Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial

doi:10.1016/S0140-6736(10)60889-6

The Lancet

Volume 376, Issue 9741, 21–27 August 2010, Pages 606-614

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https://doi.org/10.1016/S0140-6736(10)60889-6 Get rights and content

Summary

Background

Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009.

Methods

In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4–12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score ≥11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648.

Findings

5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610·6 person-years in the vaccine group, compared with 129 cases in 2585·9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39·3% (95% CI 19·1–54·7, p=0·0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1·5%) of 2723 infants assigned to receive vaccine and 45 (1·7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 [0·6%]; placebo 17 [0·6%]).

Interpretation

Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa.

Funding

PATH (GAVI Alliance grant) and Merck.

Introduction

Deaths related to diarrhoea are the second leading cause of mortality in children younger than 5 years in many developing countries, with an estimated 1·3 million deaths occurring worldwide every year, of which 800 000 deaths are in Africa.1, 2 Despite efforts to encourage treatment with oral rehydration solution and zinc supplementation, which reduce diarrhoea-related mortality, coverage of these interventions is low in many parts of Africa.2, 3

Rotavirus gastroenteritis contributes substantially to the overall burden of diarrhoeal disease in Africa. About 40% of hospital admissions because of diarrhoea in children younger than 5 years are attributable to rotavirus.⁴ Six of the seven countries with the highest mortality from rotavirus (>500 deaths per 100 000 livebirths) are in sub-Saharan Africa, where nearly 240 000 rotavirus-related deaths out of the global yearly estimate of 527 000 occur.5, 6 Effective rotavirus immunisation could alleviate this situation.⁶

In 2006, WHO advocated use of currently licensed rotavirus vaccines in European and Americas regions, where efficacy data had been generated, and recommended that rotavirus efficacy trials be done in Africa and Asia.⁷ Our trial in three countries in sub-Saharan Africa that were eligible for GAVI-Alliance funding aimed to assess the efficacy of the oral pentavalent rotavirus vaccine RotaTeq (Merck, Whitehouse Station, NJ, USA) for prevention of severe rotavirus-related gastroenteritis in infants.

Section snippets

Participants and study design

Our multicentre, double-blind (with sponsor blinding), placebo-controlled, randomised trial was done to assess efficacy of three doses of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants. The trial was done from April 28, 2007, to March 31, 2009, at medical facilities located in rural Kassena-Nankana district, Ghana; rural Karemo division, Siaya district, Nyanza province, western Kenya; and urban Bamako, Mali.

Study design and analysis was identical to that

Results

Figure 1 shows the trial profile. The per-protocol efficacy analysis comprised 86% of participants who had been randomly assigned to the vaccine (2357 of 2733 infants) and placebo (2348 of 2735 infants) groups. The median follow-up time, starting 14 days after the third dose of vaccine or placebo, for the primary efficacy analysis was 527 days (IQR 478–577) in the vaccine group and also 527 days (484–581) in the placebo group. The median follow-up time in Ghana was 548 days (IQR 464–604 vaccine

Discussion

In our large, double-blind, placebo-controlled trial in poor regions in three African countries, pentavalent rotavirus vaccine provided significant protection against severe rotavirus gastroenteritis in infants for nearly 2 years of follow-up. This protection was especially high through the first year of life (64·2% vaccine efficacy), when the disease burden, including mortality, is highest.11, 17 Our results are similar to those from a clinical trial in Malawi and South Africa,¹⁸ where two or

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ArticlesEfficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Participants and study design

Results

Discussion

Lancet

Diagn Microbiol Infect Dis

Int J Infect Dis

Vaccine

Vaccine

Vaccine

Vaccine

Lancet

Estimating child mortality due to diarrhoea in developing countries

Bull World Health Organ

Zinc and low osmolarity oral rehydration salts for diarrhoea: a renewed call to action

Bull World Health Organ

Global networks for surveillance of rotavirus gastroenteritis, 2001–2008

Wkly Epidemiol Rec

Global mortality associated with rotavirus disease among children in 2004

J Infect Dis

Rotavirus vaccines

Wkly Epidemiol Rec

Conclusions and recommendations from the Strategic Advisory Group of Experts to the Department of Immunization, Vaccines, and Biologicals

Wkly Epidemiol Rec

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial

Lancet

Novel rotavirus VP7 typing assay using a one-step reverse transcriptase PCR protocol and product sequencing and utility of the assay for epidemiological studies and strain characterization, including serotype subgroup analysis

J Clin Microbiol

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N Engl J Med

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Pediatr Infect Dis J

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Articles
Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial