Tuesday, February 12, 2013

Bordetella Pertussis Mutations may Reduce Vaccine Effectiveness

A recent report by the Centers for Disease Control (CDC) has discovered that mutations in a particular gene may be partially responsible for the increase in B. pertussis or whooping cough cases. CIDRAP reports that B. pertussis isolates in some children in the U.S. have been tested and found to have gene mutations in the coding region for Pertactin.
In the US study, researchers looked at pertactin genes from 12 isolates of B pertussis from children hospitalized in Philadelphia in 2011 and 2012. Most of the patients were younger than 2 years old, but the group also included a 9-year-old and 14-year-old.

They analyzed the pertactin genes from the specimens and amplified and sequenced the coding region. They determined the pulsed-field gel electrophoresis (PFGE) patterns and detected pertactin using Western blotting with antiserum and a strain from the World Health Organization (WHO) as the pertactin-positive reference.

Eleven of the 12 pertussis strains they tested were negative for pertactin. The pertactin allele in all isolates was pm2, but the mutations were different than pertactin-negative pm2 isolates from France, according to the report. (Variants in Japan and Finland had insertion sequences in the pm1 allele.)
Pertactin is a virulence factor for B. pertussis which is an adaptation of the organism that enables it to colonise its host.  Pertactin is an adhesin that promotes adhesion of B. pertussis bacteria to the tracheal epithelium of humans.  Pertactin (Prn) is one of the antigens in the acellular vaccine along with inactivated pertussis toxin (PT), filamentous hemagglutinin (FHA) and fimbriae types 2 and 3 (Fim).  The U.S. group, as reported in NEJM, found both insertions and stop codons that prevented the B. pertussis bacterium from expressing pertactin although the virulence of the pertactin negative strains was the same as pertactin positive strains.

Japan and France have also found pertactin negative strains but with different insertions and deletions in a different allele than what has been found in the U.S. although the net result is the same. The current theory is that these mutations have occurred through selective adaptations against the acellular vaccines.  The pertactin negative strains may not be as virulent as the pertactin positive strains although more research would be necessary to confirm this.
The only significant difference (p = 0.29) was that the time between the beginning of the cough and hospitalization was longer for infants infected with a PRN– isolate; this finding might reflect less severe disease in this group.
Note: I believe that the reported p-value of 0.29 is a typo and perhaps should have been 0.029.

The vaccines still remain effective for attenuating disease severity even with fewer than the age-appropriate dosing schedule of three by six months old.
Vaccination was associated with less severe clinical symptoms (Table 2): the proportion of hospitalizations in intensive care units was significantly lower in the vaccinated group (p = 0.001). Clinical symptoms, such as apnea, syncope, cyanosis, and deterioration of general condition, were also less frequent in the vaccinated group (Table 2). This confirms previous findings (12) indicating that infants who receive 1 or 2 doses of pertussis vaccine are protected to some extent.
Pertussis vaccination introduced in the U.S. in the 1940s (as a whole-cell vaccine) and around the world at various times after that have undoubtedly saved millions of lives.  This finding does not negate the necessity of infants receiving the full series and older children and adults remaining current on boosters in order to prevent widespread morbidity and mortality.  What these findings do is highlight the importance of developing more effective pertussis vaccines while maintaining a high safety profile.