January 2001
In 1934, there were more than a quarter of a million cases of pertussis reported in the United States, which had a much smaller population than at present. Subsequently, an inactivated bacterial whole cell vaccine (wP) was introduced for routine use which led to a marked decline in cases.
In 1956, it was stated "administration of any whooping cough vaccine involves a definite but remote risk of serious results. However, the mortality of whooping cough can be so high and the protective value of the vaccine is so well established that the truly remote risks should not interfere with widespread use of the vaccine" (Common Contagious Disease, Stimson and Hodes). However, as the disease became less of a problem, the reactions loomed as a major problem. The response was the development of a number of acellular pertussis vaccines (aP) which have markedly reduced the reactions to wP. However, the initial vaccines were "experiential" with little basic understanding of the role of the various components of Bordetella pertussis in the pathogenesis of whooping cough.
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Although much has been learned in the interim, the varied composition of aP suggests that we are not there yet. The recent Advisory Committee on Immunization Practices (ACIP) announcement on the reactions to the fourth and fifth injections of aP-containing vaccines [MMWR 2000;49 (RR13)] may be a reflection of this void. It is not clear, moreover, whether these reactions are due to the pertussis components of the DTaP.
It has been observed that children tend to have increased reactivity to successive doses of aP. Those who have received booster doses of aP have been reported to have more redness, induration, pain and fever within two days following immunization than after the initial three doses. Swelling involving the entire limb has been reported following booster doses of different aP in 1% to 3% of vaccinees lasting an average of four days in one series. These children tend to be more irritable and have more pain, redness and warmth at the injection site than vaccinees without this complication. The preferred vaccine for the fourth and fifth doses continues to be aP. The vaccinees have suffered no other significant ill effects and no intervention appears to be indicated, as the swelling is self-limited. However, it is important that parents be alerted to the possibility of this reaction prior to giving the fourth or fifth dose of aP.
There is little experience with administration of a fifth dose to children who have had whole limb swelling after the fourth dose, however, the ACIP statement states the "extensive swelling after the fourth dose should not be considered a contraindication for receipt of the fifth dose of the DTaP series." Peg Rennels, MD, said that three children who had entire limb swelling after the fourth dose of DTaP and were reimmunized did not report a problem after dose five [Pediatrics 2000;105:e12]. It would be interesting to see how many parents will be willing to try another dose of aP after total limb swelling following the fourth dose. (These reactions should be reported to the Vaccine Adverse Events Reporting System at (800) 822-7927 or www.fda.gov/cber/vaers/report.htm.)
The reason for these local reactions is not understood at this time. Pertussis toxin, aluminum and diphtheria content all have been suspected. It has been observed with all of the aP-containing vaccines. The reactions seem to be complex, in that entire limb swelling and other severe local reactions have different kinetics and also may be related to different components of aP. The diphtheria toxoid content appears to be most closely related to reactivity [Pediatrics 2000;105:e12]. This is not surprising, since we reduce the amount of diphtheria toxoid after the sixth birthday because of increasing reactivity with increasing age. It is entirely possible that some 5-year-old vaccinees may be among the older group who react adversely. In the olden days, prior to reducing the amount of diphtheria toxoid given to adults (dt rather than DT) we used to test for reactivity to diphtheria toxoid with the intradermal Moloney test. Perhaps the use of this test at the present time might at least elucidate the role of diphtheria toxoid in these reactions.
At the present time only Acel-Imune (Lederle) and Tripedia (Aventis-Pasteur) are licensed for the fifth dose of DTaP, although applications for this dose for Infanrix (Smith Kline Beecham) and Ceriva (North American Vaccine) are now pending. As aP vaccines contain different components of pertussis and there are insufficient data to make a judgement on mixing brands, a preference is expressed for continuing the series with the same preparation when feasible.
In the absence of data regarding which antibody is responsible for protection against pertussis, clinical trials had to be done to establish efficacy. Unfortunately, these trials did not yield the serologic correlates which would have given us the information needed to enable us to use antibody titers in lieu of vaccine efficacy trials; to evaluate mixing brands in a vaccine series; to evaluate new combinations, new aP vaccines or to determine whether one of the licensed preparations is preferable to another.
There were no direct clinical comparisons of the four licensed products. Thus, in the absence of these data or the knowledge of the contribution of a given antibody to a pertussis component, one cannot express a preference for one of the four preparations now licensed.
Although booster doses have been used here in the United States, this in not so in many other countries. In spite of this we are reporting a greater number of cases in adults. Much of this rise in adolescent/adult cases may be attributable to the increased use of serologic diagnosis, which still is not accepted by many. In addition, there appear to be regional differences in the occurrence of adult/adolescent pertussis. Preliminary results of studies in Los Angeles, for instance, indicate that there may be fewer cases in older individuals than have been reported in Boston [J Infect Dis 2000;182:1409].
The final report of the former trials also should reveal data on the specificity and sensitivity of serologic diagnosis of pertussis. There has been interest in giving aP to adolescents and adults as a DTaP in an attempt to reduce the reservoir of pertussis in this country. This would presumably prevent the transmission of pertussis from these older individuals to infants. The recent observations on local reactions in recipients of boosters of aP will certainly enter into considerations of whether to pursue adult booster of aP.
The pertussis story continues to reveal the deficiencies in our basic knowledge of this organism. Despite this, we have had remarkable success in reducing the morbidity from this disease.
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