatopoulos Dimitri D Teunis Peter P Nagelkerke Nico N Mertsola Jussi J

Emerging infectious diseases 20090801 8

Before childhood vaccination was introduced in the 1940s, pertussis was a major cause of infant death worldwide. Widespread vaccination of children succeeded in reducing illness and death. In the 1990s, a resurgence of pertussis was observed in a number of countries with highly vaccinated populations, and pertussis has become the most prevalent vaccine-preventable disease in industrialized countries. We present evidence that in the Netherlands the dramatic increase in pertussis is temporally ass ...[more]

PMID: 19751581

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Project description:BACKGROUND:Acellular Pertussis vaccines against whooping cough caused by Bordetella pertussis present a much-improved safety profile compared to the original vaccine of killed whole cells. The principal antigen of acellular Pertussis vaccine, Pertussis Toxin (PT), must be chemically inactivated to obtain the corresponding toxoid (PTd). This process, however, results in extensive denaturation of the antigen. The development of acellular Pertussis vaccines containing PTd or recombinant PT (rPT) with inactivated S1, Filamentous Hemagglutinin (FHA), and Pertactin (PRN) has shown that the yield of PRN was limiting, whereas FHA was overproduced. To improve antigen yields and process economics, we have constructed strains of Bordetella pertussis that produce enhanced levels of both rPT and PRN. RESULTS:Three recombinant strains of Bordetella pertussis were obtained by homologous recombination using an allelic exchange vector, pSS4245. In the first construct, the segment encoding PT subunit S1 was replaced by two mutations (R9K and E129G) that removed PT toxicity and Bp-WWC strain was obtained. In the second construct, a second copy of the whole cluster of PT structural genes containing the above mutations was inserted elsewhere into the chromosome of Bp-WWC and the Bp-WWD strain was obtained. This strain generated increased amounts of rPT (3.77 ± 0.53 ?g/mL) compared to Bp-WWC (2.61 ± 0.16 ?g/mL) and wild type strain (2.2 ?g/mL). In the third construct, a second copy of the prn gene was inserted into the chromosome of Bp-WWD to obtain Bp-WWE. Strain Bp-WWE produced PRN at 4.18 ± 1.02 ?g/mL in the cell extract which was about two-fold higher than Bp-WWC (2.48 ± 0.10 ?g/mL) and Bp-WWD (2.31 ± 0.17 ?g/mL). Purified PTd from Bp-WWD at 0.8-1.6 ?g/well did not show any toxicity against Chinese hamster ovary (CHO) cell whereas purified PT from WT demonstrated a cell clustering endpoint at 2.6 pg/well. CONCLUSIONS:We have constructed Bordetella pertussis strains expressing increased amounts of the antigens, rPT or rPT and PRN. Expression of the third antigen, FHA was unchanged (always in excess). These strains will be useful for the manufacture of affordable acellular Pertussis vaccines.

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Bordetella pertussis strains with increased toxin production associated with pertussis resurgence.

Publications

Bordetella pertussis strains with increased toxin production associated with pertussis resurgence.

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