The limited studies performed in HIV-infected

The limited studies performed in HIV-infected GSK126 children suggest a satisfactory immune response [3] and [19]. Another example is the routine use of interventions, such as oral rehydration solution (ORS) that could affect the outcome of interest – severe rotavirus gastroenteritis – and potentially mask the full effects of the vaccine on severe disease [21]. Likewise, the timing of vaccination and the method of analysis in relation to rotavirus circulation may affect efficacy estimates, although the direction of the effect may be difficult to predict. For example, in the efficacy trial

in the South Africa site, all vaccinations were completed prior to the start of the rotavirus season. Thus, children exposed to rotavirus had received vaccine relatively recently, which may favor vaccine efficacy estimates if there is any waning of immunity over time. In the same trial, at the Malawi site, vaccinations occurred throughout the year, including time periods when rotavirus circulated. These differences are reflected in the percentage of children in the placebo group with detectable rotavirus IgA antibody at 18 weeks of age at the two sites – 40.5%

in Malawi as compared to 11.6% in South Africa. Another example is the RotaTeq® trial that included a cohort in Mali, where vaccinations were given before and during rotavirus season. As the per protocol definition required cases to occur at least 2 weeks Panobinostat mouse following the last dose of vaccine, fewer cases were available for the per protocol evaluation. The intention to treat analysis is arguably the more relevant

from the public health perspective, as rotavirus vaccines are given with other childhood vaccines on a year-round schedule. The use of the PP definition has led Calpain many to conclude that the vaccine was not efficacious in Mali [22]. While both the ITT and PP point estimates are imprecise due to the small number of cases that occurred in the first year of life, the ITT point estimate of 42.7% (95% CI −124.7 to 87.7) is more in line with the point estimates of efficacy from the sites in Ghana and Kenya that were part of that multicenter trial [5]. As we do not yet have a complete understanding of the protective mechanism of rotavirus vaccines in low-resource settings, additional factors that are not yet understood or easily measured could also affect trial results. In Table 2, realizing that all factors may not be fully delineated or reported, the studies of rotavirus vaccines in low-resource settings, including the recent results from the ROTAVAC® efficacy trial conducted in India [10] and [11], are categorized by important design characteristics. For the major variables of age, use of OPV, outcome definition, and type of randomization, the ROTAVAC® efficacy trial design is similar to the design of the individually randomized RotaTeq® and Rotarix® studies.

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