A meta-analysis initially done by Jefferson et al (1) of acellular (acP) vaccine efficacy and safety in children was revisited by Zhang et al in the Cochrane Library (2). Zhang correctly did not perform a formal meta-analysis, stating that it was not appropriate due to the small number of efficacy trials and the significant heterogeneity across these trials with respect to immunization schedules, case definitions, follow-up duration, products used, and background pertussis rates. The inappropriateness of applying a meta-analysis methodology to these studies was previously highlighted by Desauziers et al (3) and Simondon (4) following Jefferson et al’s previous publication (1).
The review by Zhang et al concludes that “of the currently available acellular vaccines, multi-component vaccines confer better protection, against both classical whooping cough and mild pertussis infection, than vaccines containing only one or two components.” Although it is intuitively attractive to adopt a “more components is better” position on acP vaccines, this strong conclusion on differential efficacy of acellular vaccines is not objectively supported by the reviewed trials nor by the data these trials generated. Nor is this conclusion supported by previously published commentaries or by the positions expressed by professional pediatric and national immunization policy bodies.
Zhang et al included in their review six controlled trials that were designed well enough to ensure high internal validity and one trial without active surveillance of cases. All of these trials were performed between 1988 and 1997. Only three of these trials were efficacy trials that directly compared different acellular vaccines in a double-blind, randomized design, with an active follow-up, and laboratory confirmation of cases. The majority of currently licensed pertussis vaccines have not been compared in head-to-head efficacy trials. Most critically there are no clinical trials that directly compare the efficacy of licensed 2-acP vaccines with that of licensed 3-acP or 5-acP vaccines. In fact, the only study in which a 2-acP vaccine was less efficacious than multi-component acellular vaccines involved an experimental 2-acP vaccine that was never licensed/registered, precisely because of its limited efficacy. Since other 2-acP vaccines did demonstrate sufficient efficacy to be licensed, the more appropriate interpretation of the experimental 2-acP vaccine data is that it is not the number of acP components but rather some other feature or combination of features (e.g. the source of the antigens, their relative concentrations, the processes for their purification and detoxification, or the nature and concentration of the adjuvants) of each individual vaccine that determine efficacy. The biasing potential of including data from the unlicensed, experimental 2-acP vaccine is not clearly discussed in Zhang et al’s review.
The Zhang et al publication highlights the continuing debate over the relative merits of data from randomized controlled trials (RCTs) versus data from observational studies in evidence-based reviews. Our belief is that, in the real world of vaccination policy decision making, these two different data sets are entirely complementary. Well-designed RCTs offer higher internal validity, while equally well-designed observational studies provide higher external validity and a better reflection of the real world. For example, a well-designed case-control study performed in Germany by Liese et al (5) reported that a licensed 2-acP vaccine was 93% effective in prevention of 21 or more days of paroxysmal cough that was laboratory-confirmed as pertussis. This study was excluded from the review because it was not a RCT. The exclusion of this study and the associated potential for bias should also have been discussed by Zhang et al.
Other published effectiveness data clearly support the effectiveness of both 1- and 2-acP vaccines as well as other multi-component acP vaccines. These data, with their high external validity, have been reported not only from Japan, the United States and Canada (6-10) but also from France, Austria, Finland, Denmark, Sweden and Germany (11-16), and underscore the effectiveness of national vaccination programs in preventing whooping cough in children, regardless of the number of acP components in the licensed vaccines used.
Observational studies might overestimate vaccine effectiveness, if persons included as cases in the studies had more severe pertussis than persons not included, or if the vaccination status would influence the likelihood of the diagnosis of pertussis in a coughing person. Nonetheless, none of these studies identified a lower effectiveness of 2-acP licensed vaccines in pre-school children compared to “multi-component vaccines or whole cell vaccines” (9, 15). These results contradict the conclusions of Zhang et al and as a result they should have been discussed.
The studies included in the review did not use the same follow-up duration but these differences are not addressed even though they contribute to the heterogeneity of the data. The impact of duration of follow-up on efficacy estimates has been well illustrated. In one study (17), a highly effective whole cell vaccine and a 2-acP vaccine demonstrated equivalent efficacies until 18 months of age with a relative risk: 1.16 (95%CI 0.77-1.72). Only after 18 months of age was the whole cell vaccine shown to retain higher efficacy (relative risk: 1.76 [95%CI 1.33-2.33]) than the acellular vaccine in the absence of a booster dose in the two groups.
The inappropriateness of relating acP vaccine efficacy to the number of pertussis components has been addressed by both American and European regulatory authorities (18, 19) and by international expert panels charged with comparing results between studies (20-22). These groups have concluded that the available data support the practical policy guidance that all licensed acellular vaccines are highly effective.
In summary, the overall body of available data supports a conclusion that all licensed acP vaccines, regardless of the number of pertussis components, have proven highly effective. Despite the intrinsic attractiveness of such a conclusion, these data do not support the Zhang et al conclusion that 1- and 2-acP vaccines are less effective than those with more acellular components. The dangers of this conclusion coming from such respected authors include confusion in the vaccination community and the inappropriate preference for one group of vaccines over another. This in turn might lead to negative impacts on vaccine supply and immunization rates.
1 Sanofi Pasteur, Lyon France
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2. Zhang L, Prietsch SOM, Axelsson I, Halperin SA. Acellular vaccines for preventing whooping cough in children. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD001478. DOI:10.1002/14651858.CD001478.pub4.
3. Desauziers E, Hessel L, Decker MD, Caro JJ, Liese JG. Systematic review of the effects of pertussis vaccines in children. Vaccine. 2004 Jul 29;22(21-22):2681-4; author reply 2685.
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We thank Philippe P. J. André and David R. Johnson from Sanofi Pasteur (Lyon, France) for their interests and comments on our review. Their main concern is one of the review’s conclusions “Of the currently available acellular vaccines, multi-component vaccines confer better protection against both classical whooping cough and mild pertussis infection than vaccines containing only one or two components”. We recognise that this conclusion is based on indirect evidence since the majority of currently licensed pertussis vaccines have not been compared in head to head efficacy trials as André and Johnson pointed out.
André and Johnson’s comments are likely to provoke an old and ongoing debate on the comparative efficacy of acellular pertussis vaccines with different antigen components which is ironic since Sanofi Pasteur markets both two and five component acellular pertussis vaccines. This question has been well addressed by Patrick Olin in 1997 (1). In this commentary, Olin stated that “Contrary to the position taken in most commentaries, analysis of the results of the four placebo-controlled trials of two one-component, two two-component, two three-component and one five-component vaccine unequivocally demonstrate the multi-component vaccines to have better protective efficacy against both mild and typical pertussis than one- and two-component vaccines”. The results from another recent systematic review with 49 randomised controlled trials (RCTs) and 3 cohort studies are also consistent with the findings of our review (2). The current evidence on comparative efficacy of acellular pertussis vaccines with different antigen components has been cited by the most recent WHO position paper on pertussis vaccines (3).
We are conscious that the clinical implication of any possible superiority of multi-component vaccines over mono- and bivalent vaccines in the efficacy demonstrated by RCTs needs to consider the transferability of this conclusion to whole countries and vaccine delivery systems. The effectiveness of vaccination programmes on a national scale for controlling infectious disease depends not only on the efficacy of the vaccine but also other factors such as the vaccination schedule and adherence, and transportation and storage of the vaccine. Moreover, indirect effects in producing herd immunity in the population may also contribute to the effectiveness of large-scale vaccination in controlling infectious diseases (4,5). Therefore, successful control of pertussis infections by two-component vaccines in Japan and in other countries (5-7) does not necessarily exclude the potential additional benefits of large-scale vaccination with multi-component vaccines.
This is a systematic review of RCTs, so we did not included observational studies in the review. In the next update, we will devote a special paragraph in the discussion to compare the results from RCTs and observational studies, and to address the potential contribution of follow-up duration for the heterogeneity across the studies, as suggested by André and Johnson. We will also modify the conclusion to be “Currently available evidence suggests that multi-component vaccines confer better protection against both classical whooping cough and mild pertussis infection than vaccines containing only one or two components”.
1. Olin P. Commentary: The best acellular pertussis vaccines are multicomponent. Pediatr Infect Dis J 1997;16(5):517-519.
2. Jefferson T, Rudin M, DiPietrantonj C. Systematic review of the effects of pertussis vaccines in children. Vaccine 2003; 21(17-18):2003-2014.
3. WHO. Pertussis vaccines: WHO position paper. Weekly Epidemiol Record 2010;85:385-400.
4. Stephens DS. Vaccines for the unvaccinated: Protecting the herd. JID 2008;197:643-645.
5. Carlsson RM, Trollfors B. Control of pertussis--lessons learnt from a 10-year surveillance programme in Sweden. Vaccine. 2009;27(42):5709-5718.
6. Kuno-Sakai H, Kimura M. Safety and efficacy of acellular pertussis vaccine in Japan, evaluated by 23 years of its use for routine immunization. Pediatr Int. 2004;46(6):650-655.
7. Hviid A, Stellfeld M, Andersen PH, Wohlfahrt J, Melbye M. Impact of routine vaccination with a pertussis toxoid vaccine in Denmark. Vaccine. 2004;22(27-28):3530-3534.