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Department of Pediatrics, David Geffen School of Medicine at UCLA, and Division of Infectious Diseases, Mattel Children's Hospital at UCLA, University of California, Los Angeles
The Perspective article by Robbins et al. calls attention to the important emerging problem of excessive local adverse reactions after the administration of booster doses of diphtheria-tetanus toxoidsacellular pertussis (DTaP) vaccines [1]. Many of the issues they raise are controversial, but because they have been addressed by myself and others elsewhere, it is not necessary to do so again [2, 3].
Robbins et al. should be commended, however, for calling attention to a very real emerging problem. They are correct in recognizing that excessive local reactions to booster doses of DTaP vaccines will result in negative publicity and may reduce public acceptance of these vaccines.
Presently, 3 DTaP vaccines for children are available in the United States (table 1). As can be seen in table 1, the 2 most commonly used products (Infanrix and Daptacel) contain significant concentrations of both diphtheria toxoid and pertussis toxoid.
I anticipated this emerging problem with local reactions >10 years ago, and similar problems were noted >15 years ago in Canada and Australia when European-formulated diphtheria-tetanus toxoidswhole-cell pertussis (DTP) vaccines were used ([4, 5]; personal observation during 1989 visit to Australia). During the last 2 decades of the 20th century, the DTP and diphtheria-tetanus toxoids (DT) vaccines used in the United States contained <15 limits of flocculation (Lf) of diphtheria toxoid and 5 Lf of tetanus toxoid per dose, whereas the DTP and DT vaccines used in Europe, Canada, and Australia contained 25 Lf of diphtheria toxoid per dose. In the past, DTP immunization in much of Europe, Canada, and Australia involved a 3-dose schedule without booster doses. When booster doses were added to the schedule in Canada and Australia, marked local reactions were observed ([5]; personal observation during 1989 visit to Australia). In contrast, similar local reactions to booster doses were not a major problem in the United States [6]. In a study by our research group in Germany, it was found that the frequency of significant erythema and induration at the injection site was greater after the administration of 3 doses of German DT vaccine (containing 25 Lf of diphtheria toxoid and 10 Lf of tetanus toxoid) than after the administration of 4 doses of Lederle DTP vaccine (containing 12.5 Lf of diphtheria toxoid and 5 Lf of tetanus toxoid) [4].
In the DTaP vaccine efficacy trials conducted in Italy and Sweden during the early 1990s, 3 doses of vaccine were administered at 2, 4, and 6 months of age, and no booster doses were employed [7, 8]. With this regimen, good efficacy was demonstrated for both Infanrix and Daptacel, and protection persisted for >4 years [9, 10].
One solution to the problem of excessive local reactions is a modification of that suggested by Robbins et al. [1]. Specifically, the use of genetically inactivated mutant diphtheria and pertussis toxins in a DTaP vaccine that also contains filamentous hemagglutinin, pertactin, and fimbriae could reduce the vaccine's specific protein content and therefore decrease the number of local reactionsand the vaccine would still be expected to be efficacious. However, the development and licensure of such a vaccine would be unlikely to occur in the near future.
The more immediate solution to the problem is to realize that our present one-size-fits-all immunization schedule, which was fine for the DTP vaccines used in the United States, is not satisfactory for the 2 most efficacious DTaP vaccines presently available, Infanrix and Daptacel. Both vaccines have been shown to provide extended protection after a total of 3 doses administered at 2, 4, and 6 months of age [710]. Therefore, protection against pertussis would not be compromised if the booster dose that is typically administered during the second year of life was omitted from the DTaP immunization schedule. Furthermore, it is likely that the booster dose that is typically administered at 46 years of age could be replaced in the DTaP immunization schedule with a dose of one of the soon-to-be-licensed vaccines that have been formulated for adolescents and adults and that have significantly less protein content than do the traditional DTaP vaccines. The major concern regarding these suggestions relate to protection against diphtheria and tetanus. However, the experience in Germany and in some other western European countries with DT and DTP vaccines during the previous 2 decades is reassuring in this regard. My suggestions would, of course, need to be evaluated in controlled comparative immunogenicity studies.
References
1. Robbins JB, Schneerson R, Trollfors B, et al. The diphtheria and pertussis components of diphtheria-tetanus toxoidspertussis vaccine should be genetically inactivated mutant toxins. J Infect Dis 2005; 191:818. First citation in article
2. Cherry JD. The science and fiction of the "resurgence" of pertussis. Pediatrics 2003; 112:4056. First citation in article
3. Cherry JD, Heininger U. Pertussis. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan S, eds. Textbook of pediatric infectious diseases. 5th ed. Philadelphia: WB Saunders, 2004. First citation in article
4. Cherry JD. Strategies for diphtheria, tetanus, and pertussis (DTP) immunization. In: Strategies for pediatric vaccines: conventional and molecular approaches: report of the 104th Ross Conference on Pediatric Research. Columbus, OH: Ross Products Division, Abbott Laboratories, 1994:21822. First citation in article
5. Scheifele DW, Meekison W, Grace M, et al. Adverse reactions to the preschool (fifth) dose of adsorbed diphtheria-pertussis-tetanus vaccine in Canadian children. CMAJ 1991; 145:6417. First citation in article
6. Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 1981; 68:65060. First citation in article
7. Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. Progetto Pertosse Working Group. N Engl J Med 1996; 334:3418. First citation in article
8. Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996; 334:34955. First citation in article
9. Salmaso S, Mastrantonio P, Tozzi AE, et al. Sustained efficacy during the first 6 years of life of 3-component acellular pertussis vaccines administered in infancy: the Italian experience. Pediatrics 2001; 108:e81. Available at: http://www.pediatrics.org/cgi/content/full/108/5/e81. Accessed 8 March 2005. First citation in article
10. Olin P, Gustafsson L, Barreto L, et al. Declining pertussis incidence in Sweden following the introduction of acellular pertussis vaccine. Vaccine 2003; 21:201521. First citation in article