Harm Cohort study
Intussusception risk increased after rotavirus vaccination but outweighed by benefits 10.1136/eb-2014-101793 Evan J Anderson,1,2 Bethany K Sederdahl1 1
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA; 2Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA Correspondence to: Dr Evan J Anderson, Departments of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA; [email protected]
Commentary on: Weintraub ES, Baggs J, Duffy J, et al. Risk of intussusception after monovalent rotavirus vaccination. N Engl J Med 2014;370:513–19. And Yih WK, Lieu TA, Kulldorff M, et al. Intussusception risk after rotavirus vaccination in U.S. infants. N Engl J Med 2014;370:503–12.
Context Prior to the introduction of paediatric rotavirus vaccination, rotavirus was the most common cause of infectious gastroenteritis to result in the hospitalisation of children and accounted for about 450 000 deaths in children per year worldwide.1 Use of the first rotavirus vaccine, RotaShield (Wyeth Lederle), was discontinued within 1 year of US licensure after intussusception was identified in about 1 of every 10 000 children within 2 weeks of vaccination.2 Two new rotavirus vaccines, RotaTeq (RV5, Merck) and Rotarix (RV1, GlaxoSmithKline), when assessed in prelicensure studies of >60 000 infants were not associated with an increased risk of intussusception. Since US licensure of RV5 in 2006 and RV1 in 2008, these vaccines have been carefully monitored for safety. Postlicensure studies in Mexico, Brazil and Australia have identified a relationship between rotavirus vaccination and intussusception.3 Although a clustering of intussusception events has been noted by the Vaccine Adverse Event Reporting System (VAERS) in the 3–6 days following the first dose of RV5, active surveillance by the Vaccine Safety Datalink (VSD) has not observed an increased risk with RV5.4 5
Methods Yih and colleagues, as part of the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) programme, assessed the risk of intussusception in infants (5.0–36.9 weeks) vaccinated with RV5 or RV1 within 7 and 21 days of vaccination. Cases of intussusception were identified by procedural and diagnostic codes and verified by blinded review of medical records using the Brighton Collaboration criteria. Both selfcontrolled risk-interval (SCRI) and cohort designs were used in analysis of intussusception risk from January 2004 through September 2011. Similarly, Weintraub and colleagues, as part of the VSD, assessed risk in infants (4–34 weeks) within 7 days of vaccination. Intussusception incidents were determined by diagnostic coding and unblinded review of medical records using the Brighton Collaboration criteria. The observed rate of intussusception from April 2008 through March 2013 was compared with baseline rates from 2001 through 2005.
Findings PRISM was underpowered to assess risk with RV1 since only 53 638 first doses were administered. In contrast, 507 874 first doses of RV5 were administered in PRISM. The primary analysis (SCRI) identified an attributable risk of intussusception for the first dose of 1.1/100 000 infants within 7 days of receiving RV5, 1.5/100 000 infants within 21 days of receiving RV5, and in the secondary cohort analysis 1.2/100 000 infants within 21 days of receiving RV5. No increase in risk was identified after the second or third doses. In the VSD, 493 560 first doses of RV5 and 115 908 first doses of RV1 were included in the analysis. A clustering of intussusception events was observed within 3–6 days after RV1 vaccination. The attributable risk of intussusception after two doses of RV1 was found to be 5.3/100 000 infants vaccinated. RV5 was not associated with an increased risk of intussusception.
Commentary With RotaShield in 1999, increased risk of intussusception was noted by the VAERS within 1 year of vaccine licensure. Although prelicensure data did not demonstrate an increased risk of intussusception with RV5 or RV1, postlicensure international data and now US data demonstrate increased risk of intussusception in children shortly after receipt of either rotavirus vaccine.3 Why has it taken so long to identify this risk? Intussusception events have been carefully followed after licensure of RV5 and RV1. Data suggest that the risk of intussusception associated with RV5 and RV1 are one-half to one-tenth of the risk noted with RotaShield. Prior studies of RV5 and RV1 after vaccine licensure have not been powered to detect this level of risk. In a prior VSD study assessing intussusception risk from 2006 through 2010, no significant increase of intussusception was identified.5 The updated VSD data by Weintraub and colleagues, including 493 560 first doses, also do not identify increased risk with RV5. It is of interest that a trend may be developing towards increased risk with the first dose in the VSD (4 cases vs 1.52 cases expected; relative risk=2.63; 95% CI 0.72 to 6.74), but this is not statistically significant. Although prior data from the VAERS did not identify an increased risk, the most recent VAERS data identified an increased risk of 0.79/ 100 000 doses of RV5 within 3–6 days after the first dose of RV5.4 The PRISM cohort, with 507 874 first doses of RV5, was large enough to identify an attributable risk of 1.5/100 000 first doses of RV5 within 21 days of vaccination. Because RV1 was introduced later, and because its use in the US has been more limited, postlicensure studies have been underpowered.4 5 Data from PRISM regarding the risk with RV1 was also underpowered, but a trend towards an increased risk of intussusception was noted. The VSD study identified increased risk after both doses of RV1 of 5.3/100 000 infants. Notably the risks of RV5 and RV1 are much lower than the risk associated with RotaShield. It is also important to appreciate that although intussusception events are increased in the first 7–21 days after vaccination, no net increase in intussusception events in infants
Intussusception risk increased after rotavirus vaccination but outweighed by benefits 10.1136/eb-2014-101793 Evan J Anderson,1,2 Bethany K Sederdahl1 1
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA; 2Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA Correspondence to: Dr Evan J Anderson, Departments of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA; [email protected]
Commentary on: Weintraub ES, Baggs J, Duffy J, et al. Risk of intussusception after monovalent rotavirus vaccination. N Engl J Med 2014;370:513–19. And Yih WK, Lieu TA, Kulldorff M, et al. Intussusception risk after rotavirus vaccination in U.S. infants. N Engl J Med 2014;370:503–12.
Context Prior to the introduction of paediatric rotavirus vaccination, rotavirus was the most common cause of infectious gastroenteritis to result in the hospitalisation of children and accounted for about 450 000 deaths in children per year worldwide.1 Use of the first rotavirus vaccine, RotaShield (Wyeth Lederle), was discontinued within 1 year of US licensure after intussusception was identified in about 1 of every 10 000 children within 2 weeks of vaccination.2 Two new rotavirus vaccines, RotaTeq (RV5, Merck) and Rotarix (RV1, GlaxoSmithKline), when assessed in prelicensure studies of >60 000 infants were not associated with an increased risk of intussusception. Since US licensure of RV5 in 2006 and RV1 in 2008, these vaccines have been carefully monitored for safety. Postlicensure studies in Mexico, Brazil and Australia have identified a relationship between rotavirus vaccination and intussusception.3 Although a clustering of intussusception events has been noted by the Vaccine Adverse Event Reporting System (VAERS) in the 3–6 days following the first dose of RV5, active surveillance by the Vaccine Safety Datalink (VSD) has not observed an increased risk with RV5.4 5
Methods Yih and colleagues, as part of the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) programme, assessed the risk of intussusception in infants (5.0–36.9 weeks) vaccinated with RV5 or RV1 within 7 and 21 days of vaccination. Cases of intussusception were identified by procedural and diagnostic codes and verified by blinded review of medical records using the Brighton Collaboration criteria. Both selfcontrolled risk-interval (SCRI) and cohort designs were used in analysis of intussusception risk from January 2004 through September 2011. Similarly, Weintraub and colleagues, as part of the VSD, assessed risk in infants (4–34 weeks) within 7 days of vaccination. Intussusception incidents were determined by diagnostic coding and unblinded review of medical records using the Brighton Collaboration criteria. The observed rate of intussusception from April 2008 through March 2013 was compared with baseline rates from 2001 through 2005.
Findings PRISM was underpowered to assess risk with RV1 since only 53 638 first doses were administered. In contrast, 507 874 first doses of RV5 were administered in PRISM. The primary analysis (SCRI) identified an attributable risk of intussusception for the first dose of 1.1/100 000 infants within 7 days of receiving RV5, 1.5/100 000 infants within 21 days of receiving RV5, and in the secondary cohort analysis 1.2/100 000 infants within 21 days of receiving RV5. No increase in risk was identified after the second or third doses. In the VSD, 493 560 first doses of RV5 and 115 908 first doses of RV1 were included in the analysis. A clustering of intussusception events was observed within 3–6 days after RV1 vaccination. The attributable risk of intussusception after two doses of RV1 was found to be 5.3/100 000 infants vaccinated. RV5 was not associated with an increased risk of intussusception.
Commentary With RotaShield in 1999, increased risk of intussusception was noted by the VAERS within 1 year of vaccine licensure. Although prelicensure data did not demonstrate an increased risk of intussusception with RV5 or RV1, postlicensure international data and now US data demonstrate increased risk of intussusception in children shortly after receipt of either rotavirus vaccine.3 Why has it taken so long to identify this risk? Intussusception events have been carefully followed after licensure of RV5 and RV1. Data suggest that the risk of intussusception associated with RV5 and RV1 are one-half to one-tenth of the risk noted with RotaShield. Prior studies of RV5 and RV1 after vaccine licensure have not been powered to detect this level of risk. In a prior VSD study assessing intussusception risk from 2006 through 2010, no significant increase of intussusception was identified.5 The updated VSD data by Weintraub and colleagues, including 493 560 first doses, also do not identify increased risk with RV5. It is of interest that a trend may be developing towards increased risk with the first dose in the VSD (4 cases vs 1.52 cases expected; relative risk=2.63; 95% CI 0.72 to 6.74), but this is not statistically significant. Although prior data from the VAERS did not identify an increased risk, the most recent VAERS data identified an increased risk of 0.79/ 100 000 doses of RV5 within 3–6 days after the first dose of RV5.4 The PRISM cohort, with 507 874 first doses of RV5, was large enough to identify an attributable risk of 1.5/100 000 first doses of RV5 within 21 days of vaccination. Because RV1 was introduced later, and because its use in the US has been more limited, postlicensure studies have been underpowered.4 5 Data from PRISM regarding the risk with RV1 was also underpowered, but a trend towards an increased risk of intussusception was noted. The VSD study identified increased risk after both doses of RV1 of 5.3/100 000 infants. Notably the risks of RV5 and RV1 are much lower than the risk associated with RotaShield. It is also important to appreciate that although intussusception events are increased in the first 7–21 days after vaccination, no net increase in intussusception events in infants
