Rotavirus vaccine safety update

In December 2011, GACVS initially reviewed the safety of currently administered rotavirus vaccines.⁵ The Committee noted that both RotaTeq® and Rotarix® vaccines had a good safety profile and that although they may be associated with an increased (up to 6-fold) risk of intussusception, the benefit of the vaccines outweighed the potential risk. In December 2013, GACVS reviewed additional data that had become available from Australia and the United States of America (USA).⁶ It noted that both countries confirmed a risk of intussusception following vaccine administration, particularly within the first 7 days after the first dose, although attributable risk estimates varied across studies. The Committee concluded that the benefits of the vaccine outweighed the small potential risk of intussusception (in the range of 1–2 cases per 100 000 first doses).⁷ GACVS also suggested that given possible population differences in the risk of intussusception, active surveillance should be undertaken in countries where rotavirus vaccines are being introduced to ensure that benefits and risks can continue to be assessed.

The GACVS session in December 2017 reviewed recent evidence on the impact of rotavirus vaccine, an updated Cochrane review on rotavirus vaccines and intussusception, and recent data from multicountry studies from sub-Saharan Africa and South Africa.

As regards vaccine impact, data from randomized controlled clinical trials (RCTs) showed that RV1, RV5, Rotasiil® and Rotavac® vaccines reduced severe rotavirus gastroenteritis by 52–94% after 1 year of follow-up. Overall, weak evidence from observational studies suggested that the introduction of RV1 and RV5 vaccines reduced diarrhoea-related deaths in children. While the effectiveness was lower in some low-income countries, the benefit was still large due to the high disease burden.

A systematic review⁸ was conducted to update a 2012 Cochrane systematic review regarding the efficacy and safety of rotavirus vaccines. This review included RCTs (low power, low bias); historical controls (low power, high risk of bias); case-control studies (high power, high risk of bias); cohort studies (high power, high risk of bias); and self-controlled case series (SCCS) (high power, unclear risk of bias). Data were insufficient to evaluate many of the new vaccine products. For those reviews with sufficient data, evidence from RCTs showed that there was no difference in incidence of serious adverse events in the use of RV1, RV5, Rotasiil®, or Rotavac® compared with placebo, up to 2 years after vaccination. There was conflicting evidence from different sources as to whether RV1 or RV5 was associated with an increased risk of intussusception. While RCTs of RV1 and RV5 found no association between intussusception and vaccination, SCCS studies suggested an increased risk in the weeks following vaccination.

In the African Intussusception Surveillance Network that was formally established in 2014, and included 7 countries using Rotarix® (Ethiopia, Ghana, Kenya, Malawi, United Republic of Tanzania, Zambia and Zimbabwe), surveillance for intussusception (defined using Brighton case definition criteria) was conducted at 28 sentinel paediatric hospitals. Vaccination status was identified via vaccination card or medical/clinic record. The potential association between oral rotavirus vaccine and intussusception was analysed using an SCCS study, in which each of the 717 identified case-patients (aged 28–245 days) served as their own control (risk periods were 1–7 days, 8–21 days, and 1–21 days following each dose, while the control periods were the other time windows). No increased risk of intussusception was identified after either dose 1 or 2.

Post-marketing monitoring is also ongoing in South Africa, where an SCCS study (using the same methods as described above) is being conducted among >300 case-patients aged 28–275 days. Thus far, no risk following the first dose, and a small risk (approximately 2-fold) in the first 7 days following the second dose, have been identified, but no overall increased risk 1–21 days following the second dose. Enrolment is ongoing.

While the reason behind the difference in potential risk of intussusception in different countries is not clear, hypotheses include: differences in age at vaccination; differences in effectiveness of vaccine (e.g. lower effectiveness may be associated with lower risk of intussusception); concurrent use of inactivated polio vaccine (IPV) versus oral poliovirus vaccine (OPV) (e.g. concurrent use of OPV may reduce both effectiveness of the rotavirus vaccine and risk of intussusception); and the “trigger” hypothesis (that vaccination could potentially trigger intussusception in a susceptible individual who may have developed intussusception later in the absence of vaccination). The Committee suggested that future follow-up studies continue to assess these variables. In addition, as countries transition from OPV to IPV, studies evaluating both effectiveness and risk of intussusception should be considered. Countries should also continue to assess risk of new vaccines as they are licensed and introduced. Overall, the Committee continues to be reassured that the benefit of rotavirus vaccination in preventing severe diarrhoea is greater than the small potential risk of intussusception identified in most, but not all post-licensure studies.

⁵ See No. 06, 2012, pp. 54–56.

⁶ See No. 07, 2014, pp. 57–58.

⁷ See information sheet

⁸ Soares-Wiser et al. Vaccines for preventing rotavirus diarrhoea: vaccines in use. http://www.cochrane.org/CD008521/INFECTN_vaccines-for-preventing-rotavirus-diarrhoea-vaccines-in-use

Full report of GACVS meeting of 6-7 December 2017, published in the Weekly Epidemiological Record on 19 January 2018

Safety profile of a novel live attenuated rotavirus vaccine

Rotavirus gastroenteritis remains a major cause of morbidity and mortality among young children. Two rotavirus vaccines are currently widely used in national immunization programmes. A new rotavirus vaccine, Rotavac, was licensed in India in January 2014. The vaccine is derived from a naturally attenuated human neonatal strain containing 1 bovine segment (G9P[11]) that was originally isolated from an asymptomatic infant at the All India Institute of Medical Sciences in 1988. The strain was further studied by Indian and U.S. investigators, with safety trials conducted in adults and children in Cincinnati, United States of America. In 2000, the strain was then licensed to Bharat Biotech International (Hyderabad, India), which developed the vaccine with clinical testing in Phase 1, 2 and 3 studies in India. The current vaccine formulation requires -20 °C storage, although the product may be stored at +2 to
+8 °C for the final 6 months prior to expiry. Several different presentations have been licensed, but the manufacturer expects the main presentation to be in a 5-dose vial, which could be used for 8 hours after opening. An oral antacid buffer is currently administered prior to administration of the vaccine.

The randomized, double-blind, placebo-controlled Phase 3 study was carried out with active monitoring for safety in 4532 infants who received the rotavirus vaccine and 2267 placebo recipients. The study was conducted during their routine childhood immunization series, and the subjects were followed up to the age of 2 years. There was no imbalance noted between the Rotavac and placebo groups with respect to adverse events, death or intussusception.

There were 11 confirmed cases of intussusception; importantly, no case occurred in proximity to the time of vaccination. The earliest case following receipt of placebo was 36 days post dose 3. The earliest case following receipt of Rotavac was 112 days post dose 3. The lack of a temporal association argues strongly against a causative relationship between Rotavac and intussusception since most rotavirus vaccine-attributable cases are expected to occur within the first week following vaccination. The observed incidence of confirmed intussusception was 94 per
100 000 child-years (95% confidence interval [CI]: 41–185) among vaccinated infants and 71 per 100 000 child-years (95% CI:15–206) among those who received placebo. This incidence is similar to that measured, in the absence of vaccine, from countries with active surveillance systems for intussusception.

As the available safety data support further use of the vaccine, a post-licensure study of at least 45 000 vaccinated infants is planned. However, based on the experience with similar vaccines, it will be important that additional data be continuously collected in order to assess the risk of intussusception as well as to identify any other rare adverse events that may occur. Based on the experience with other rotavirus vaccines, the infrastructure of sentinel sites that exists in India should be utilized for continued intussusception surveillance in order to fully characterize the safety profile of this new rotavirus vaccine.

Full report of GACVS meeting of 11-12 June 2014, published in the WHO Weekly Epidemiological Record on 18 July 2014