Vaccines and toxin evolution

Despite high vaccination coverage, the once nearly eradicated diseases diphtheria and pertussis have unfortunately reemerged as a health threat in the developed countries (Bass and Stephenson, 1987; Bass and Wittler, 1994; De Serres et al., 1995; Galazka et al., 1995; Wilson, 1995; Andrews et al., 1997; de Melker et al., 1997; Baron et al., 1998). One possible explanation for this reemergence is that the constant selective pressure imposed by immunization might have resulted in increased antigenic divergence in the remaining bacterial population. Consequently, the effects of vaccination on toxin evolution are beginning to be examined (Pappenheimer and Murphy, 1983; Mencarelli et al., 1992; van der Zee et al., 1996b; Mooi et al., 1998; Guiso et al., 2001; Weber et al., 2001; von Hunolstein et al., 2003).

Comparative genetic analysis of the genes for B. pertussis PT and pertactin (an outer membrane protein) between recent epidemic isolates and the vaccine strains revealed that expansion of strains antigenically distinct from vaccine strains has occurred (Khattak and Matthews, 1993; Mooi et al., 1998; Weber et al., 2001). These findings strongly implicate vaccination as a strong driving force in the continuous evolution of the B. pertussis population and may forebode the emergence of novel variants resistant to vaccination. Moreover, since pertactin and PT are the primary bacterial components in acellular pertussis vaccines (ACV) that were introduced in the 1970s and have replaced the whole-cell vaccines (WCV) in some countries, these findings place into question the long-term efficacy of both ACV and WCV.

As a result of long-standing immunization programs using the diphtheria toxoid, most current isolates of Corynebacterium diphtheriae or C. ulcerans are non-toxi-genic (Galazka and Robertson, 1995; Galazka, 2000a; Holmes, 2000; von Hunolstein et al., 2003). Of these non-toxigenic strains, most are devoid of the tox gene; however, these strains could potentially be converted into toxigenic strains by exposure to a corynebacterio-phage P carrying the tox gene (Pappenheimer and Murphy, 1983; Buck et al, 1985; Cianciotto and Groman, 1985; Cianciotto and Groman, 1997). While there are no definite examples of this sort of genetic transfer having occurred for diphtheria, there is fear that the continued presence of non-toxigenic strains in immunized populations (Galazka and Robertson, 1995; Reacher et al., 2000) and the potential import of toxigenic strains from endemic areas such as Russia (Galazka, 2000b; Skogen et al., 2002) might allow for phage conversion to occur. In addition, it is possible that recombination events might occur within tox genes between non-toxigenic strains that harbor defective tox genes, and, even though this has not yet been experimentally observed (Cianciotto and Groman, 1997), the possibility still remains that this could result in reversion to full toxigenicity.

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