This hypothesis was based on two main observations: first, the routine childhood vaccinations have non-specific effects, the live BCG and MV reduce mortality more than can be explained by prevention of the target diseases  and , whereas the inactivated DTP vaccine is associated with increased
mortality in areas with herd immunity to pertussis  and ; second, the mortality benefit pattern after VAS resembles that of vaccines, with a beneficial effect in the time windows dominated by BCG (at birth) and MV (after 6 months of age) but no beneficial effect between 1 and 5 months of age, in the time window of DTP . The hypothesis implied that VAS would probably be beneficial when provided with the live BCG and MV, but harmful when provided with DTP vaccine. We have subsequently tested the hypothesis in observational studies  and , randomized trials BKM120 supplier , ,  and  and by reanalyzing old trials  and we have been able to show repeatedly that VAS and vaccines interact.
We have also learned in the process. Initially, we did not emphasize sex as an important covariate. However, in most , , ,  and , though not all studies ,  and , we have found that VAS provided close to DTP had a negative effect for females, but not for males. Furthermore, we had not envisaged that VAS could interact with vaccines given months after. We first became aware AUY 922 of this possibility when analyzing the first NVAS trial, observing an increase in mortality in female NVAS recipients, which occurred when the children
started receiving DTP several months after NVAS . The present analysis suggests that NVAS may interact with vaccines given as much as 4–5 months later. If true, this is surprising, not only because it occurred so many months after NVAS, but also because the interaction between found NVAS and early MV was negative. If anything we would have expected the opposite. The explanation may be the three intermediate DTP vaccinations. In the early MV trial, all children were visited at the ages of DTP1, DTP2, and DTP3 and their mothers were encouraged to bring them for vaccination. Hence, all participants had received three DTP vaccines with short intervals, and they were enrolled in the early MV trial 4 weeks later. The cocktail of first NVAS, then three DTP and then early MV may have been too much. In a trial of BCG revaccination we found a negative effect of receiving BCG at 19 months of age followed by DTP and then VAS in a campaign . We have discovered interactions between NVAS and the following vaccines: DTP (negative for females)  and , and early MV (negative for males). Furthermore, we have found that NVAS primes a beneficial response to a subsequent dose of VAS provided after 12 months of age, particularly in females  and .