Non-specific and sex-differential effects of routine vaccines: what evidence is needed to take these effects into consideration in low-income countries?

None of the original vaccines used in the child immunization programmes in low-income countries, including BCG, diphtheria-tetanus-pertussis (DTP), oral polio vaccine (OPV), and measles vaccine (MV), were tested for their overall effect on child mortality before being introduced. It was assumed that the effect on overall child mortality would be equivalent to the proportion of deaths caused by the targeted disease(s) (1). However, this is no longer a tenable assumption. Many studies have shown that these routine vaccines may have more general effects on the immune system than merely protecting against the targeted disease, i.e. so-called non-specific effects (NSE) (2). The NSE may well be more important for overall child survival than the lives saved by specific disease prevention (2-4). The WHO´s Global Advisory Committee on Vaccine Safety (GACVS) has recently stated that it will keep a watch on the non-specific effects (NSE) of vaccination. GACVS indicated that "conclusive evidence for or against non-specific effects of vaccines on mortality, including a potential deleterious effect of DTP vaccination on children's survival as has been reported in some studies, was unlikely to be obtained from observational studies" (5). By insisting on new RCTs to provide conclusive evidence, GACVS is making it very difficult if not impossible to test the NSEs of the currently recommended vaccines. It would usually be considered unethical to test currently recommended vaccines as part of a trial withholding these vaccines from some children (6).