Rotavirus (RV) is the major cause of acute gastroenteritis among infants and young children worldwide.1–3 Before the introduction of currently available RV vaccines, RV gastroenteritis (RVGE) accounted for approximately 2.4 million hospitalizations and half a million deaths annually among children younger than 5 years worldwide.1–4 The burden of RV disease is significant in both developing and developed countries; however, there are marked differences in the nature of this burden, with highest mortality seen in low-income countries.3,4 The World Health Organization recommends that all infants are vaccinated to prevent RV disease.5,6
An oral rhesus-human reassortant RV tetravalent vaccine (RRV-TV; RotaShield, Wyeth) was licensed in the US in October 1998. However, 9 months later, the RRV-TV immunization program was suspended because of a temporal association between RV vaccination and occurrence of intussusception.7 The relative risk of intussusception during the 3–7 days after RRV-TV administration was 58.9 [95% confidence interval (CI): 31.7–109.6] postdose 1 and 11.0 (4.1–29.5) postdose 2.8
Intussusception is a rare condition. A recent systematic review of 82 studies worldwide reported a mean incidence of intussusception of 74 per 100,000 children aged less than 1 year, with considerable geographic variability noted (range: 9–328).9 Intussusception case fatality rate also varies between regions, being higher in Africa (9%) than in other regions (<1%).9
Two other oral, live-attenuated RV vaccines are currently recommended by the World Health Organization: a 2 dose, monovalent human RV vaccine (RV1; Rotarix, GSK) and a 3 dose, pentavalent bovine-human reassortant RV vaccine (RV5; RotaTeq, Merck & Co., Inc.). Both vaccines have been shown to be highly effective for the prevention of severe RVGE in clinical trials involving 101,671 and 84,592 children, respectively.10 Real-life data from effectiveness and impact studies in various settings around the world demonstrate considerable reductions in hospital admissions and mortality because of RVGE and diarrhea of any cause in infants and young children after inclusion of these RV vaccines into national immunization schedules.11–17 No increased risk of serious adverse events, including intussusception, was detected in prelicensure clinical studies of either RV1 or RV5,10 including 2 randomized, controlled trials each involving over 60,000 infants, which had been specifically designed to detect a risk of intussusception similar to that seen with RRV-TV.18,19
Several postlicensure surveillance studies have been undertaken to assess the risk of intussusception after vaccination with RV1 and RV5 in real-world settings,20–29 the largest involving approximately 1.5 million infants with vaccine exposure.23 These studies suggest a small temporal increase in the risk for intussusception with both currently available RV vaccines, particularly within 7 days of administration of the first vaccine dose. These studies differ in terms of design and population exposure, but all provide an estimate of the risk of intussusception during the 7-day period after vaccination with RV1 and/or RV5.
The aim of this meta-analysis was to provide a single overall estimate of the relative risk of intussusception during the 7-day period after administration of the first and second dose of both currently available RV vaccines, RV1 and RV5. Because only 2 doses of RV1 are administered and no increased risk of intussusception has been shown after the third dose of RV5,21,24–29 the relative risk of intussusception after dose 3 of RV5 was not included in the meta-analysis.
Study Selection Criteria and Search Strategy
Studies were eligible if they met the following 5 criteria: (1) postlicensure study (no clinical trials); (2) risk estimated for the 7-day period after vaccination; (3) risk estimated for dose 1 and dose 2, separately; (4) data obtained through active and/or passive surveillance for “confirmed” cases of intussusception cases (Brighton or other method of case confirmation); and (5) full publically available study report or peer-reviewed publication.
This meta-analysis considered postlicensure studies of the risk of intussusception after vaccination with RV1 and RV5 identified through systematic literature review and/or that had been presented by the US Centers for Disease Control and Prevention to the US Advisory Committee on Immunization Practices since the introduction of both vaccines beginning in 2006 through June 2013. The literature search was undertaken on November 25, 2013 in Medline, Embase and Central databases for papers published at any time using the following keywords: (Intussusception OR Intestinal Obstruction) AND (Rotavirus) AND (Vaccine OR Rotarix OR Rotateq). Two reviewers (D.R. and another GSK epidemiologist) independently screened the retrieved references to assess whether identified studies met the criteria for inclusion in this meta-analysis.
Data Extraction and Quality Assessment
Because of the differences in study methodology (self- controlled case series [SCCS], self-controlled risk interval [SCRI], case-control, cohort and observed vs. expected), the risk of intussusception was reported as relative incidence rates, odds ratios, relative risk or observed/expected ratios. For the purposes of this meta-analysis, all of these estimates were considered as estimates of the relative risk of intussusception after vaccination. If more than 1 risk estimate was reported, results of the primary analysis were used. If the primary analysis was not specified, results obtained with the most robust method were used according to the following order: self-control > case-control > cohort > observed versus expected.
The meta-analysis was based on log-transformed estimates of relative risk and corresponding 95% CI from each eligible study. Undefined risk estimates (ie, risk estimate ≅ 0 or ∞) were not included in the statistical calculations. No raw data were used. Separate analyses were performed for RV1 and RV5. For each vaccine, the relative risk of intussusception was estimated postdose 1 and postdose 2. Results were pooled using both fixed and random study effect model.30 Heterogeneity between studies was tested using the Cochran Q test. The degree of the heterogeneity was assessed by the I2 index, with 25%, 50% and 75% representing low, moderate and high heterogeneity, respectively.31,32 Results are presented as forest plots. We performed a sensitivity analysis for each vaccine after each dose including data from the study by Weintraub et al.29 This study was not included in the main analysis because nonconfirmed cases were included in the observed versus expected analysis. However, this is one of the few studies to provide an estimate of risk for both RV1 and RV5 in the same setting.
The study selection process is summarized in Figure 1. Data from a total of 5 studies met the criteria for inclusion in this meta-analysis20,23,26–28; in addition, an observed versus expected study29 including nonconfirmed cases was included in a sensitivity analysis (Table 1). For RV1, 3 studies provided information on risk of intussusception postdose 1 (all of SCCS design, 2 undertaken in Latin America and 1 in Australia) and 4 provided information on risk of intussusception postdose 2 (3 of SCCS and 1 additional study of SCRI design undertaken in the US). One of the studies undertaken in Latin America provided separate data for the risk of intussusception after RV vaccination in 2 different countries (Mexico and Brazil)20; data for both of these countries were included separately in the meta-analysis. Three studies provided information on the risk of intussusception both postdose 1 and postdose 2 for RV5 (1 of SCCS design in Australia and 2 of SCRI design in the US). One of the studies in the US provided a risk estimate for 3–6 days after vaccination and as such did not strictly meet inclusion criterion 2.27 However, there is good evidence to suggest that the risk of intussusception within 7 days of vaccination is mainly concentrated during the 3–6 day postvaccination period; as such, this study was included in the meta-analysis.
Risk of Intussusception Postdose 1
The relative risk of intussusception during the 7-day period after the first dose of RV1 ranged from 1.1 to 6.8 among the 3 studies included in the meta-analysis (Fig. 2). Heterogeneity among studies was moderate (I2 = 60.6%) and approached statistical significance (Q = 7.62, P = 0.06). This heterogeneity was primarily attributable to the data from Brazil.20 The overall estimate of relative risk of intussusception during the 7-day period after the first dose of RV1 was 5.4 (95% CI: 3.9–7.4) for the fixed-effect model and 4.7 (2.6–8.4) for the random-effect model.
The relative risk of intussusception during the 7-day period after the first dose of RV5 ranged from 3.8 to 9.9 among the 3 studies included in the meta-analysis (Fig. 2). Heterogeneity among studies was low (I2 = 34.7%) and not statistically significant (Q = 3.07, P = 0.22). The overall estimate of relative risk of intussusception during the 7-day period after the first dose of RV5 was 5.5 (3.3–9.3) for the fixed-effect model and 6.1 (3.0–12.1) for the random-effect model.
Risk of Intussusception Postdose 2
The relative risk of intussusception during the 7-day period after the second dose of RV1 ranged from 1.3 to 3.5 among the 4 studies included in the meta-analysis (Fig. 3). Heterogeneity among studies was very low (I2 = 5.3%) and not statistically significant (Q = 4.22, P = 0.38). The overall estimate of relative risk of intussusception during the 7-day period after the second dose of RV1was 1.8 (1.3–2.5) for the fixed-effect model and 1.8 (1.3–2.6) for the random-effect model.
The relative risk of intussusception during the 7-day period after the second dose of RV5 ranged from 1.4 to 2.8 among the 3 studies included in the meta-analysis (Fig. 3). No heterogeneity among studies was observed (I2 = 0%). The overall estimate of relative risk of intussusception during the 7-day period after the second dose of RV5 was 1.7 (1.1–2.6) for both fixed-effect and random-effect models.
Despite the fact that the study by Weintraub et al29 suggested a relative risk of intussusception within 7 days of RV1 compared with RV5 of 9.4 (1.4–103.8), the sensitivity analysis gave similar relative risk estimates for both vaccines after each dose.
For RV1, the overall estimate of relative risk of intussusception postdose 1 was 5.5 (4.0–7.5) for the fixed-effect model and 5.0 (3.0–8.4) for the random-effect model. For RV5, the overall estimate of relative risk of intussusception postdose 1 was 4.9 (3.0–7.8) for the fixed-effect model and 5.1 (2.8–9.3) for the random-effect model.
The overall estimate of relative risk of intussusception postdose 2 of RV1 was 2.0 (1.5–2.8) for the fixed-effect model and 2.4 (1.5–3.9) for the random-effect model. Sensitivity analysis for RV5 could not be performed postdose 2 because the risk estimate was undefined (relative risk = 0) in the study by Weintraub et al.29
Intussusception is a rare form of intestinal obstruction in which a segment of the bowel prolapses into a more distal portion; mean incidence is reported to range from 9 to 328 per 100,000 children aged less than 1 year.9 Intussusception constitutes the most frequent cause of acute intestinal obstruction among young children independent of exposure to RV vaccines. Most cases occur in infants aged less than 1 year, with peak incidence between 4 and 7 months of age.9 Intussusception had been observed in prelicensure trials of the first RV vaccine, RRV-TV, but the risk was not fully appreciated until about a million doses of the licensed vaccine had been administered in the US and about 100 cases had been reported. The risk of intussusception appeared greatest 3–7 days after administration of the first vaccine dose.8 Postlicensure surveillance studies with current RV vaccines have been undertaken in several countries.20–29 These studies have varied in terms of geographic location, design, statistical methodology and results. Of particular note, studies of intussusception risk associated with RV1 have been undertaken in both developing and developed countries (Mexico, Brazil, Australia and the US), whereas studies of RV5 were exclusively performed in developed countries (Australia and the US).
The present meta-analysis was undertaken to provide an overall estimate of the risk of intussusception after vaccination with RV1 and RV5. Despite the differences in study design, methods and geographical location, the degree of heterogeneity between the included studies was found to be low. Because of the general low heterogeneity, the fixed model estimate is, therefore, considered a good estimate of risk for the general vaccinated population. The overall estimate of relative risk of intussusception during the 7 days after vaccination with RV1 was 5.4 postdose 1 and 1.8 postdose 2. The overall estimate of relative risk of intussusception during the 7 days after vaccination with RV5 was 5.5 postdose 1 and 1.7 postdose 2. The relative risk estimates obtained are very similar for both currently available RV vaccines and are approximately 10-fold lower than those reported for RRV-TV.8
This is the first study to report an overall estimate of the relative risk of intussusception postdose 1 and postdose 2 with the 2 commercially available RV vaccines, and this study appears to indicate a class effect. We used relative risk and not attributable risk as the main parameter because of the large variation in the background incidence of intussusception worldwide.9 Moreover, attributable risk was not provided for all included studies. However, good homogeneity of relative risk estimates among the studies indicates that the overall estimate of relative risk obtained is a valuable parameter that can be used to estimate the attributable risk in a specific setting (attributable risk = relative risk multiplied by the number of expected cases in the given setting/country).
A key strength of this meta-analysis is the strict inclusion criteria used. Only postmarketing studies were included because the objective was to assess the risk of intussusception in real clinical practice. Furthermore, only data from studies that reported confirmed cases of intussusception were included. This increases the robustness of our analysis and the findings; in particular, conferring a high specificity of the endpoint to reduce a possible bias to the null hypothesis (no risk), which can occur with a lack of specificity. In addition, risk was estimated for each dose separately because all studies showed a risk difference between the 2 doses.
The risk of intussusception beyond the 7-day postvaccination period was not assessed in this study because of lack of homogeneity in the definition of these other risk periods among the various studies. All included studies provided an estimate of risk for the 7-day postvaccination period. Most studies also provided risk estimates for other time periods; however, these other risk periods varied among studies (1–7, 1–14, 1–21, 1–30, 8–14, 15–21 and 8–21 days). Furthermore, most studies20,21,23,25 did not show evidence of increased risk after the 7-day postvaccination period; one study in Mexico20 showed a small elevated risk (~2) during the 8–21 day period postdose 2 of RV1 and another study in Australia26 showed an elevated risk during the 8–21 day period postdose 1 for both RV1 (~3) and RV5 (~6).
Another limitation could be the limited number of studies included in the present meta-analysis (3 or 4 depending on the vaccine and the dose). However, strict inclusion criteria were used to have a very specific endpoint and to avoid bias to the null hypothesis of absence of risk. Although methodology differed between studies, all controlled for age effect either by age-adjustment analysis (SCCS and SCRI studies) or by using age-specific expected number (observed vs. expected study). In addition, a sensitivity analysis, which included the study by Weintraub et al,29 yielded very similar relative risk estimates for both vaccines postdose 1 and for RV1 postdose 2. This shows the risk estimates derived by this meta-analysis to be robust.
During preparation of this article, 2 other studies of the risk of intussusception after RV vaccination have been published.33,34 The first study reported risk of intussusception after vaccination with RV1 using worldwide spontaneous reports33; however, because there was no case ascertainment, this study does not meet the inclusion criteria of our meta-analysis. The second study reported observed versus expected standardized morbidity ratio for RV1 and RV5.34 This study used confirmed cases of spontaneously reported intussusception in Germany from 2006 to 2010 and met the inclusion criteria for our meta-analysis. Despite the low number of observed cases of intussusception (7 for RV1 and 8 for RV5), the risk estimates obtained are consistent with the overall risk estimates of our meta-analysis.
The findings of this meta-analysis for RV1 and RV5, and the previous experience with RRV-TV, provide an indication that the slight increase in the risk of intussusception postvaccination may be a class effect of oral RV vaccines, albeit with different risk levels for RRV-TV and the currently licensed RV1 and RV5 vaccines. This meta-analysis shows that RV1 and RV5 have virtually identical risk estimates for intussusception after each vaccine dose, and that this risk is slightly higher in postdose 1 than in postdose 2. The availability of a single global estimate for relative risk of intussusception after administration of currently licensed RV vaccines will support healthcare decision-making and enables benefit–risk assessments to be made, especially in countries with limited local intussusception surveillance infrastructure. Any new RV vaccine licensed in the future will have to undergo an extensive period of postlicensure evaluation for intussusception with appropriate study designs to ascertain the risk associated with the individual product. Even though the risk of intussusception with RV vaccines appears to be a class effect, the risk of intussusception can vary substantially as the experience with RRV-TV and the 2 currently licensed vaccines (RV1 and RV5) has shown, with implications for overall benefit–risk depending on the setting in which the vaccine will be used.
It remains to be fully determined whether the short-term increased risk of intussusception immediately after vaccination translates into an overall population-level increase in intussusception incidence during the first year of life and beyond, or whether there is a compensatory effect in the more distant postvaccination periods as suggested by some data for the RRV-TV vaccine.35 The studies included in this meta-analysis concentrated on a specific period of observation (7 days postvaccination) and did not attempt to define the possible impact of RV vaccination on the overall incidence of intussusception. However, there has been no evidence of sustained population level changes in intussusception rates in the United States before and after RV vaccine introduction.36 Similarly, a recent German study also found no overall increase in intussusception rate after the introduction of RV vaccination.37 Available data confirm that the documented benefits of the currently available RV vaccines by far outweigh the small temporal increase in risk for intussusception immediately after vaccination.20,38–43 Accordingly, public health agencies worldwide continue to strongly endorse routine RV vaccination of infants.40,41,43,44
The etiology of intussusception remains poorly understood, and better understanding of the biological mechanism of intussusception and the overall risk of intussusception in vaccinated children is needed. Previous epidemiological studies have failed to demonstrate an association between natural RV infection and intussusception.45–47 Apparent clustering of intussusception in the first 7 days after RV vaccination coincides with the peak period of vaccine-virus viral replication48,49; viral shedding has been detected with all RV vaccines after each vaccine dose and is highest postdose 1.50,51 However, whether there is any causal association between occurrence of viral replication in the gastrointestinal tract of vaccinated infants and the development of intussusception remains unknown.
The small increase in risk of intussusception after vaccination is already reflected in the prescribing information for both RV1 and RV5 and acknowledged by regulatory authorities worldwide. This risk should be taken into context with the overall benefit–risk evaluation of RV vaccination. Early diagnosis and treatment of intussusception is essential to prevent injury to the intestine and associated sequelae. Accordingly, healthcare professionals should follow-up on any symptoms possibly indicative of intussusception (severe abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/or high fever), and parents/guardians should be advised to promptly report such symptoms to their healthcare provider.
In summary, results of this meta-analysis show a similar increase in the overall estimate of relative risk of intussusception mostly during the first 7 days after administration of dose 1 and, to a lesser extent, dose 2, for both currently available RV vaccines, RV1 and RV5. This suggests that intussusception may be a class effect of currently available oral RV vaccines.
The authors thank Nicolas Praet (GSK epidemiologist) for his assistance with the retrospective literature review, Jean-Yves Pirçon (GSK statistician) for his contribution to the statistical calculations and Laurence Baril (GSK epidemiologist) for her assistance with data interpretation and manuscript review. The authors also thank Jennifer Coward (independent medical writer on behalf of GSK) for her help with preparing the manuscript and Uta Gomes (independent publication manager ginkgosolutions Ltd. on behalf of GSK) for editing and publication coordination.
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