4 per 1000 child-years (95% CI, 87.2, 97.9). The use of these broad criteria for active surveillance resulted in many children with non-specific illness being screened at a hospital and undergoing an ultrasound examination. The screening protocol resulted in only 1.6% of the possible cases being classified as PI3K inhibitor ultrasound-evidenced intussusception and 0.8% Brighton level 1 confirmed intussusception. Based on this study, the broad screening approach met the safety criterion of protecting children participating in the trial by ensuring that every case was detected and managed quickly. However, this required intense effort

from the study teams, and resulted in identification of a large proportion of transient cases, illustrating the difficulties in diagnosing cases that could have resulted in a need for intervention in routine practice versus incident cases of any severity. This suggests that criteria employed in the trial are inefficient for any form of routine surveillance for intussusception, and future trials may rely MG-132 in vitro on the passive surveillance employed for previous large safety studies. The incidence rate of ultrasound-diagnosed intussusception of 140/100,000 child-years

in the placebo arm is higher than most observational studies but consistent with recent data from Vietnam [18] and is likely attributable to the low threshold for ultrasound evaluation of a potential second case. In the 116E study, the earliest intussusception event in a vaccinated child was 112 days after the third dose. The lack of temporal association between vaccination and event among those vaccinated suggests a causal relationship is very unlikely for cases identified in this trial, but does not preclude a risk similar to that seen with available licensed vaccines. Rotavirus vaccines are recommended for global

use by the World Health Organization [19] and evidence from both developing and developed countries demonstrates the impact of these vaccines on disease reduction in young children [20], [21], [22] and [23]. Increased risk of intussusception has been detected in Australia, Mexico, Brazil and the USA, but the risks of intussusception outweigh the potential benefits of vaccination in disease and mortality reduction, particularly in areas where diarrheal disease continues to be a major killer of children. Nonetheless, monitoring safety will continue to be critical both pre-licensure and after introduction because vaccination safety at the level of the individual child and of programs is necessary to manage rare side effects and to prevent undue harm from newly developed vaccines.