Rotavirus vaccines and intussusception
Extract from report of GACVS meeting of 11-12 December 2013, published in the Weekly Epidemiological Record on 14 February 2014
GACVS last reviewed the safety profile of RotaTeq and Rotarix vaccines during its December 2011 meeting.7 At that time, the Committee concluded that both vaccines had a good safety profile, but that they may be associated with an increased (up to 6-fold) risk of intussusception after the first dose of vaccine in some populations. During the current meeting, new data from Australia and the USA were reviewed in order to update the assessment of intussusception risk related to both vaccines.
In Australia, a recently published study of intussusception cases identified from national hospitalization databases, supplemented by active hospital-based surveillance from July 2007 through June 2010, was reviewed.8 As both vaccines are available in the country, the study allowed estimation of product-specific risks of intussusception. Findings were similar for both vaccines, suggesting that a significant risk of intussusception exists after the first and second dose of both vaccines. The average vaccine-attributable risk for intussusception, based on the estimated relative incidence in the 1–21 days after dose 1 and the 1–7 days after dose 2, was estimated to be 5.6 additional cases per 100 000 vaccinated infants.
In the USA, data are available from the spontaneous reporting system for vaccine safety (VAERS), as well as from 2 distinct vaccine safety monitoring systems that allow for cohort study designs: the Vaccine Safety Datalink (VSD) and the Post-licensure Rapid Immunization Safety Monitoring system (PRISM). VSD is a network of linked databases, involving 9 integrated health-care delivery institutions, whilst PRISM is a sentinel-like system using claims data from national health insurance companies. VAERS data showed that for RotaTeq, from 2006 to 2012, 584 confirmed cases of intussusception were reported for 47 million doses distributed. A cluster of cases was observed between days 3 and 6 after doses 1 and 2. For Rotarix, 66 confirmed intussusception cases were reported for 7.4 million doses distributed. The VSD analyses identified a small cluster of cases following Rotarix, with 6 cases of intussusception for 200 000 doses administered. In contrast, no such cluster was found with RotaTeq, with 8 intussusception cases identified (4 each after dose 1 and dose 3) for 1.3 million doses administered. The PRISM data suggest that RotaTeq is also associated with clusters of intussusception cases with an attributable risk of approximately 1 case per 100 000 doses whilst the number of cases is currently too small to allow calculation of an attributable risk for Rotarix.
GACVS acknowledged that the findings from both countries tend to confirm a risk of intussusception following administration of both vaccines, in particular during the first 7 days following a first dose. The Committee noted that attributable risk estimates vary across studies. This might reflect differences in the background rate of intussusception (estimated to be double in Australia compared to the USA) but could also reflect sampling uncertainty in all available estimates and limitations of the surveillance systems that lead to some uncontrolled biases (e.g. differences in diagnostic tests and case definitions in different settings). Overall, the findings remain reassuring that the risk of intussusception following current rotavirus vaccines remains small compared to the benefits of preventing the impact of severe diarrhoea. Given possible population differences in risk of intussusception, it is important that rotavirus vaccine introduction in other parts of the world be accompanied by similar active intussusception surveillance studies together with rotaviral disease surveillance so that the benefits and risks can be ascertained with relevant evidence.
7See No. 6, 2012, pp. 54–56.
8 Carlin JB et al. Clin Infect Dis. 2013; 57:1427-34.
Full report of GACVS meeting of 11-12 December 2013, published in the Weekly Epidemiological Record on 14 February 2014
Extract from report of GACVS meeting of 7-8 December 2011, published in the WHO Weekly Epidemiological Record on 10 February 2012
Rotavirus vaccines (RotaTeq and Rotarix) are being introduced into immunization programmes in many countries. In Brazil and Mexico, use of Rotarix has been associated with large reductions in all-cause diarrhoeal deaths. However, because a previous rotavirus vaccine (RotaShield) was associated with a ~30-fold increase in risk of intussusception during the week following receipt of the first vaccine dose, large clinical trials involving more than 70 000 children were carried out with RotaTeq and Rotarix. In the trials of RotaTeq, children were vaccinated with dose 1 at age 6–12 weeks; with Rotarix, children were vaccinated at age 6–14 weeks (in Latin America) or age 6–15 weeks (in Europe). RotaTeq is delivered in a 3-dose schedule; Rotarix requires only 2 doses. After licensure, the maximum age indicated for the last dose of vaccine was 32 weeks for RotaTeq or 24 weeks and 6 days for Rotarix. No evidence of increased risk of intussusception was identified during clinical trials with administration at those recommended ages.
Based on these data, and in order to align schedules between the vaccines, the Strategic Advisory Group of Experts (SAGE) on Immunization and GACVS recommended in 2009 that the first dose of either Rotarix or RotaTeq should be administered at age 6–15 weeks, and the maximum age for administering the last dose of either vaccine should be 32 weeks. It was noted that this expansion of the age range for use of these vaccines might potentially increase coverage of the first dose in developing countries from about 57% to 70% and full-course coverage from about 36% to 54%.
Not all countries are able to deliver early childhood immunization to most children by the recommended ages; delays in timing of vaccination are noted in many countries, in particular in countries with high rates of rotavirus-associated infant mortality.5 Therefore, there has been consideration of liberalizing the age restrictions for use of both Rotarix and RotaTeq, in order to extend the benefits of vaccination to children who otherwise would not receive the vaccines.
Since the recommendation in 2009, post-licensure safety investigations in some countries revealed an increased risk of intussusception after use of Rotarix (Australia and Mexico) and RotaTeq (Australia). The risks – where they have been found – are substantially lower than those previously associated with RotaShield. Studies with active case finding indicated that, with the current vaccines in use, 4- to 6-fold increases in risk were clustered within the first week after the first dose. In other populations, no increase in risk has been observed or reported. An updated risk–benefit analysis predicted that use of current rotavirus vaccines without age restriction would prevent an additional 49 500 (range: 35 000–67 000) rotavirus deaths while potentially causing about 300 (range: 180–400) excess intussusception deaths, compared with the current age-restricted strategy. This analysis incorporated updated estimates of risk of intussusception (similar to those hypothesized in the 2009 published analysis), updated estimates of rotavirus mortality for the year 2008, and newly available data on efficacy of rotavirus vaccines in low-income settings in Africa and Asia.
Because Rotarix and RotaTeq are now generally being used in accordance with the recommended age restrictions, data on the risk of intussusception for administration of either vaccine at older ages are not available. However, an analysis of intussusception risk following RotaShield in the USA found no significant difference in the relative risk of intussusception after administration of the first dose at 7–13 weeks, 14–21 weeks, or 22–52 weeks, although the confidence limits of those estimates were wide.
The Committee concluded that available data suggest that both Rotarix and RotaTeq continue to exhibit a good safety profile, but may be associated with an increased (up to 6-fold) risk of intussusception after the first dose of vaccine in some populations. The levels of risk observed are substantially less than those observed with the previous vaccine, RotaShield. The Committee reiterates that, based on available evidence, the benefits of rotavirus vaccination to all infants, without age restriction, would greatly exceed the risks, particularly in developing countries with moderate and high mortality from rotavirus disease. Active surveillance of intussusception in African and Asian countries that plan to introduce rotavirus vaccines should be seriously considered, because the data accrued would eventually provide additional benefit–risk information related to these important vaccines.
5Clark A, Sanderson C. Timing of children’s vaccinations in 45 low-income and middle-income countries: an analysis of survey data. Lancet, 2009, 373:1543–1549.
Full report of GACVS meeting of 7-8 December 2011, published in the WHO Weekly Epidemiological Record on 10 February 2012
Extract from report of GACVS meeting of 8-9 December 2010, published in the WHO Weekly Epidemiological Report on 28 January 2011
In December 2009, WHO recommended that all infants be routinely immunized to prevent rotavirus disease, the most common cause of serious gastroenteritis among infants worldwide. Two rotavirus vaccines are available: Rotarix (manufactured by GSK Biologicals) and RotaTeq (manufactured by Merck & Co., Inc.). Because a previous rotavirus vaccine (RotaShield, manufactured by Wyeth) was associated with an increased incidence of intussusception, an uncommon form of bowel obstruction, the risk of this adverse event was specifically evaluated in prelicensure trials of the currently licensed vaccines. In trials prior to registration no increased risk of intussusception was observed: each trial involved >70 000 participants. The trials were conducted mainly in Finland and the United States of America for RotaTeq, and in 11 countries in Latin America for Rotarix. Nonetheless, WHO has recommended that postmarketing surveillance for this adverse event should continue whenever these vaccines are introduced into new populations. On 6 and 13 August 2010, GACVS reviewed (during a teleconference) the preliminary data from postmarketing studies that suggested an increased risk of intussusception associated with Rotarix in some populations. On 22 September 2010, the United States Food and Drug Administration approved a label change for Rotarix advising practitioners of the new data on intussusception,3 and WHO provided an update related to the preliminary findings from those active surveillance studies.4
Since 2007, the Pan American Health Organization has collaborated with ministries of health, the United States Centers for Disease Control and Prevention (CDC), and PATH to evaluate the potential risk of intussusception after routine use of Rotarix in Brazil and Mexico. Preliminary analyses of the surveillance data have identified 18 hospitalizations following intussusception (none of which were associated with death). These occurred within 1–7 days after administration of the first dose in Mexico; after adjusting for age, this rate is about 4–5 times higher than that occurring during later periods after vaccination. No similar excess was observed after administration of the first dose in Brazil. A case-control analysis of the data from Mexico found an association similar to that in the case-only analysis. These data from Mexico correspond to a risk of about 1–2 additional hospitalizations for intussusception per 100 000 infants vaccinated, or about 20–40 additional cases per year nationwide at current vaccination rates (the Mexican birth cohort is approximately 2 million). A similar study sponsored by GSK Biologicals in a different population in Mexico also found an increased risk of intussusception: an approximately 1.7-fold increase during the 30 days following the first dose, with a cluster of cases occurring during the first week after vaccination.
In Australia, postmarketing surveillance studies found no increased risk of intussusception among children aged ≤9 months with either vaccine; however, the studies found a temporal increase in intussusception with both vaccines during the first week after vaccination, although these findings were based on relatively few cases. In the United States, data from both the CDC and from an evaluation sponsored by Merck & Co., Inc., did not show evidence of an increased risk of intussusception with RotaTeq; however, the population of children under active surveillance in the United States who have received RotaTeq is not yet large enough to rule out the level of risk during the first week after vaccination that has been suggested by preliminary analyses of Rotarix in Mexico and with both vaccines in Australia.
In summary, postmarketing surveillance indicates the possibility of an increased risk of intussusception shortly after the first dose of rotavirus vaccine in some populations. If the findings are confirmed, the level of risk observed in these studies is substantially lower than the risk of 1 case/5000–10 000 in infants who received the RotaShield vaccine. The benefits of rotavirus vaccination in preventing rotavirus gastroenteritis and its consequences are substantial. For example, in Mexico it is estimated that nationwide use of Rotarix would prevent approximately 12 000 hospitalizations and 700 deaths from diarrhoea each year, a benefit that greatly outweighs the potential risk of 20–40 cases of vaccine-associated intussusception found in these preliminary analyses. Additional data are being collected and analysed from Latin America and other areas. GACVS will continue to review these data as they become available.
3Information on Rotarix: labelling revision pertaining to intussusception. Washington, DC, United States Food and Drug Administration, 2010 (http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm226690.htm, accessed December 2010).
4Statement on Rotarix and RotaTeq vaccines and intussusception. Geneva, World Health Organization, 2010 (http://www.who.int/vaccine_safety/topics/rotavirus/rotarix_and_rotateq/intussusception_sep2010/en/index.html; accessed January 2011).
Full report of GACVS meeting of 8-9 December 2010, published in the WHO Weekly Epidemiological Report on 28 January 2011