Elsevier

The Lancet

Volume 370, Issue 9601, 24–30 November 2007, Pages 1757-1763
The Lancet

Articles
Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study

https://doi.org/10.1016/S0140-6736(07)61744-9Get rights and content

Summary

Background

We aimed to assess the efficacy of the oral live attenuated human rotavirus vaccine Rotarix (RIX4414) for prevention of rotavirus gastroenteritis in European infants during their first 2 years of life.

Methods

3994 study participants were enrolled from six countries and were randomly assigned two oral doses of either RIX4414 (n=2646) or placebo (n=1348), which were coadministered with the first two doses of specific childhood vaccinations. Follow-up for gastroenteritis episodes was undertaken from 2 weeks post-dose two through the two consecutive rotavirus seasons following vaccinations (combined efficacy follow-up period; mean duration 17 months [SD 1·6]). Our primary endpoint was vaccine efficacy against rotavirus gastroenteritis of any severity during the first efficacy follow-up period (2 weeks post-dose two to the end of the first rotavirus season). Stool specimens obtained during gastroenteritis episodes were tested for rotavirus by ELISA and typed by RT-PCR. Episodes scoring 11 or greater on the 20-point Vesikari scale were classified as severe. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140686 (eTrack102247).

Findings

120 infants were excluded from the according-to-protocol analysis. During the first efficacy follow-up period (mean duration 5·7 months [SD 1·2]), 24 of 2572 infants allocated RIX4414 versus 94 of 1302 given placebo had rotavirus gastroenteritis episodes of any severity, resulting in a vaccine efficacy of 87·1% (95% CI 79·6–92·1; p<0·0001). For the combined efficacy follow-up period, vaccine efficacy against severe rotavirus gastroenteritis was 90·4% (85·1–94·1; p<0·0001), for admission owing to rotavirus gastroenteritis 96·0% (83·8–99·5; p<0·0001), and for rotavirus-related medical attention 83·8% (76·8–88·9; p<0.0001), and significant protection against severe rotavirus gastroenteritis by circulating G1, G2, G3, G4, and G9 rotavirus types was shown.

Interpretation

In a European setting, two doses of RIX4414 coadministered with childhood vaccines provided high protection against any and severe rotavirus gastroenteritis, with an overall reduction of admissions for gastroenteritis over two consecutive rotavirus epidemic seasons.

Introduction

Worldwide, an estimated 611 000 children die every year from rotavirus disease, mainly in low-income countries.1 In the European Union, the annual burden of rotavirus disease is estimated at more than 200 deaths, over 87 000 admissions, and almost 700 000 outpatient visits in children younger than 5 years of age.2

An oral live attenuated human rotavirus vaccine Rotarix (RIX4414) containing the G1P[8] strain, derived from the 89-12 parent candidate,3, 4, 5 has been developed by GlaxoSmithKline (GSK) Biologicals. Two doses of the vaccine tested at different concentrations in phase II clinical trials were immunogenic, well-tolerated, and protective against rotavirus gastroenteritis.6, 7, 8, 9 In a multicentre phase III trial in Latin America (n=17 867), 85% vaccine efficacy was noted in the first efficacy follow-up period (from 2 weeks post-dose two until 1 year of age) against severe rotavirus gastroenteritis and rotavirus-related admissions, reaching 100% efficacy against the most severe episodes.10 Findings of the safety trial in 63 225 infants showed no increased risk of intussusception in vaccinated infants versus placebo.10

We aimed to investigate the efficacy of RIX4414 at the titre level and composition corresponding to the licensed Rotarix vaccine when administered concomitantly with other routine childhood vaccines, following typical European routine immunisation schedules. We report vaccine efficacy recorded during follow-up of infants over two consecutive rotavirus epidemic seasons after vaccination.

Section snippets

Participants

We undertook a phase IIIb, double-blind, randomised, placebo-controlled trial in six European countries. The protocol, amendments, and consent forms were reviewed and approved by the independent ethics committee for every centre and country. The study was done according to good clinical practice guidelines and the 1996 version of the Declaration of Helsinki.

We enrolled healthy infants aged 6–14 weeks who weighed more than 2000 g at birth and whose parent or legal guardian signed an informed

Results

Between Sept 8, 2004, and Feb 1, 2005, 3994 infants were enrolled into the study (figure 1), from the Czech Republic (n=299), Finland (2890), France (146), Germany (289), Italy (25), and Spain (345). All enrolled infants received the first dose of vaccine or placebo and 3959 (99%) received both doses. The two treatment arms were similar for demographic characteristics in terms of age, sex, race, height, and weight (table 1). The study population was predominantly white. One infant received dose

Discussion

Our findings confirm the high incidence of rotavirus gastroenteritis during the first 2 years of life and, hence, a need for long-term protection induced by rotavirus vaccination. The human rotavirus vaccine RIX4414 showed high and sustained efficacy against severe rotavirus gastroenteritis and admission for rotavirus gastroenteritis. Efficacy against rotavirus gastroenteritis of any severity was high in the first year after vaccination but fell in the second year, which is in line with

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