Rotavirus Vaccines Carry Low Risk for Intussusception

Neil Osterweil

January 14, 2014

Risk for intussusception, a common cause of intestinal obstruction in infants and toddlers, is slightly but significantly elevated after vaccination with currently licensed rotavirus vaccines, according to the results of 2 large surveillance studies.

However, the studies, both published online January 14 in the New England Journal of Medicine, indicate that the overall risk for intussusception is low. They differ, however, on whether the added risk is greater with the pentavalent (RV5; RotaTeq, Merck) or monovalent (RV1; Rotarix, GlaxoSmithKline) vaccine formulations.

Authors of both studies emphasize that the relatively small risks for intussusception should be weighed against the potentially large benefits from preventing severe gastrointestinal illnesses, hospitalizations, and deaths associated with rotaviral infections.

In one study, W. Katherine Yih, PhD, MPH, from Harvard Medical School and Harvard Pilgrim Health in Boston, Massachusetts, and colleagues looked at data from the US Food and Drug Administration Post-Licensure Rapid Immunization Safety program. The data set included information on 1,277,556 total doses of pentavalent vaccine and 103,098 doses of monovalent vaccines given to infants aged 5 to 36.9 weeks in 3 US health plans. Overall, there were 267 confirmed cases of intussusception.

The authors conducted 2 analyses of the data. In the first analysis, they calculated the risk for intussusception during 2 windows of time (from 1 to 7 or from 1 to 21 days after exposure) and compared it with a control interval of 22 to 42 days after exposure. In the second analysis, they used a cohort design including data on both exposed and unexposed person-time.

In the risk-interval analysis, the risk for intussusception was significantly higher after the first dose of the pentavalent vaccine for both the 7-day risk window (attributable risk, 1.1; 95% confidence interval [CI], 0.3 - 2.7) and the 21-day window (attributable risk, 1.5; 95% CI, 0.2 - 3.2). There was no increase in risk after the second or third dose.

Similarly, the cohort analysis showed a significant increase in risk for the 21-day risk interval after the first dose, but not subsequent doses (attributable risk, 1.2; 95% CI, 0.2 - 3.2).

When they looked at the monovalent vaccine, however, they found that attributable risk was not significant in the risk interval analysis after either of 2 prescribed doses. The cohort analysis did uncover a significant attributable risk after the second dose (7.3; 95% CI, 0.8 - 22.5). The authors caution that although there was a risk signal seen with the cohort analysis, the study of the monovalent vaccine was underpowered.

Vice Versa?

In a separate study, Eric S, Weintraub, MPH, from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and colleagues examined data from the CDC's Vaccine Safety Datalink surveillance program. They reviewed data on children given a total of 207,955 doses (115,908 first and 92,047 second doses) of monovalent rotavirus vaccine and compared the rate of intussusception cases occurring within 7 days of exposure with historical background rates.

They found that there were 6 cases of intussusception that occurred within 7 days of either dose compared with an expected number of 0.72 cases, which translated into a relative risk of 8.4.

They also conducted an updated analysis of the group's previous study of intussusception risk after the pentavalent vaccine.

"Our updated analysis of pentavalent rotavirus vaccination included nearly 1.3 million doses and continued to find no significant increased risk of intussusception," they write.

Low Risk, High Rewards

An accompanying editorial calls for caution in interpreting the results of the 2 studies, noting that RV1, the monovalent vaccine, was introduced into the United States 2 years after RV5, the pentavalent vaccine, and that the risk assessment of the former is therefore based on fewer doses.

"The differences between the studies are marginal, and it appears that both vaccines cause intussusception at low rates; therefore small variations in case detection and in confirmation of vaccination status, as well as chance alone, can introduce considerable uncertainty into the analysis," write Roger I. Glass MD, PhD, from the National Institutes of Health in Bethesda, Maryland, and Umesh D. Parashar, MB, MPH, from the National Center for Immunixatin and Respiratory Diseases at the CDC.

They estimate the overall risk for intussusception with current vaccines to be low, ranging from 1 to 5 cases per 100,000 infants.

"Given this low risk and the major impact that these vaccines have had on the reduction of hospitalizations, emergency department visits, and in some cases, deaths from diarrhea, policy makers have concluded that rotavirus vaccine remains a valuable addition to the national program for childhood immunizations," they write.

The study by Dr. Yih and colleagues was supported by the US Food and Drug Administration. One coauthor has reported being an employee of and stockholder in Aetna, one of the insurers participating in the study. The other authors of this study have disclosed no relevant financial relationships. The study by Weintraub and colleagues was supported by the CDC. One coauthor has reported receiving grant support from GSK, and one has reported receiving grant support from GSK and Merck. Dr. Glass has disclosed a patent on an Indian rotavirus vaccine that is held by the CDC and given to the government of India. One coauthor is employed by the CDC.

N Engl J Med. Published online January 14, 2014.


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