Global Vaccine Safety

Rotavirus vaccines and intussusception

Extract from report of GACVS meeting of 7-8 December 2011, published in the WHO Weekly Epidemiological Record on 10 February 2012

Rotavirus vaccines (RotaTeq and Rotarix) are being introduced into immunization programmes in many countries. In Brazil and Mexico, use of Rotarix has been associated with large reductions in all-cause diarrhoeal deaths. However, because a previous rotavirus vaccine (Rotashield) was associated with a ~30-fold increase in risk of intussusception during the week following receipt of the first vaccine dose, large clinical trials involving more than 70 000 children were carried out with RotaTeq and Rotarix. In the trials of RotaTeq, children were vaccinated with dose 1 at age 6–12 weeks; with Rotarix, children were vaccinated at age 6–14 weeks (in Latin America) or age 6–15 weeks (in Europe). RotaTeq is delivered in a 3-dose schedule; Rotarix requires only 2 doses. After licensure, the maximum age indicated for the last dose of vaccine was 32 weeks for RotaTeq or 24 weeks and 6 days for Rotarix. No evidence of increased risk of intussusception was identified during clinical trials with administration at those recommended ages.

Based on these data, and in order to align schedules between the vaccines, the Strategic Advisory Group of Experts (SAGE) on Immunization and GACVS recommended in 2009 that the first dose of either Rotarix or RotaTeq should be administered at age 6–15 weeks, and the maximum age for administering the last dose of either vaccine should be 32 weeks. It was noted that this expansion of the age range for use of these vaccines might potentially increase coverage of the first dose in developing countries from about 57% to 70% and full-course coverage from about 36% to 54%.

Not all countries are able to deliver early childhood immunization to most children by the recommended ages; delays in timing of vaccination are noted in many countries, in particular in countries with high rates of rotavirus-associated infant mortality.5 Therefore, there has been consideration of liberalizing the age restrictions for use of both Rotarix and RotaTeq, in order to extend the benefits of vaccination to children who otherwise would not receive the vaccines.

Since the recommendation in 2009, post-licensure safety investigations in some countries revealed an increased risk of intussusception after use of Rotarix (Australia and Mexico) and RotaTeq (Australia). The risks – where they have been found – are substantially lower than those previously associated with Rotashield. Studies with active case finding indicated that, with the current vaccines in use, 4- to 6-fold increases in risk were clustered within the first week after the first dose. In other populations, no increase in risk has been observed or reported. An updated risk–benefit analysis predicted that use of current rotavirus vaccines without age restriction would prevent an additional 49 500 (range: 35 000–67 000) rotavirus deaths while potentially causing about 300 (range: 180–400) excess intussusception deaths, compared with the current age-restricted strategy. This analysis incorporated updated estimates of risk of intussusception (similar to those hypothesized in the 2009 published analysis), updated estimates of rotavirus mortality for the year 2008, and newly available data on efficacy of rotavirus vaccines in low-income settings in Africa and Asia.

Because Rotarix and RotaTeq are now generally being used in accordance with the recommended age restrictions, data on the risk of intussusception for administration of either vaccine at older ages are not available. However, an analysis of intussusception risk following Rotashield in the USA found no significant difference in the relative risk of intussusception after administration of the first dose at 7–13 weeks, 14–21 weeks, or 22–52 weeks, although the confidence limits of those estimates were wide.

The Committee concluded that available data suggest that both Rotarix and RotaTeq continue to exhibit a good safety profile, but may be associated with an increased (up to 6-fold) risk of intussusception after the first dose of vaccine in some populations. The levels of risk observed are substantially less than those observed with the previous vaccine, Rotashield. The Committee reiterates that, based on available evidence, the benefits of rotavirus vaccination to all infants, without age restriction, would greatly exceed the risks, particularly in developing countries with moderate and high mortality from rotavirus disease. Active surveillance of intussusception in African and Asian countries that plan to introduce rotavirus vaccines should be seriously considered, because the data accrued would eventually provide additional benefit–risk information related to these important vaccines.

5Clark A, Sanderson C. Timing of children’s vaccinations in 45 low-income and middle-income countries: an analysis of survey data. Lancet, 2009, 373:1543–1549.