Why Has the Number of Child Deaths Halved Since 1990?

W the number of children dying before 5 years of age halved from 12.7 million in 1990 to 6.3 million in 2013. This improvement was not due solely to economic development; even in the countries with little or no economic development in the 1980s and 1990s, the under-5 mortality rate halved from 153 to 76 per 1000 live births. A major contributor to the spectacular reduction in child mortality may well have been widespread use of 3 live vaccines: measles vaccine, oral polio vaccine (OPV) and CalmetteGuérin bacillus vaccine (BCG), all of which reduce mortality from nontarget infections such as pneumonia and sepsis (in addition to their effects on measles, polio and tuberculosis). This issue of the Journal presents important information from a remarkable database in Guinea-Bissau. Since 1990, a sample of 100 randomly selected clusters of 100 women and their children has provided data about child health in rural Guinea-Bissau, one of the poorest countries on earth. Few high-income countries have longitudinal information of this nature from a representative sample over a period of 25 years. In this setting, a single measles immunization campaign reduced all-cause mortality by 20% (95% confidence interval: 4%–34%) overall and by 52% (16%–75%) among children who had already received routine measles vaccine and their last dose of diphtheria, tetanus and whole-cell pertussis vaccine (DTP) before the campaign; these reductions were not explained by fewer deaths from measles. Although the before and after design of this study is inherently weak, the findings are consistent with other evidence that measles immunization reduces mortality from diseases other than measles, and that this effect is greater in girls; the effect is seen only with the second or subsequent dose of measles vaccine or in the presence of maternal measles antibody and only when there are no subsequent doses of DTP or Penta vaccine (DTP plus hepatitis b and haemophilus influenzae type b vaccines). There is also evidence that OPV may have similar beneficial nonspecific (heterologous) effects, reducing mortality from infections other than polio, but that inactivated polio vaccine (IPV) may increase mortality from diseases other than polio in girls. DTP, another inactivated vaccine, also has adverse nonspecific effects: it increases mortality from infections other than diphtheria, tetanus and pertussis in girls. The nonspecific effects of vaccines are large: until a different vaccine is given, measles vaccine and BCG approximately halve all-cause mortality. OPV has a smaller effect, but it is likely to be cumulative—and Guinea-Bissau had 7 OPV campaigns between March 2010 and March 2012 alone. Since 1990, billions of doses of measles vaccine, BCG and OPV have been given in the routine Expanded Program on Immunization and in Supplementary Immunization Activity campaigns, and it is very likely that their widespread use contributed substantially to the halving of the number of child deaths since 1990. This supposition is supported by the finding from Guinea-Bissau that a single measles immunization campaign reduced mortality by 20%; the 95% confidence interval was 4%–34%, but even a 4% reduction in all-cause mortality represents a spectacular return on a single dose of measles vaccine costing about 27 cents. The evidence that measles vaccine reduces mortality from diseases other than measles has important implications. First, the fact that the reduction in nonmeasles mortality is greater after the second or subsequent doses supports the World Health Organization policy of a 2-dose measles vaccination strategy (even though it was designed to reduce measles rather than other infections) and suggests that even more doses may be beneficial. Second, the evidence that the nonspecific effect may be greater in the presence of maternal antibody suggests that the first dose of measles vaccine should be given as early as possible, and that we should investigate the effect of giving a small amount of measles antibody with the first dose. Third, the evidence that the beneficial effects of measles vaccine are negated if it is followed by DTP or Penta suggests that DTP or Penta should not be given once a child has received measles vaccine. Fourth, the main Expanded Program on Immunization indicator should be the proportion of children given 2 doses of measles vaccine (that reduces mortality from pneumonia and sepsis) rather than the proportion given 3 doses of Penta (that increases mortality from pneumonia and sepsis). Fifth, even if measles is eliminated from a region, children should still be given at least 2 doses of measles vaccine to obtain the beneficial nonspecific effects. Given the evidence that OPV has beneficial nonspecific effects, but that IPV may have harmful nonspecific effects for girls, the planned change from OPV to IPV could substantially increase all-cause mortality. This change in policy was influenced only by consideration of the effect on polio, and we need careful prospective studies of the effect of this change on all-cause mortality. The overriding principle is that immunization policy in high-mortality countries should be determined by the overall effect on all-cause mortality and not just the disease-specific effects of individual vaccines. The old simplistic model of immunization is outdated: we can no longer assume that vaccines influence only their target disease, and that there are no interactions between vaccines. Surely, robust evidence of the effect on all-cause mortality is needed for any therapy that is routinely administered to entire populations, especially young children; there are numerous examples of therapies that have had beneficial specific effects but harmful effects on all-cause mortality. Diphtheria, tetanus and pertussis are very serious diseases that are prevented by DTP, but even in unimmunized communities, they cause far fewer deaths than pneumonia and sepsis, so a small increase in mortality from pneumonia and sepsis following DTP would cause more deaths than the number saved by preventing diphtheria, tetanus and pertussis. A major reason that child mortality has halved since 1990 may well be the widespread use of measles vaccine, OPV and BCG; this was designed to reduce measles, polio and tuberculosis but coincidently reduced mortality from pneumonia and sepsis. It is crucially important that this possibility be fully investigated as a matter of urgency, and that immunization policy moves on from a narrow consideration of the disease-specific effects of individual vaccines and considers the overall effect on all-cause mortality.