After years of anticipation, acellular pertussis vaccines are mow licensed for use in Canada. In the past several months, two acellular pertussis vaccines, combined with diphtheria and tetanus toxoids (DTaP vaccines), have been licensed for use for the fourth and fifth doses in children 15 months of age or older. Licenses for infant use (at two, four and six months of age) will likely follow within a year, thereby permitting replacement of the whole-cell pertussis vaccine that has been in use for over 50 years with an acellular pertussis vaccine for all doses.
The milestones will be achieved, in part, as a result of the recently reported series of seven vaccine efficacy studies involving eight DTaP vaccines performed in Europe and Africa. Although employing different study designs, all of the studies showed the DTaP vaccines to be safe and efficacious for the prevention of pertussis (defined by the World Health Organization case definition: as 21 days or more of paroxysmal cough and a culture, laboratory, or in some instances epidemiological link). When a whole-cell pertussis vaccine was included, the acellular pertussis vaccines were as effective as or more effective than the whole-cell pertussis vaccine. The studies were not designed to compare the efficacy of different DTaP vaccines; therefore, few inferences and no conclusions can be drawn that would favour one DTaP over another. All of the acellular pertussis vaccines contained pertussis toxoid (PT) with or without the addition of other pertussis components (filamentous hemagglutinin [FHA]; the 69 kDA protein [69K]; fimbriae [FIM]). Although one must use caution in comparisons of data between any individual studies, perhaps the safest comparisons can be made among the three studies with the optimal study design, that being prospective, randomized, double-blind placebo controlled cohort studies (Stockholm, Sweden; Göteberg, Sweden; Italy). The lowest efficacy of a DTaP reported was 59% (95% CI 51 to 86; SmithKline Beecham, Rixensart, Belgium) using a PT- and FHA-containing DtaP; the addition of 69K to this vaccine increased the protective efficacy to 84% (95% CI 76 to 89, SmithKline Beecham; 95% CI 76 to 90; Chiron/Biocine, Siena, Italy), suggesting an incremental benefit of 69K. A PT monocomponent vaccine also resulted in a lower efficacy of 71% (95% CI 63 to 78; Amvax, Maryland) suggesting that there may be incremental benefit with the inclusion of FHA. Further addition of FIM to PT, FHA, and 69K did not increase the protective efficacy (85%, 95% CI 81 to 89; Connaught Laboratories Ltd); however, preliminary data may suggest better protection against milder disease with this multicomponent product.
Although these ‘soft’ inferences may be made from these clinical trials, the data from some of the other efficacy studies using other study designs complicate the situation. In Munich, Germany a PT/FHA vaccine had an efficacy of 89% (95% CI 77 to 95; Connaught Laboratories Inc, Pennsylvania) in a prospective case-control study design. Another PT/PHA vaccine had an efficacy of 83% (95% CI 61 to 93; Pasteur-Merieux, Lyon, France) in Senegal, West Africa using a prospective, randomized double-blind cohort design with a parallel diphtheria and tetanus vaccine (DT) nonstudy control group. In Erlangen, Germany, a vaccine with PT, FHA, 69K and FIM (Wyeth-Lederle) had an efficacy of 74% after three doses and 82% after four doses in a randomized, double-blind cohort study design with an open, randomized DT cohort control. Finally, in Mainz, Germany, the same PT/FHA/69K-containing vaccine that had been used in Italy had an efficacy of 89% (95% CI 77 to 95, SmithKline Beecham) in a prospective blinded household contact study. In addition to differences in study design, different immunization schedules (two, four, six months; three, four, five months; or three, five, 12 months) and the number of doses administered (three or four) may also have contributed to the difference in efficacy observed.
The striking similarities in the efficacy of the DTaP vaccines is in marked contrast to the wide range of efficacy demonstrated with the whole-cell pertussis vaccines. The effect of study design and dosing frequency may have even more influence on the results observed with the whole-cell pertussis vaccines than with the acellular pertussis vaccines. In Italy, the efficacy of three doses of the American Connaught vaccine was 36% (95% CI 14 to 52) whereas the same vaccine had an efficacy of 48% (95% CI 37 to 58) in the Stockholm trial. The Wyeth-Lederle whole-cell vaccine had an efficacy of 85% after three doses and 93% after four doses, while a French and German whole-cell vaccine had efficacies in excess of 95% in Senegal. Mainz and Munich. Parenthetically, there are no data available from these studies about the efficacy of the whole-cell pertussis vaccine in use in Canada; however, recent epidemiological data suggest an efficacy well below that demonstrated with the acellular pertussis vaccines.
From these recent studies, it can be concluded that the acellular pertussis vaccines are safe and efficacious and, if the manufacturers choose to license the products in Canada, there will be a number of excellent products available for use. The selection of a particular product may well involve factors other than safety and efficacy, such as cost, availability and ability to combine it with other vaccines given concurrently. Vaccine providers will need to await further analysis of this wealth of data as well as recommendations from the National Advisory Committee on Immunization.
TABLE 1.
Summary of efficacy studies with acellular pertussis vaccines combined with diptheria and tenanus toxoids in infants
| Study site | Vaccine composite | Vaccine manufacturer | Study design | Vaccine efficacy (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|---|
| PT | FHA | 69K | FIM | Design* | Schedule (mon) | DTAP | DTwP | ||
| Munich, Germany | ✓ | ✓ | Connaught Inc (USA) | A | 2, 4, 6 | 89(77–95) | 98 (83–100) | ||
| Erlangen, Germany | ✓ | ✓ | ✓ | ✓ | Wyeth-Lederle | B | 2, 4, 6 | 74 (NR) | 85 (NR) |
| Wyeth-Lederle | B | 2, 4, 6, 15–18 | 82 (75)† | 93 (86)† | |||||
| Stockholm, Sweden | ✓ | ✓ | ✓ | ✓ | Connaught Ltd (Canada) | C | 2, 4, 6 | 85 (81–89) | 48 (37–58) |
| ✓ | ✓ | SmithKline Beecham | C | 2, 4, 6 | 59 (51–66) | ||||
| Italy | ✓ | ✓ | ✓ | Chiron-Biocine | C | 2, 4, 6 | 84 (76–90) | 36 (14–52) | |
| ✓ | ✓ | ✓ | SmithKline Beecham | C | 2, 4, 6 | 84 (76–89) | |||
| Göteborg, Sweden | ✓ | Amvax | C | 3, 5, 12 | 71 (63–78) | none | |||
| Mainz, Germany | ✓ | ✓ | ✓ | SmithKline Beecham | D | 3, 4, 5, 15–19 | 89 (77–95) | 98 (83–100) | |
| Senegal, West Africa | ✓ | ✓ | Pasteur-Merieux | E | 2, 4, 6 | 85 (66–93) | 96 (86–99) | ||
A Prospective case control study; B Randomized, double-blind cohort study, nonrandomized open diphtheria-tetanus control; C Prospective, randomized, double-blind placebo controlled cohort study; D Prospective, blinded household contact study; E Prospective, randomized, double-blind cohort study with a parallel nonstudy diphtheria-tetanus control.
One-sided 95% CI. 69K 69 kDa protein; DTaP Acellular pertussis vaccine, combined with diphtheria and tetanus toxoids; DTwP Whole pertussis vaccines, combined with diphtheria and tetanus toxoids; FHA Filamentous hemagglutinin; FIM Fimbriae; mon Months; NR Not Reported; PT pertussis toxoid
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