Editorial commentary: intussusception and rotavirus vaccination--balancing risk against benefit.

An association between intussusception, a form of bowel obstruction, and live oral rotavirus vaccines was first identified with Rotashield, a rhesus-human reassortant rotavirus vaccine that was recommended for routine immunization of US infants in 1998 [1]. During the first year after vaccine introduction, a cluster of intussusception cases temporally linked to Rotashield vaccination was reported to the US Vaccine Adverse Event Reporting System (VAERS), a national passive reporting system [2]. This prompted a national case-control study, which confirmed the association between Rotashield and intussusception [3], with the greatest risk (an approximately 37-fold increase) occurring 3–7 days after the first vaccine dose. A smaller increase was seen in the second week after dose 1 and during the first week after dose 2. The excess risk of approximately 1 intussusception case in 10 000 Rotashield recipients led to withdrawal of the vaccine from the US market in 1999 [4]. Because of the legacy of Rotashield, the 2 other live oral rotavirus vaccines in advanced stages of clinical testing at the time—a pentavalent bovine-human reassortant vaccine (RV5, RotaTeq, Merck.) and a monovalent human vaccine (RV1, Rotarix, GSK Biologicals)—each underwent large clinical trials of approximately 60 000–70 000 infants specifically to assess the risk of intussusception [5, 6]. No elevated risk was found 42 and 30 days after vaccination after any of the 3 doses of RV5 and either of the 2 doses of RV1, respectively, in these trials. This facilitated licensure of both products and a recommendation for universal use in the United States and around the world. The World Health Organization (WHO) recommends both RV5 and RV1 for global use and encourages postlicensure monitoring to further assess the intussusception risk during routine programmatic use [7]. In this issue, Carlin et al present an elegant analysis of postlicensure intussusception data from Australia that has several notable strengths [8]. First, given that different states in Australia exclusively implemented either RV5 or RV1 with a relatively equitable national distribution of the 2 vaccines, this evaluation was able to evaluate risk with both vaccines during contemporaneous use in demographically similar populations. Second, robust and nationally representative evidence could be generated because of a relatively comprehensive capture of intussusception cases through examination of hospital discharge databases (with review of case records to restrict analysis to cases that met the highest Brighton Collaboration level 1 diagnostic certainty) and because of the availability of immunization data though a national registry with a near-complete (>98%) capture of vaccines provided through the National Immunization Program. Third, both the case-series and case-control methods were used to assess intussusception, and the consistency of estimates from both approaches provides additional reassurance about the validity of the findings. Fourth, the authors present side-by-side data on both the excess number of intussusception cases that might be caused by vaccination against the expected reduction in rotavirus hospitalizations, so that the risks could be interpreted in the context of benefits. Last, a range of sensitivity analyses were conducted around various assumptions and parameters that informed the analysis, with none influencing the overall conclusions substantially. The results show that in Australia both rotavirus vaccines are associated with an increased risk of intussusception in the first 3 weeks after the first vaccine dose and the first week after the second dose, with the greatest risk in the first week after dose 1. An increased intussusception risk in the first week after dose 1 of RV1 was also documented in a previous smaller study from Australia and in 2 separate evaluations in Mexico [9–11]. In Received 1 July 2013; accepted 5 July 2013; electronically published 19 August 2013. Correspondence: Walter A. Orenstein, MD, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30338 (dmill06@emory.edu). Clinical Infectious Diseases 2013;57(10):1435–7 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit532