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

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

In This Article

Editorial Note

The suspected association between RRV-TV and intussusception based on a review of VAERS data led CDC, in conjunction with state and local health departments, to implement a case-control study and case-series analysis[6] and a retrospective cohort study.[4] These studies subsequently confirmed that intussusception was associated with RRV-TV in vaccine recipients. On the basis of evaluation of all available information, on February 21, 2002, ACIP reaffirmed its decision to withdraw the recommendation for use of RRV-TV in the United States.[8]

The case-control study was conducted in 19 U.S. states among 429 infants and 1,763 matched controls. Infants who received RRV-TV were 37 times more likely to have intussusception 3-7 days after the first dose than infants who did not receive RRV-TV (95% confidence interval [CI] = 12.6-110.1).[6] The population-based, retrospective cohort study among 463,277 children in managed care organizations demonstrated that of 56,253 infants vaccinated with RRV-TV, those who received the vaccine were 30 times more likely to have intussusception 3-7 days after the first dose than infants who did not receive the vaccine (95% CI = 8.8-104.9). The excess risk was estimated between one case in 5,000 vaccinees and one case in 11,000 vaccinees.[4,6] In addition to intussusception,[5] subsequent analysis of all VAERS reports documented a broader spectrum of gastrointestinal illnesses (e.g., bloody stool, vomiting, diarrhea, gastroenteritis, and abdominal pain) after receipt of RRV-TV.

Passive surveillance systems such as VAERS are subject to multiple limitations, including underreporting, reporting of purely temporal associations or unconfirmed diagnoses, lack of denominator data, and unbiased comparison groups.[2] In addition, determining causal associations between vaccines and adverse events from VAERS reports is not possible. Nevertheless, because VAERS is a national surveillance system with a simple reporting mechanism, it yields timely information and has high sensitivity for new vaccine safety concerns. Despite estimated underreporting of intussusception after RRV-TV of approximately 50%,[7] VAERS successfully provided an alert.

Recent reevaluations of the RRV-TV experience have assessed the strength of association, the attributable risk, and the possibility that RRV-TV triggered intussusception in those at risk.[8] Follow-up of the managed care cohort showed equal risk for intussusception among vaccinated and unvaccinated infants >21 days postvaccination, arguing against the trigger hypothesis.[9] Rotavirus infection is associated with increased distal ileum wall thickness and lymphadenopathy, suggesting a possible mechanism by which rotavirus infection or RRV-TV could cause intussusception.[10]

Rotavirus is the most common cause of severe gastroenteritis in the United States, resulting in approximately 500,000 physician visits, 50,000 hospitalizations, and 20-40 deaths annually; worldwide, rotavirus accounts for an estimated 600,000 deaths annually among children aged <5 years.[3] In the United States, where high routine vaccination coverage has nearly eliminated childhood vaccine-preventable diseases, concerns regarding vaccine safety are increasing. Rotavirus vaccines under development will be measured for safety by lessons learned from the RRV-TV/intussusception experience.[2,9]

The causal association between RRV-TV and intussusception was established in the postlicensure period because a unique adverse event occurred shortly after vaccination, at a frequency (approximately one case per 10,000 doses) detectable by surveillance tools. This frequency contrasts with paralysis after oral poliovirus vaccine (no longer used in the United States) of one case in 750,000-1.2 million doses. Evaluation of other vaccine safety concerns, which include disorders involving delayed/insidious onset (e.g., autism) or other diseases (e.g., yellow fever vaccine-associated viscerotropic and neurotropic disease) in smaller populations, is more challenging. CDC and FDA will continue to develop new surveillance tools for timely detection of rare or unanticipated vaccine adverse events and to ensure confidence in vaccination.

The investigation of RRV-TV and intussusception had 145 years of historical precedent in John Snow's epidemiologic methodology. The rapid elimination of risk based on systematic investigation, surveillance, and ongoing scientific confirmation averted any other cases of intussusception associated with RRV-TV.

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