The human rotavirus vaccine RotarixTM in infants An integrated analysis of safety and reactogenicity

Rotavirus (RV) is a leading cause of severe acute diarrhea in infants and young children worldwide. RV gastroenteritis (RVGE) accounts for approximately 2.4 million hospitalizations and more than half a million deaths annually among children younger than 5 y. The burden of RV disease varies widely, but is significant in both developing and developed countries. The availability of safe and effective vaccines against RV offers the potential to reduce the global burden of RVGE. The World Health Organization (WHO) recommends that all infants be routinely immunized to prevent RV disease. An oral live-attenuated human RV vaccine (RotarixTM, GlaxoSmithKline Vaccines) has been shown to be efficacious for the prevention of severe RVGE in large-scale clinical trials conducted in Latin America, Europe, Asia, Africa, and Japan, and has been licensed in more than 120 countries worldwide. This paper presents the results of an integrated clinical analysis of safety and reactogenicity data from 28 randomized, placebocontrolled, double-blind Phase II and III trials (DBRCTs) of the human RV vaccine, involving over 100 000 infants worldwide. Such a large safety database facilitates the detection of adverse events (AEs) that might occur at low frequencies, and which may therefore not be detected in individual studies. Because a previous RV vaccine (RotaShieldTM, Wyeth) was associated with an increased incidence of intussusception, particular attention was focused on this event. Another adverse event of interest was Kawasaki disease. Regulatory authorities requested monitoring for this event following reports during prelicensure studies of the bovine-human reassortant pentavalent RV vaccine (RotateqTM, Merck Vaccines). The DBRCTs included in this analysis were conducted from May 2000 to July 2010 in countries spanning the global spectrum of development and national wealth (Table S1). Healthy infants aged 6–20 wk received 2 or 3 doses (3 studies only) of vaccine or placebo at 4to 8-wk intervals. Solicited general AEs (irritability/fussiness, cough/runny nose [selected studies], fever, loss of appetite, vomiting, and diarrhea) were recorded for 8 d after each vaccine dose (days 0–7). Severity was assessed using a tiered grading system, where grade 0 was ‘absent’ and grade 3 was “severe” according to pre-specified criteria. Unsolicited AEs, serious AEs (SAEs) and deaths reported within 31 d post-vaccination (days 0–30) were also considered in this analysis, which was conducted on the total vaccinated cohort, including all infants who had received at least one dose of vaccine or placebo. The relative risk (RR) with 95% confidence intervals (CI) for vaccine vs. placebo was estimated for each safety endpoint. The 95% CI for the RR was based on the exact conditional likelihood approach