Rotavirus vaccine and intussusception
In December 2009, WHO recommended that all infants be routinely immunized to prevent rotavirus disease, the most common cause of serious gastroenteritis among infants worldwide. Two rotavirus vaccines are available: Rotarix (manufactured by GSK Biologicals) and RotaTeq (manufactured by Merck & Co., Inc.). Because a previous rotavirus vaccine (Rotashield, manufactured by Wyeth) was associated with an increased incidence of intussusception, an uncommon form of bowel obstruction, the risk of this adverse event was specifically evaluated in prelicensure trials of the currently licensed vaccines. In trials prior to registration no increased risk of intussusception was observed: each trial involved >70 000 participants. The trials were conducted mainly in Finland and the United States of America for RotaTeq, and in 11 countries in Latin America for Rotarix. Nonetheless, WHO has recommended that postmarketing surveillance for this adverse event should continue whenever these vaccines are introduced into new populations. On 6 and 13 August 2010, GACVS reviewed (during a teleconference) the preliminary data from postmarketing studies that suggested an increased risk of intussusception associated with Rotarix in some populations. On 22 September 2010, the United States Food and Drug Administration approved a label change for Rotarix advising practitioners of the new data on intussusception,3 and WHO provided an update related to the preliminary findings from those active surveillance studies.4
Since 2007, the Pan American Health Organization has collaborated with ministries of health, the United States Centers for Disease Control and Prevention (CDC), and PATH to evaluate the potential risk of intussusception after routine use of Rotarix in Brazil and Mexico. Preliminary analyses of the surveillance data have identified 18 hospitalizations following intussusception (none of which were associated with death). These occurred within 1–7 days after administration of the first dose in Mexico; after adjusting for age, this rate is about 4–5 times higher than that occurring during later periods after vaccination. No similar excess was observed after administration of the first dose in Brazil. A case-control analysis of the data from Mexico found an association similar to that in the case-only analysis. These data from Mexico correspond to a risk of about 1–2 additional hospitalizations for intussusception per 100 000 infants vaccinated, or about 20–40 additional cases per year nationwide at current vaccination rates (the Mexican birth cohort is approximately 2 million). A similar study sponsored by GSK Biologicals in a different population in Mexico also found an increased risk of intussusception: an approximately 1.7-fold increase during the 30 days following the first dose, with a cluster of cases occurring during the first week after vaccination.
In Australia, postmarketing surveillance studies found no increased risk of intussusception among children aged ≤9 months with either vaccine; however, the studies found a temporal increase in intussusception with both vaccines during the first week after vaccination, although these findings were based on relatively few cases. In the United States, data from both the CDC and from an evaluation sponsored by Merck & Co., Inc., did not show evidence of an increased risk of intussusception with RotaTeq; however, the population of children under active surveillance in the United States who have received RotaTeq is not yet large enough to rule out the level of risk during the first week after vaccination that has been suggested by preliminary analyses of Rotarix in Mexico and with both vaccines in Australia.
In summary, postmarketing surveillance indicates the possibility of an increased risk of intussusception shortly after the first dose of rotavirus vaccine in some populations. If the findings are confirmed, the level of risk observed in these studies is substantially lower than the risk of 1 case/5000–10 000 in infants who received the Rotashield vaccine. The benefits of rotavirus vaccination in preventing rotavirus gastroenteritis and its consequences are substantial. For example, in Mexico it is estimated that nationwide use of Rotarix would prevent approximately 12 000 hospitalizations and 700 deaths from diarrhoea each year, a benefit that greatly outweighs the potential risk of 20–40 cases of vaccine-associated intussusception found in these preliminary analyses. Additional data are being collected and analysed from Latin America and other areas. GACVS will continue to review these data as they become available.
3Information on Rotarix: labeling revision pertaining to intussusception. Washington, DC, United States Food and Drug Administration, 2010 (http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm226690.htm, accessed December 2010).
4Statement on Rotarix and Rotateq vaccines and intussusception. Geneva, World Health Organization, 2010 (http://www.who.int/vaccine_safety/topics/rotavirus/rotarix_and_rotateq/intussusception_sep2010/en/index.html; accessed January 2011).