Correspondence

Acellular Pertussis Vaccines

N Engl J Med 1996; 334:1547-1548June 6, 1996

Article

To the Editor:

As a participating observer at the International Symposium on Pertussis Vaccine Trials, I was surprised to read the following statement in the editorial by Edwards and Decker (Feb. 8 issue)1: “All the acellular vaccines evaluated in the six studies that included a whole-cell vaccine had absolute efficacies that approached or exceeded those of their comparison whole-cell vaccine.”

Table 1Table 1Comparative Efficacy of Whole-Cell and Acellular Pertussis Vaccines. shows the relevant data from these studies. On the basis of these data, a different conclusion can easily be drawn. In four of the six trials, the efficacy of the whole-cell vaccine exceeded that of the acellular vaccine, and in two trials, the efficacy of the whole-cell vaccine, manufactured by the same U.S. company, was unexpectedly low. The efficacy rate for a new vaccine should consistently be in the 90 percent range before it is recommended for general use.

The disadvantages of the acellular pertussis vaccines are the lack of an optimal antigen composition and quantity. As stated at the symposium, the present annual production capacity of 15 million to 30 million doses is insufficient to cover the yearly need for pertussis vaccines throughout the world (900 million doses). Hence, the symposium's recommendation to continue with the use of the whole-cell vaccine on a global scale can easily be understood.

Further disadvantages of the acellular pertussis vaccines have become apparent. There are more local reactions after boosters with acellular vaccine in children who were initially immunized with this vaccine than in those who were initially immunized with the whole-cell vaccine and then received boosters with acellular vaccine.2,3 Mixing the whole-cell pertussis vaccine with diphtheria and tetanus toxoid as well as with Haemophilus influenzae type b vaccine (conjugated with either tetanus or diphtheria toxoid) does not reduce the immunogenicity of the haemophilus vaccines,4 whereas mixing acellular pertussis vaccine with it does reduce its immunogenicity (unpublished data). Such incompatibility among vaccines may be an important practical drawback. Other outstanding issues concerning acellular pertussis vaccines have been summarized recently.5

A single-dose vaccine would represent real progress in immunization against pertussis, but such an approach was not even mentioned at the symposium. The use of multiple injections will continue into the next millennium, unless vaccine research becomes more innovative.

Anton Alexander Poltera, M.D.
Swiss Vaccine and Serum Institute, CH-3001 Berne, Switzerland

5 References

1
Edwards KM, Decker MD. Acellular pertussis vaccines for infants. N Engl J Med 1996;334:391-392
Full Text | Web of Science | Medline

2
Blennow M, Granstrom M. Adverse reactions and serologic response to a booster dose of acellular pertussis vaccine in children immunized with acellular or whole-cell vaccine as infants. Pediatrics 1989;84:62-67
Web of Science | Medline

3
Halperin SA, Mills E, Barreto L, Pim C, Eastwood BJ. Acellular pertussis vaccine as a booster dose for seventeen- to nineteen-month-old children immunized with either whole cell or acellular pertussis vaccine at two, four and six months of age. Pediatr Infect Dis J 1995;14:792-797
CrossRef | Web of Science | Medline

4
Begg NT, Miller E, Fairley CK, et al. Antibody responses and symptoms after DTP and either tetanus or diphtheria Haemophilus influenzae type B conjugate vaccines given for primary immunisation by separate or mixed injection. Vaccine 1995;13:1547-1550
CrossRef | Web of Science | Medline

5
Poland GA. Acellular pertussis vaccines: new vaccines for an old disease. Lancet 1996;347:209-210
CrossRef | Web of Science | Medline

To the Editor:

. . . Efficacy varies among whole-cell and acellular vaccines. The different designs, vaccines, and immunization schedules used in the six studies make a sound meta-analysis impossible. Yet it seems unfair to conclude, as Edwards and Decker do, that all the acellular vaccines “had absolute efficacies that approached or exceeded those of their comparison whole-cell vaccine.” It is more appropriate to say that one of the whole-cell vaccines, evaluated in two randomized, controlled trials in a three-dose schedule, has an unacceptably low efficacy, whereas other whole-cell vaccines, widely used around the world and evaluated in two controlled and two uncontrolled trials, have efficacies that are similar to or higher than those of the comparison acellular vaccines.

We agree that because of the better safety profile of acellular vaccines, demonstrated in all but one study (in Senegal), the best-performing acellular vaccines should be considered for routine use: their greater acceptability will probably favor increased coverage. But the achievement of worldwide high coverage is strictly related to cost. Even if one considers the savings associated with the reduced incidence of side effects, acellular vaccines currently cost two to three times more than whole-cell vaccines. Unless the cost of acellular vaccines decreases substantially, there will be no alternative to the use of whole-cell vaccines in countries with scarce resources. But even in rich countries, and particularly where high coverage has already been achieved with whole-cell vaccines despite concern about their adverse effects, advisory committees should carefully assess the cost effectiveness of switching to acellular vaccines. This careful assessment was not carried out in Italy, where many local health authorities switched to acellular vaccines in an overly hasty manner and on the basis of incomplete information about the results of the Italian trial, with no discernible effort to consider an alternative and more cost-effective use of resources.

Giorgio Tamburlini, M.D.
Paola Materassi, M.D.
Istituto per l'Infanzia, 34137 Trieste, Italy

Author/Editor Response

The authors reply:

To the Editor: We appreciate and have little disagreement with the comments of Drs. Tamburlini, Materassi, and Poltera; whether the glass is more full than empty depends on one's perspective. Consider Dr. Poltera's table: clearly, the efficacies of the acellular vaccines evaluated in Sweden and Italy exceed those of the control whole-cell vaccine. We cannot escape the conclusion that the efficacies of the acellular vaccines in the other studies so markedly exceed those of the U.S.-licensed whole-cell vaccine used as the control in Sweden and Italy that there is no doubt that the former vaccines are all more effective than the latter. Thus, the point of dispute is whether the efficacies of the acellular vaccines in the other trials approach those of the whole-cell vaccines in the same trials. Does 93 percent approach 96 percent? Does 86 percent approach 96 percent? How about 89 percent and 98 percent, or 82 percent and 91 percent? One's judgment depends on one's expectations.

Our minimal expectations were defined at meetings held early in this decade to plan the efficacy studies sponsored by the National Institutes of Health and are reflected in the sample-size calculations in the technical report of the Swedish trial1: a true efficacy of 80 or 85 percent for whole-cell vaccine, as compared with a true efficacy of at least 70 percent (i.e., up to 15 percent less) for acellular vaccine. The efficacies of the acellular vaccines evaluated in Germany and Senegal exceeded these expectations, both in absolute terms and as compared with the control whole-cell vaccines. For us, the glass is much more than half full. We believe the vaccines performed more than well enough to warrant licensure. But what about recommendations for use — an entirely separate question?

We do not agree that a vaccine must have an efficacy in the 90 percent range to be recommended for general use. Indeed, such a criterion would eliminate the standard influenza and pneumococcal vaccines, among others. The correct question is whether the benefits of a proposed vaccine exceed the disadvantages sufficiently to warrant its adoption. The answer should take into consideration efficacy, adverse effects, and cost. Whole-cell pertussis vaccine is inexpensive and highly effective, and its continued use will be the obviously correct choice in some jurisdictions; other jurisdictions may face difficult choices between the acellular and the whole-cell pertussis vaccine. For the United States, we believe the choice is not difficult. We are convinced that all the acellular vaccines that have been studied are more effective and safer than at least one of the whole-cell vaccines commonly administered to U.S. infants.

Michael D. Decker, M.D., M.P.H.
Kathryn M. Edwards, M.D.
Vanderbilt University School of Medicine, Nashville, TN 37232

1 References

1
Gustafsson L, Hallander H, Olin P, Reizenstien E, Storsaeter J. Efficacy trial of acellular pertussis vaccines: technical report, trial 1. Stockholm, Sweden: Swedish Institute for Infectious Disease Control, 1995:12.

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