Elsevier

The Lancet

Volume 350, Issue 9091, 29 November 1997, Pages 1569-1577
The Lancet

Articles
Randomised controlled trial of two-component, three-component, and five-component acellular pertussis vaccines compared with whole-cell pertussis vaccine

https://doi.org/10.1016/S0140-6736(97)06508-2Get rights and content

Summary

Background

Trials in Italy and Sweden showed high efficacy for three-component and five-component pertussis vaccines, and poor efficacy for a whole-cell vaccine licensed in the USA and a two-component vaccine. We compared the efficacy of three acellular vaccines with a UK whole-cell vaccine.

Methods

We enrolled 82892 babies aged 2–3 months. Babies were vaccinated at age 3 months, 5 months, and 12 months, or age 2 months, 4 months, and 6 months. They were randomly assigned a two-component acellular diphtheria-tetanus-pertussis (DTP) vaccine (n=20697), a three-component acellular DTP vaccine (n=20728), a five-component acellular DTP vaccine (n=20747), or a UK whole-cell DTP vaccine (n=20720). We collected data for all reported cases of culture-confirmed pertussis during 3 years of follow-up. The treatment status of the two-component-vaccine group had to be made known midway through the trial for boosting because of poor efficacy. We included data for the two-component vaccine in the analysis of safety and immunogenicity, and data up its unmasking in secondary analyses of relative efficacy. Analyses were by intention to treat.

Findings

During follow-up from the third dose (mean 22 months), in the 3 months, 5 months, 12 months schedule, there were 15 cases of culture-confirmed pertussis with at least 21 days of paroxysmal cough in the whole-cell group, relative risk 1·00, compared with 13 in the five-component group (0·85 [95% Cl 0·41–1·79]), and 21 in the three-component group (1·38 [0·71–2·69]). For culture-confirmed pertussis, with or without cough, there were 19 cases in the whole-cell group (1·00), 27 in the five-component group (1·40 [0·78–2·52]), and 49 in the three-component group (2·55 [1·50–4·33]). In the intention-to-treat analyses, from the first dose in the 3 months, 5 months, 12 months schedule the whole-cell vaccine was significantly more protective than the three-component vaccine against typical pertussis.

Between the second and the third doses, culture-confirmed pertussis with any cough and with at least 21 days of paroxysmal cough was significantly more frequent in the two-component group than in the three-component group, and in the three-component group than in the five-component and the whole-cell groups, respectively.

The serological response of the acellular vaccines in the 2 months, 4 months, 6 months schedule were similar to those previously reported. The whole-cell vaccine was highly immunogenic for fimbriae, pertactin, and filamentous haemagglutinin, but had a low antipertussis toxin response. Hypotonic hyporesponsiveness occurred significantly more frequently in the whole-cell group (p<0·05) and was more frequent in the acellular groups than previously reported. High fever and seizures occurred more frequently after whole-cell vaccine than after any of the acellular vaccines (p<0·001).

Interpretations

The efficacy of the UK whole-cell vaccine and the five-component and three-component vaccines was similar against culture-confirmed pertussis with at least 21 days of paroxysmal cough. The lower efficacy of the three-component vaccine against mild disease suggests that fimbriae have a role in protection against infection. The efficacy of acellular vaccines depends on the number of components, and different whole-cell vaccines have variable efficacies.

Introduction

Two trials in Italy1 and Sweden2 showed high efficacy for two three-component acellular, pertussis vaccines containing inactivated pertussis toxin, filamentous haemagglutinin, and pertactin, and one five-component acellular pertussis vaccine containing the same components plus fimbriae 2 and 3, given to babies at 2 months, 4 months, and 6 months. By contrast, a tested US-licensed whole-cell pertussis vaccine, and a two-component acellular pertussis vaccine containing inactivated pertussis toxin and filamentous haemagglutinin, had inadequate efficacy. However, commentators on these and other pertussis-vaccine trials take the view that most acellular vaccines have similar protective efficacy,3, 4, 5 and that all acellular vaccines are less effective than the best whole-cell vaccines.6 In addition, Robbins and colleagues7 have argued that pertussis toxoid alone is protective. However, a critical review of available data suggested that protection, especially against infection with mild disease, increases with the number of vaccine components.8

We compared in a randomised, double-blind trial the earlier-studied two-component and three-component acellular pertussis vaccines1, 2 and a modified five-component acellular pertussis vaccine with a UK whole-cell vaccine. Because we found low efficacy in a previous trial,2 we had to make known the treatment status of the two-component vaccine group midway through this trial.9 We present the main results of the planned analysis of the trial. Further details are given elsewhere.10

Section snippets

Patients

Babies born between June 1, 1993, And May 31, 1994, in 22 of 25 Swedish counties, or between June 1, 1993, and June 30, 1994, in Malmohus, Sweden, were eligible for enrolment. We informed parents about the trial in person during visits to clinics and in writing through the child-health nurse or district nurse when the child was aged 1–3 weeks. The nurses asked parents whether they wanted their child to participate. Babies were excluded if no parent could understand the written information, if

Results

100 471 children were eligible for the study, according to population data from Statistics Sweden (figure 1). 82 892 children were randomised at the time of the first trial dose: 82 864 of the babies belonged to the eligible cohort (82–5% of eligible children), and 28 had a birth date outside the eligible period of birth. All children were randomly assigned vaccines at the time of first injection. 72 698 were enrolled in centres using the 3 months, 5 months, 12 months schedule and 10 194 in

Discussion

We enrolled 82·5% of eligible babies in the 23 participating counties in Sweden. Few children had protocol violations and the rate of withdrawal from the study was small. There was little variation in geographical distribution between groups, or in basic characteristics such as sex, age at first dose, and interval between doses. Randomisation gave a balanced distribution between groups even among children vaccinated at the individual child-health centre. Potential confounders, such as

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