BACKGROUND: In 2006 and 2008, 2 new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States.
METHODS: We assessed intussusception events reported to the Vaccine Adverse Event Reporting System from February 2006 through April 2012 for RV5 and from April 2008 through April 2012 for RV1. For RV5, we conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception comparing average daily reports 3 to 6 versus 0 to 2 days after vaccination. We calculated reporting rate differences based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates. Few reports were submitted after RV1, allowing only a descriptive analysis.
RESULTS: The Vaccine Adverse Event Reporting System received 584 confirmed intussusception reports after RV5 and 52 after RV1, with clustering 3 to 6 days after both vaccines. The DRR comparing the 3- to 6-day and the 0- to 2-day periods after RV5 dose 1 was 3.75 (95% confidence interval = 1.90 to 7.39). There was no significant increase in reporting after dose 2 or dose 3. Over all 3 doses, the excess risk of intussusception was 0.79 events (95% confidence interval = –0.04 to 1.62) per 100 000 vaccinations. From the sensitivity analyses, we conclude that under a worst-case scenario, the DRR could be 5.00 and excess risk per 100 000 doses could be 1.36.
CONCLUSIONS: We observed a persistent clustering of reported intussusception events 3 to 6 days after the first dose of RV5 vaccination. This clustering could translate to a small increased risk of intussusception, which is outweighed by the benefits of rotavirus vaccination.
- CI —
- confidence interval
- DRR —
- daily reporting ratio
- RV1 —
- RV5 —
- SCRI —
- self-controlled risk interval
- VAERS —
- Vaccine Adverse Event Reporting System
- VSD —
- Vaccine Safety Datalink
What’s Known on This Subject:
A low-level risk of intussusception after rotavirus vaccines, ∼1 to 2 cases per 100 000 vaccinees, exists in some settings. In the United States, a risk of 1 in 65 000 was excluded, but lower risk could exist.
What This Study Adds:
A persistent clustering of intussusception events 3 to 6 days after dose 1 indicates the possibility of a low-level risk of intussusception of ∼0.8 cases per 100 000 vaccinees. The documented benefits of rotavirus vaccine far outweigh this low-level risk of intussusception.
In 1999, a rhesus-human reassortant rotavirus vaccine, RotaShield, was withdrawn from the US market because of an association with intussusception.1 For the 2 subsequently licensed live, oral rotavirus vaccines, pentavalent bovine-human reassortant vaccine (RV5, RotaTeq, Merck, Whitehouse Station, NJ) and monovalent human vaccine (RV1, Rotarix, GlaxoSmithKline Biologicals, Philadelphia, PA), risk of intussusception was evaluated in 2 large clinical trials, each of which involved >60 000 infants.2,3 No elevated risk of intussusception was found during the 42-day and 30-day periods after vaccination with 3 doses of RV5 and 2 doses of RV1. RV5 and RV1 were recommended for routine vaccination of US infants in 2006 and 2008, respectively,4 and their use has resulted in an annual decline of ∼40 000 gastroenteritis hospitalizations in 2008 and 2009 in US children, with an annual reduction of about $140 million in treatment costs.5
Recent postlicensure studies from Australia and Mexico have demonstrated a transient increased risk of intussusception during the first week after the first dose of both RV5 and RV1, at an estimated excess risk of ∼1 to 2 cases per 100 000 vaccinated infants.6,7 Postlicensure studies in the United States have not documented an increased risk of intussusception with RV5, but available data are insufficient to confidently exclude a risk as small as seen in international settings. The US Vaccine Safety Datalink (VSD) found no increased risk of intussusception after >800 000 RV5 doses, including >300 000 first doses8,9; the study could confidently exclude an excess risk as small as 1 intussusception event per 65 000 vaccinees, but a lower level of risk similar to that seen in Mexico and Australia could exist.
A previous analysis from the Vaccine Adverse Event Reporting System (VAERS), after ∼9 million doses of RV5 were distributed in the United States, suggested a clustering of intussusception reports 3 to 6 days after the first dose of RV5,10 but firm conclusions about risk could not be derived because of the relatively small number of intussusception cases reported to VAERS at the time and limitations of voluntary reporting to VAERS.
We conducted a self-controlled risk interval (SCRI) analysis to evaluate more fully the possible temporal clustering of intussusception reports to VAERS after >47 million RV5 doses. We also present the first descriptive data on intussusception reports after RV1 vaccination to VAERS.
VAERS is a national passive surveillance system that receives reports of adverse events after vaccination.11,12 VAERS accepts reports from vaccine manufacturers, health care providers, vaccine recipients, and others. Signs and symptoms of adverse events, as well as physician diagnosis, are coded by using the Medical Dictionary for Regulatory Activities.13 VAERS generally cannot assess causality of an adverse event after vaccination, but it may be useful to detect signals of potential vaccine safety concerns. Serious adverse events such as intussusception are more likely to be reported.12,14,15
We reviewed all US reports of intussusception after rotavirus vaccination with RV5 in VAERS from the time of US Food and Drug Administration approval on February 1, 2006, through April 30, 2012. We also reviewed all reports of intussusception after RV1 from its approval on April 1, 2008, through April 30, 2012. We followed up and confirmed all reported intussusception reports. We obtained information on clinical features, treatment, hospital course, and vaccination history, including vaccine type, dose number, and date of vaccination, along with copies of vaccination records. In this analysis, intussusception events were considered confirmed if they met the Level 1 criteria included in the Brighton Collaboration case definition.16 Onset date of intussusception was defined as the day of symptom onset. We compared the onset interval of intussusception reports after RV5 dose1 reports with all RV5 dose 1 non-intussusception reports for the same age group, to illustrate the difference in reporting.
Design and Analysis
We applied the SCRI method17–19 to compare the reports per day of intussusception in risk and nonrisk periods after vaccination. The risk period was classified as 3 to 6 days after vaccination because this was found to be the period of most pronounced increased risk of intussusception after RotaShield1 and recently after RV1,7,20 as well as our observation of persistent clustering of intussusception events 3 to 6 days after RV5 reported to VAERS during 2006–2010.10,21 Because reporting efficiency to VAERS is known to decrease with increasing time from the date of vaccination,12 we selected 0 to 2 days after vaccination as the comparison period, assuming that reporting efficiency is generally highest 0 to 2 days after vaccination, resulting in conservative estimates of possible increased risk during the 3- to 6-day postvaccination period.
To determine if the events in days 3 to 6 were clustered during a specific time during the calendar year and assess reporting efficiency over time, we plotted the ratio of cumulative number of events to the cumulative number of vaccine doses by calendar month from February 2007 through February 2011, the time period for which monthly vaccine distribution data were available. We did this for the 3- to 6-day and 0- to 2-day intervals.
We calculated dose-specific daily reporting ratios (DRR) and 95% confidence intervals (CIs) using a conditional Poisson regression model by comparing the average daily number of reports within the 3- to 6-day risk period with the 0- to 2-day comparison period.
From the estimates of DRR, we estimated the total number of excess intussusception events per year that would be expected to occur after rotavirus vaccination in a fully mature US rotavirus vaccination program (ie, similar to current rates of diphtheria, tetanus, and acellular pertussis vaccine coverage). First, we calculated the excess risk of intussusception after RV5 vaccination per 100 000 doses relative to background as (DRR – 1) * p, where p equals the age-specific background rates of intussusception per 100 000 vaccinations during the 3- to 6-day period.8 Age-specific background rates (6–14, 15–23, 24–35 weeks) used in the analysis were obtained from hospital discharges and emergency department visits for intussusception in 8 VSD sites. These background rates were obtained for the years 2000 through 2006, when no rotavirus vaccine was in use.8
We calculated this risk separately for each dose and for all 3 doses combined. Second, we calculated the excess number of events in the United States, which was a product of risk of intussusception relative to background, births per year, and vaccine coverage. For this analysis, we assumed the 2009 US birth cohort of 4.26 million and vaccination coverage of 95.8% for dose 1, 92.7% for dose 2, and 81.8% for dose 3.22,23 The 95% confidence limits were calculated by using the upper and lower confidence limits of estimates of DRR for intussusception from the SCRI analysis.
Our estimates are based on the assumption that the reporting completeness to VAERS was the same 0 to 2 days and 3 to 6 days postvaccination. To assess the effect of a potential decrease in reporting completeness with time since vaccination, we conducted a sensitivity analysis where we varied the reporting completeness during 3 to 6 days from 100% to 75% of that during 0 to 2 days after vaccination. In addition, because background rates might vary,24 we conducted a second sensitivity analysis in which we varied the background rate between 75% and 125% of the value obtained from VSD.
Intussusception Events After RV5
Between February 1, 2006, and April 30, 2012, VAERS received 6989 reports of adverse events after RV5 vaccination including 657 intussusception reports, of which 584 (89%) were confirmed intussusception. We were unable to verify the diagnosis in 73 reports either because of lack of sufficient demographic and/or medical information to confirm the intussusception diagnosis, diagnosis date, or missing contact information (n = 36).
The reporting pattern of RV5 dose 1 intussusception was different compared with RV5 dose 1 non-intussusception reports; the onset interval for intussusception after RV5 dose 1 peaked during 3-6 days post- vaccination while the onset for RV5 dose 1 non-intussusception peaked during 0-1 days post-vaccination (Fig 1).
Of the 584 confirmed intussusception reports, 266 (45.5%) required surgery, including 73 (27.4%) that required intestinal resection. Two deaths (1 in a 6-month-old boy with intussusception diagnosis 14 days after dose 2 and 1 in a 13-week-old girl with intussusception diagnosis 16 days after dose 1) were confirmed by autopsy report to be from complications of intussusception.
Of the confirmed reports, 182 (31%) occurred after vaccine dose 1, 233 (40%) after dose 2, and 169 (29%) after dose 3. On visual inspection, there was apparent clustering of events on days 3 to 6 after dose 1 and to a lesser extent on days 2 to 6 after dose 2, but none after dose 3 (Fig 2). Mean age at vaccination was 10.3, 19.3, and 27.0 weeks for doses 1, 2, and 3, respectively. As of April 2012, the manufacturer had distributed in the United States >47 million doses of RV5 (Merck, unpublished data, 2012). Of the doses administered in VSD, 35%, 35%, and 30% of the doses were given to infants aged 6 to 14, 15 to 23, and 24 to 35 weeks, respectively; an estimated 39% were dose 1, 34% were dose 2, and 27% were dose 3.
Intussusception Events After RV1
Between April 1, 2008, and April 30, 2012, VAERS received 583 adverse event reports after RV1 vaccinations including 58 intussusception reports, of which 54 (93%) were confirmed. Of the 54 confirmed intussusception events, 25 (46.3%) occurred after dose 1, 23 (42.6%) after dose 2, and 6 (11.1%) after dose 3 (although RV1 is a 2-dose series, a third dose was administered in some situations). An apparent visual clustering of intussusception reports in the week after RV1 administration was observed; of the 25 intussusception reports after dose 1, 13 occurred within 1 to 7 days of RV1 vaccination and of the 23 cases after dose 2, 9 occurred within 1 to 7 days of RV1 vaccination (Fig 3). Of the 13 reports within 1 to 7 days, 9 required surgery, 1 spontaneously resolved, and 2 resolved with barium enema; none died. As of April 30, 2012, the manufacturer had distributed 6.1 million doses of RV1 in the United States (GlaxoSmithKline Biologicals, unpublished data, 2012).
Assessment of Intussusception Risk With RV5
During the study period, a clustering of events occurred 3 to 6 days after dose 1 of RV5 (n = 50) compared with 0 to 2 days (n = 10) after vaccination (DRR = 3.75 [1.90 to 7.39]). After dose 2 of RV5, 42 intussusception events occurred during the 3- to 6-day period compared with 22 events during the 0- to 2-day period after vaccination (DRR = 1.43 [0.85 to 2.40]). After dose 3 of RV5, the number of events during the 3- to 6-day period (n = 19) was the same as that during the 0- to 2-day period (n = 19) after vaccination (DRR = 0.75 [0.40 to 1.42]; Table 1). The difference in reporting between the 2 time windows after RV5 dose 1 was consistent during 2007–2011 (Fig 4).
The DRR after RV5 would translate to an excess risk of intussusception of 0.74, 0.21, and –0.16 events per 100 000 vaccinated infants in the 3 to 6 days after doses 1, 2, and 3, respectively (Table 1). Thus, the total excess risk of intussusception after all 3 doses of RV5 is 0.79 events (95% CI = –0.04 to 1.62) per 100 000 vaccinated infants, translating to 33 additional events per year (95% CI = 0 to 66) in the United States under a fully mature rotavirus vaccination program.
Under assumptions of decreasing reporting completeness by 25% during days 3 to 6 relative to days 0 to 2 after vaccination, we estimate the risk of intussusception after dose 1 would increase to 1.08 per 100 000 vaccinated infants. If we were to assume pessimistically this scenario of lower reporting completeness and a scenario in which background intussusception rates were actually 25%, higher than estimated in VSD,8 the excess risk of intussusception after RV5 vaccination, 1.36 per 100 000 vaccinations, would translate to 55 additional cases per year in the United States under a fully mature rotavirus vaccination program.
A causal link between rotavirus vaccination and intussusception cannot be established by this analysis of VAERS data alone; however, several findings suggest such an association is plausible. First, intussusception reports to VAERS clustered during days 3 to 6 and days 4 to 7 after the first dose of both RV5 and RV1, respectively, which corresponds to the dose and period of peak intestinal replication of vaccine virus and is also similar to the risk pattern observed with current rotavirus vaccines in Australia and Mexico and with RotaShield.1,6,7 Although at this point we did not quantify risk after RV1 due to the lower vaccine uptake compared with RV5, the similarity of clustering of cases during 3 to 6 days or 4 to 7 days for both vaccines suggests a potential increased risk after both vaccines. Second, although reporting of adverse events to VAERS is known to be more complete for events that occur in the first week after vaccination compared with later weeks,12 the relative lack of reports during days 0 to 2 after dose 1 suggests that the clustering during days 3 to 6 is not likely to be explained by reporting bias alone. Third, the clustering 3 to 6 days after dose 1 could occur due to a possible healthy vaccine bias in that children with gastrointestinal symptoms (vomiting, diarrhea) may be less likely to be vaccinated, thus potentially reducing the number of intussusception events during the 0- to 2-day period. However, the presence of a significant signal after the first dose but not the second or third dose argues against this bias. Fourth, the temporal clustering after dose 1 of RV5 was maintained throughout the 5-year reporting period, supporting that this was not a chance occurrence. Overall, we estimated an excess risk of ∼0.79 intussusception events for every 100 000 vaccinated infants, which would translate to 33 excess annual intussusception events after rotavirus vaccination with the coverage expected for a fully mature US rotavirus vaccine program.
Our study applied a SCRI method to VAERS, but spontaneous reporting systems, such as VAERS, generally violate a key criterion of self-control designs that ascertainment of cases should not be influenced by exposure history.25 Here, however, we were presented with a special set of circumstances to apply the SCRI method. We were able to address the known decline in reporting efficiency to VAERS with increasing time since vaccination by limiting the analysis to a narrow time window of 0 to 6 days, and we used the 0- to 2-day interval as the comparison time period. Because reporting efficiency is likely to be greatest in the first few days after vaccination, using the 0- to 2-day window as the comparison period should result in conservative relative risk estimates if reporting completeness is lower during the interval from 3 to 6 days compared with 0 to 2 days after vaccination. To illustrate this, we conducted a sensitivity analysis in which we assumed reporting completeness during 3 to 6 days after vaccination was 75% of that during 0 to 2 days after vaccination. This analysis demonstrated that risk of intussusception after vaccination could increase to from 0.79 to 1.08 excess events per 100 000 doses.
A varying degree of risk of intussusception with current rotavirus vaccines has been identified in several countries The nearly fourfold increase in the risk of intussusception during the 3- to 6-day period after dose 1 that we found in VAERS is consistent with the fivefold increased risk identified in Mexico and Australia during 1 to 7 days after dose 1. In Australia, an increased risk of intussusception was identified during the first week after dose 1 for both RV1 and RV5, translating to an excess risk of ∼1 to 2 cases per 100 000 vaccinated infants.6 A study conducted in Mexico and Brazil found an excess risk of 1 in 51 000 infants after RV1 dose 1 in Mexico but no increased risk after RV1 dose 1 in Brazil.7 In the current study, we identified a combined excess risk of 0.74 events per 100 000 vaccinated infants after dose 1. The ability to precisely quantify such low-level risks (excess rate of 1 to 2 cases per 100 000) is difficult even with large sample sizes and robust databases, and random variation could well explain the varying findings.
A postlicensure safety study in the United States using the VSD did not identify an increased risk of intussusception after ∼310 000 administered first doses of RV5 (relative risk = 1.21; 95% CI = 0.03 to 6.75), but the wide confidence bounds demonstrated that a risk of the magnitude suggested in the current VAERS analysis could not be confidently excluded.8 The VSD includes precise and complete information on vaccination status and adverse outcomes, and the lack of an increased intussusception risk from these data are reassuring, although it must be acknowledged that the VSD study could have been underpowered. VAERS receives intussusception reports from throughout the country allowing for capture of a greater number of intussusception cases to be included in the analysis. A recent ecologic study using national hospital discharge data from the United States for intussusception also identified a small increase in the incidence of intussusception among infants 8 to 11 weeks of age who receive most first doses of rotavirus vaccine, but no increase was noted among older age groups.26
In summary, after distribution of 47 million doses of RV5 in the United States, we observed a persistent clustering of intussusception events during days 3 to 6 after the first-dose vaccination. When we combined all 3 doses of RV5, we estimated a small overall excess risk of ∼0.79 intussusception event for every 100 000 vaccinated infants. This level of increased risk in the United States would translate to 33 excess annual intussusception events after rotavirus vaccination with the coverage expected for a fully mature rotavirus vaccine program. This is substantially lower than the number of diarrhea hospitalizations prevented annually (∼40 000) since rotavirus vaccine introduction.5,23
We thank Claudia Vellozzi and Karen Broder for critically reviewing this article.
- Accepted February 25, 2013.
- Address correspondence to Penina Haber, MPH, 1600 Clifton Rd, MS D-26 Atlanta, GA 30333. E-mail:
Ms Haber and Dr Patel participated in the design, data gathering and analysis, and manuscript preparation and have seen and approved the final version of the article. They had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Baggs participated in the initial design, data review, and manuscript revision aspects of the study and approved the final version of the article. Drs Pan and M. Haber participated in the design, data analysis, and manuscript revision aspects of the study and have seen and approved the final version of the article. Ms Museru, Ms Yue, and Ms Lewis participated in the data gathering, data review, and manuscript revision aspects of the study and have seen and approved the final version of the article. Dr Parashar and Dr DeStefano participated in the design, data interpretation, and manuscript revision aspects of the study and approved the final version of the article.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
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- Copyright © 2013 by the American Academy of Pediatrics