Suspension of Rotavirus Vaccine After Reports of Intussusception ---United States, 1999

Morbidity & Mortality Weekly Report. 2004;53(34) 

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On July 16, 1999, CDC recommended that health-care providers suspend use of the licensed rhesus-human rotavirus reassortant-tetravalent vaccine (RRV-TV) (RotaShield®, Wyeth Laboratories, Inc., Marietta, Pennsylvania) in response to 15 cases of intussusception (i.e., a bowel obstruction in which one segment of bowel becomes enfolded within another segment) among infants who received RRV-TV.[1] The Vaccine Adverse Event Reporting System (VAERS) monitored for adverse events following licensure of RRV-TV on August 31, 1999. After the recommendation to suspend use of the vaccine, no additional cases were reported.[2] This report describes the surveillance activities used to identify this vaccine adverse event, the emergency response, and follow-up investigations. Suspension of RRV-TV after the initial cases of intussusception parallels the removal of the Broad Street pump handle in response to John Snow's epidemiologic studies; both were decisive, life-saving public health actions.

VAERS, operated by CDC and the Food and Drug Administration (FDA), is a national passive surveillance system that monitors the safety of vaccines.[3] Health-care providers, consumers, and vaccine manufacturers are encouraged to report adverse events involving all U.S.-licensed vaccines. During 1998-1999, CDC and FDA monitored VAERS for reports of intussusception and other severe gastrointestinal events among RRV-TV recipients. As a requirement for FDA licensure, the vaccine manufacturer funded a postlicensure phase IV trial of RRV-TV at Northern California Kaiser Permanente (NCKP) to monitor possible adverse events.[4] Intussusception had been observed at low rates in prelicensure clinical trials, but a causal association with the vaccine was not proven; this information and a request for reporting to VAERS were included in the vaccine product label and recommendations of the Advisory Committee on Immunization Practices (ACIP).

During December 18, 1998-June 2, 1999, a total of 10 cases of intussusception were reported to VAERS (Figure 1). Four cases of intussusception involving other vaccines had been reported to VAERS during the preceding 8 years.[2,5] The cases appeared to be nonrandom in distribution; among the majority of infants, intussusception occurred after receiving the first dose of RRV-TV and within 1 week after receiving any dose. The temporal clustering after receipt of RRV-TV suggested a causal relationship. These early findings prompted CDC to request data from NCKP and initiate two validation studies, a 19-state case-control study and case-series analysis,[6] and a cohort study in 10 managed care organizations.[4] CDC alerted ACIP on June 17, 1999.

By July 6, 1999, the number of cases reported to VAERS had increased to 15, a higher number than expected, accounting for likely underreporting, available baseline estimates of intussusception, and the estimated number of doses of RRV-TV distributed[1]; ( Table ). Preliminary data from both NCKP and from Minnesota, a state participating in one of the CDC studies, suggested a similar elevated risk for intussusception within the first week after RRV-TV vaccination.[4] On July 16, 1999, in an MMWR report, CDC recommended temporarily suspending use of RRV-TV, pending the results of CDC studies that subsequently confirmed the initial observation that the greatest risk for intussusception was within 3-7 days after the first dose of RRV-TV.[4,6]

By December 31, 1999, a total of 112 cases of intussusception with illness onset before August 15, 1999, had been reported to VAERS (Figure 2) 1 month after the suspension of the rotavirus vaccination program.[7] Ninety-five cases among infants were confirmed by review of medical records, and three were confirmed by primary-care providers.[2] No cases of RRV-TV-associated intussusception occurred in infants and children vaccinated after July 16, 1999. When the VAERS findings were confirmed by more definitive studies,[4,6] the manufacturer voluntarily recalled the vaccine, and the ACIP recommendations were withdrawn in October 1999.[2]

Reported by: Food and Drug Administration. J Iskander, MD, P Haber, MPH, TV Murphy, RT Chen, MD, Epidemiology and Surveillance Div, National Immunization Program; M Sabin, PhD, EIS Officer, CDC.

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