Vaccines for preventing rotavirus diarrhoea: vaccines in use

What is the aim of this review?

The aim of this Cochrane Review was to find out if rotavirus vaccines are effective in preventing diarrhoea and deaths in infants and young children. We also aimed to find out if the rotavirus vaccines are safe. We collected and analyzed all relevant studies to answer these questions, and found 55 studies.

Key messages

RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea (moderate- to high-certainty evidence). We found no increased risk of serious adverse events (moderate- to high-certainty evidence) including intussusception (where the bowel telescopes on itself, and can cause obstruction) (very low to low-certainty evidence).

What was studied in the review?

Rotavirus infection is a common cause of diarrhoea in infants and young children, and can cause mild illness, hospitalization, and death. Since 2009, the World Health Organization (WHO) has recommended that a rotavirus vaccine be included in all national infant and child immunization programmes, and 95 countries have so far followed this recommendation. In the years before infants and children started receiving rotavirus vaccine, rotavirus infection resulted in about half a million deaths a year in children aged under five years, mainly in low- and middle-income countries.

In this review we included randomized controlled trials in infants and young children that evaluated a monovalent rotavirus vaccine (RV1; Rotarix, GlaxoSmithKline) or a pentavalent rotavirus vaccine (RV5; RotaTeq, Merck). These vaccines have been evaluated in several large trials and are approved for use in many countries. We also included trials that evaluated another monovalent rotavirus vaccine (Rotavac; Bharat Biotech), which is used in India only. The rotavirus vaccines were compared with placebo or with no vaccine. The included studies did not allow comparisons between the vaccines.

What are the main results of the review?

We found 55 relevant studies with 216,480 participants. The trials took place in several locations worldwide. These studies compared a rotavirus vaccine versus placebo or versus no vaccine for infants and young children. The vaccines tested were RV1 (36 trials with 119,114 participants), RV5 (15 trials with 88,934 participants), and Rotavac (four trials with 8432 participants). Fifty-one studies were funded or co-funded by vaccine manufacturers, while four were independent of manufacturer funding.

In the first two years of life, RV1:

●prevents more than 80% of severe cases of rotavirus diarrhoea in countries with low death rates (high-certainty evidence)
●prevents 35% to 63% of severe rotavirus diarrhoea in countries with high death rates (high-certainty evidence)
●probably prevents 37% to 41% of severe cases of diarrhoea from all causes (such as any viral infection, bacterial infection, or parasitic infection) in countries with low death rates (moderate-certainty evidence)
●probably prevents 18% to 27% of severe cases of diarrhoea from all causes in countries with high death rates (moderate- to high-certainty evidence).

In the first two years of life, RV5:

●probably prevents 82% to 92% of severe cases of rotavirus diarrhoea in countries with low death rates (moderate-certainty evidence)
●prevents 41% to 57% of severe cases of rotavirus diarrhoea in countries with high death rates (high-certainty evidence)
●probably prevents 15% of severe cases of diarrhoea from all causes in countries with high death rates (moderate- to high-certainty evidence); we did not identify any studies that reported on diarrhoea from all causes in countries with low death rates.

In the first two years of life, Rotavac:

●probably prevents more than 50% of severe cases of rotavirus diarrhoea in India, a country with high death rates (moderate-certainty evidence)
●probably prevents 18% of severe cases of diarrhoea from all causes in India (moderate-certainty evidence). Rotavac has not been evaluated in a randomized controlled trial in a country with low death rates.

We found little or no difference in the number of serious adverse events (moderate- to high-certainty evidence), or intussusception cases (low- to very low-certainty evidence), between those receiving RV1, RV5, or Rotavac compared with placebo or no intervention.

How up-to-date is this review?

We searched for studies that had been published up to 4 April 2018.

Authors' conclusions: 

RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea. Whilst the relative effect estimate is smaller in high-mortality than in low-mortality countries, there is a greater number of episodes prevented in these settings as the baseline risk is much higher. We found no increased risk of serious adverse events.

Read the full abstract...
Background: 

Rotavirus results in more diarrhoea-related deaths in children under five years than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Rotavirus vaccines that have been prequalified by the World Health Organization (WHO) include a monovalent vaccine (RV1; Rotarix, GlaxoSmithKline), a pentavalent vaccine (RV5; RotaTeq, Merck), and, more recently, another monovalent vaccine (Rotavac, Bharat Biotech).

Objectives: 

To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children.

Search strategy: 

On 4 April 2018 we searched MEDLINE (via PubMed), the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, and BIOSIS. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies and relevant systematic reviews.

Selection criteria: 

We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention.

Data collection and analysis: 

Two review authors independently assessed trial eligibility and assessed risks of bias. One review author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analysis by country mortality rate and used GRADE to evaluate evidence certainty.

Main results: 

Fifty-five trials met the inclusion criteria and enrolled a total of 216,480 participants. Thirty-six trials (119,114 participants) assessed RV1, 15 trials (88,934 participants) RV5, and four trials (8432 participants) Rotavac.

RV1

Children vaccinated and followed up the first year of life

In low-mortality countries, RV1 prevents 84% of severe rotavirus diarrhoea cases (RR 0.16, 95% CI 0.09 to 0.26; 43,779 participants, 7 trials; high-certainty evidence), and probably prevents 41% of cases of severe all-cause diarrhoea (RR 0.59, 95% CI 0.47 to 0.74; 28,051 participants, 3 trials; moderate-certainty evidence). In high-mortality countries, RV1 prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.23 to 0.60; 6114 participants, 3 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (RR 0.73, 95% CI 0.56 to 0.95; 5639 participants, 2 trials; high-certainty evidence).

Children vaccinated and followed up for two years

In low-mortality countries, RV1 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.14 to 0.23; 36,002 participants, 9 trials; high-certainty evidence), and probably prevents 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, 2 trials; moderate-certainty evidence). In high-mortality countries RV1 probably prevents 35% of severe rotavirus diarrhoea cases (RR 0.65, 95% CI 0.51 to 0.83; 13,768 participants, 2 trials; high-certainty evidence), and 17% of severe all-cause diarrhoea cases (RR 0.83, 95% CI 0.72 to 0.96; 2764 participants, 1 trial; moderate-certainty evidence).

No increased risk of serious adverse events (SAE) was detected (RR 0.88 95% CI 0.83 to 0.93; high-certainty evidence). There were 30 cases of intussusception reported in 53,032 children after RV1 vaccination and 28 cases in 44,214 children after placebo or no intervention (RR 0.70, 95% CI 0.46 to 1.05; low-certainty evidence).

RV5

Children vaccinated and followed up the first year of life

In low-mortality countries, RV5 probably prevents 92% of severe rotavirus diarrhoea cases (RR 0.08, 95% CI 0.03 to 0.22; 4132 participants, 5 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (RR 0.80, 95% CI 0.58 to 1.11; 1 trial, 4085 participants; moderate-certainty evidence).

Children vaccinated and followed up for two years

In low-mortality countries, RV5 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.08 to 0.39; 7318 participants, 4 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, 2 trials; high-certainty evidence).

No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.86 to 1.01; moderate to high-certainty evidence). There were 16 cases of intussusception in 43,629 children after RV5 vaccination and 20 cases in 41,866 children after placebo (RR 0.77, 95% CI 0.41 to 1.45; low-certainty evidence).

Rotavac

Children vaccinated and followed up the first year of life

Rotavac has not been assessed in any RCT in countries with low child mortality. In India, a high-mortality country, Rotavac probably prevents 57% of severe rotavirus diarrhoea cases (RR 0.43, 95% CI 0.30 to 0.60; 6799 participants, moderate-certainty evidence); the trial did not report on severe all-cause diarrhoea at one-year follow-up.

Children vaccinated and followed up for two years

Rotavac probably prevents 54% of severe rotavirus diarrhoea cases in India (RR 0.46, 95% CI 0.35 to 0.60; 6541 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (RR 0.84, 95% CI 0.71 to 0.98; 6799 participants, 1 trial; moderate-certainty evidence).

No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.85 to 1.02; moderate-certainty evidence). There were eight cases of intussusception in 5764 children after Rotavac vaccination and three cases in 2818 children after placebo (RR 1.33, 95% CI 0.35 to 5.02; very low-certainty evidence).

There was insufficient evidence of an effect on mortality from any rotavirus vaccine (198,381 participants, 44 trials; low- to very low-certainty evidence), as the trials were not powered to detect an effect at this endpoint.

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