Safety of rotavirus vaccines

The Committee had previously reviewed the safety of RotaTeq and Rotarix vaccines, mainly in the context of data gathered from large-scale clinical trials set up before both vaccines had been registered. The results of these trials had been reassuring in terms of providing information indicating that any risk of intussusception associated with either of the 2 new vaccines was lower than the level that had been associated with the (withdrawn) RotaShield vaccine. It was recognized that as the new vaccines were used in public health programmes, and as larger numbers of infants were vaccinated, it would be possible to get better estimates of any risk of intussusception or other adverse effects associated with either vaccine. The Committee has previously emphasized the importance of such studies.

At the meeting, the Committee was presented with post-marketing information on the rotavirus vaccines from each of the 2 manufacturers, from the Immunization Safety Office of the United States Centers for Disease Control and Prevention using data from the Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink (VSD) surveillance systems, from the Australian National Immunization Program and from the PAHO Network for Rotavirus Vaccines.

Surveillance data from the manufacturer of RotaTeq from several ongoing studies did not indicate an increased risk of intussusception following vaccination compared with background rates, but these studies were relatively small and the confidence intervals of the possible risk were wide.

Data from 2 years of experience in VAERS with the use of RotaTeq in the United States were presented. During this time, 267 cases of intussusception had been reported among recipients of >14 million doses of vaccine distributed. Analyses of these data did not identify signals indicative of an increased risk of intussusception associated with RotaTeq, but use of VSD would provide a better assessment. In VSD, analysis of 5 cases of intussusception (only 2 of which were validated after medical record review) among recipients of 205 000 doses of RotaTeq did not indicate an increased risk of intussception and enabled a risk of the level of 1/25 000 doses to be ruled out with reasonable confidence (a risk about 10-fold lower than that associated with RotaShield).

Data from the manufacturer on cases of intussusception following vaccination with Rotarix indicated that about 32 million doses of Rotarix had been distributed, predominantly in several Latin American countries. A total of 161 cases of intussusception had been reported following vaccination, 106 within 30 days of vaccination. Crude analysis indicated that the measured incidence rates were generally below background rates of disease incidence, but these data were difficult to interpret because of the likely high level of underreporting and some possible delays in the use of distributed doses. More detailed prospective studies are ongoing in Mexico and are due to start in the United States.

The Committee was also informed of ongoing studies to assess the safety of Rotarix in healthy infants, HIV-infected infants and pre-term infants in Africa, and noted the encouraging early findings of these studies with respect to both efficacy and safety.

In Australia, rotavirus vaccines had been introduced for the indigenous population in October 2006 and nationally in July 2007. Different vaccines had been chosen by different states. Data on cases of intussusception are being ascertained through a national passive reporting system, and enhanced surveillance is being undertaken in 4 sentinel sites. The Committee was presented with preliminary data indicating that a small number of cases of intussusception had been observed in infants who had received a rotavirus vaccine and that there appeared to be some clustering in the first 10 days following vaccination. However, a reporting bias could not be excluded and it was not yet clear whether the number of cases was raised above background rates; detailed analysis was pending the acquisition of further data.

The Committee was encouraged by the description of the surveillance network being developed in some Latin American countries, with facilitation by PAHO. No clear signals of vaccine-related adverse effects were yet apparent, but further strengthening of the surveillance network is a priority. These studies were also serving to accumulate data on the background natural frequency of intussusception among infants. From the above-mentioned reports, the Committee was reassured that an intussusception risk of the order of that which had been associated with RotaShield could be ruled out with confidence, but the available post-marketing surveillance data were still too few to rule out, with confidence, a risk of substantially lower magnitude. The Committee emphasized the importance of continuing to accumulate post-marketing surveillance data on intussusception and other possible adverse effects and stressed particularly the importance of setting up surveillance systems for such effects as the vaccines were introduced into increasing numbers of developing countries.

Full report of GACVS meeting of 17-18 December 2008, published in the WHO Weekly Epidemiological Record on 30 January 2009

The Committee was asked to consider whether the use of tetravalent rhesus reassortant rotavirus vaccine (commercially known as RotaShield®) might be associated with a significantly lower risk of vaccine-induced intussusception if immunization is completed before 2 months of age. This had been suggested in a recent publication of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States, in the Journal of Infectious Diseases.

The Committee studied a re-analysis of the original case-control study data from the United States Centers for Disease Control and Prevention (CDC), which showed a lower relative risk of intussusception in infants immunized before 60 days of age than those immunized later in infancy. The authors concluded that the relative risk of intussusception might be substantially reduced if a neonatal immunization schedule is used rather than the vaccination strategy in older infants that had been used in the introduction of the vaccine in the United States. It was suggested to the Committee that an age-dependent risk of intussusception might also apply to the 2 novel rotavirus vaccines that are currently in advanced development. The Committee noted that although the point estimates of relative risk differed between older and younger infants, the confidence intervals on the estimates overlapped substantially and the differences were not statistically significant.

Representatives from CDC, who where involved with the initial analysis and investigation of the association between RotaShield® and intussusception, presented the Committee with a re-analysis of the initial data set. The CDC confirmed a high relative risk in infants immunized after day 60. Too few children had been immunized before day 60 in the CDC studies to assess adequately the hypothesis of a lower relative risk in younger infants. No efficacy data are available using a neonatal schedule for any of the rotavirus vaccines.

The Committee concluded as follows:

• The studies provide clarification and confirmation of a high risk of RotaShield®-associated intussusception in infants immunized after day 60.
• The available evidence is not sufficient to conclude that the use of RotaShield® at an age less than 60 days is associated with a lower relative risk of intussusception.
• Even strict recommendations for adherence to an early immunization schedule would be extremely difficult to implement in the field in many countries.

The Committee will continue to review the safety data of new rotavirus vaccines from clinical trials and post-marketing surveillance. It noted that the possibility of an age-dependent risk of intussusception should be taken into account in assessing rotavirus vaccines.

Full report of GACVS meeting of 1-2 December 2005, published in the WHO Weekly Epidemiological Record on 13 January 2006