The first rotavirus vaccine and intussusception: epidemiological studies and policy decisions.

Received 21 January 2003; accepted 28 January 2003; electronically published 2 April 2003. The authors have no commercial or other association that might pose a conflict of interest. Reprints or correspondence: Dr. Trudy V. Murphy, National Immunization Program, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mail Stop E-61, Atlanta, GA 30333 (tkm4@cdc.gov). The Journal of Infectious Diseases 2003;187:1309–13 This article is in the public domain, and no copyright is claimed. 0022-1899/2003/18708-0017 Gastroenteritis caused by rotaviruses results in significant morbidity from dehydration among infants worldwide and is an important cause of death in developing countries [1]. RotaShield (also referred to as rhesus-human reassortant rotavirus tetravalent vaccine [RRV-TV]; Wyeth Lederle), the first licensed rotavirus vaccine, was withdrawn ! 1 year after it was released when it was found to increase the risk of intussusception [2, 3]. Rapid progress has since been made by manufacturers in the United States, Europe, and India on new rotavirus vaccines. These efforts are being fostered as one of the priorities of the Global Alliance for Vaccines and Immunization [4]. One of the experimental vaccines has been administered to 140,000 children in the United States, Europe, and Latin America in extended phase III trials (personal communication, Merck). International investigations of the epidemiology of rotavirus gastroenteritis are being conducted, and extensive information about intussusception has been acquired in preparation for use of these new rotavirus vaccines [4, 5]. In the “Perspective” in this issue of The Journal of Infectious Diseases [6], colleagues at the National Institute of Allergy and Infectious Diseases question the October 1999 precedent-setting decision by the Advisory Committee on Immunization Practices (ACIP) to withdraw the recommendation for use of RRV-TV [7] in the United States. B. Murphy et al. [6] express concern about the interpretation of the epidemiological data that supported the ACIP decision and the decision-making process that led to withdrawing the recommendation for RRV-TV, as well as highlight the importance of rotavirus infections globally. The epidemiological data in question were from several studies that investigated a possible association between intussusception and RRV-TV conducted by the Centers for Disease Control and Prevention (CDC), including cohort [8] and matched casecontrol studies [9], as well as a case-series analysis of the cases of intussusception identified in the case-control study [9]. In addition, to measure the effect of RRV-TV in states where the vaccine was used, Simonsen et al. [10] subsequently performed an ecological analysis of intussusception using hospital discharge databases from 10 states and an expanded, unpublished 20state analysis [6]. B. Murphy et al. [6] suggest that the “particular strengths” of the ecological analyses were not “widely appreciated” in considerations of policy decisions. Specifically, they assert that the ecological studies were conducted in a “large segment of the general US infant population” and assessed trends in intussusception over a “longer time window” than the case-control and cohort studies. These and other concerns, including an apparent lack of power of the ecological analyses to detect estimated increases in intussusception caused by RRV-TV and insufficient evidence to support hypotheses of a compensatory decrease in intussusceptions after RRV-TV were discussed extensively at a meeting sponsored by the National Vaccine Advisory Committee (NVAC) [5] and by a working group of the ACIP. After reviewing all relevant data and concerns, the ACIP voted in February 2002 to reaffirm its decision to withdraw the recommendation for use of RRV-TV in the United States [11]. Here, we reflect on these concerns and other considerations that led to the ACIP decision.