Measles vaccination and reduced child mortality: Prevention of immune amnesia or beneficial non-specific effects of measles vaccine?

Measles vaccine (MV) has been observed to reduce all-cause mortality more than explained by prevention of measles infection. Recently, prevention of "measles-induced immune amnesia" (MIA) has been proposed as an explanation for this larger-than-anticipated beneficial effect of measles vaccine (MV). According to the "MIA hypothesis", immune amnesia leads to excess non-measles morbidity and mortality, that may last up to five years after measles infection, but may be prevented by MV. However, the benefits of MV-vaccinated children could also be due to beneficial non-specific effects (NSEs) of MV, reducing the risk of non-measles infections (The "NSE hypothesis"). The epidemiological studies do provide some support for MIA, as exposure to measles infection before 6 months of age causes long-term MIA, and over 6 months of age for 2-3 months. However, in children over 6 months of age, the MIA hypothesis is contradicted by several epidemiological patterns: First, in community studies that adjusted for MV status, children surviving acute measles infection had lower mortality than uninfected controls (44%(95%CI: 0-69%)). Second, in six randomised trials and six observational studies comparing MV-vaccinated and MV-unvaccinated children, the benefit of MV changed minimally from 54%(43-63%) to 49%(37-59%) when measles cases were censored in the survival analysis, making it unlikely that prevention of measles and its long-term consequences explained much of the reduced mortality. Third, several studies conducted in measles-free contexts still showed significantly lower mortality after MV (55%(40-67%)). Fourth, administration of MV in the presence of maternal measles antibody (MatAb) is associated with much stronger beneficial effect for child survival than administration of MV in the absence of MatAb (55%(35-68%) lower mortality). The MIA hypothesis alone cannot explain the strongly beneficial effects of MV on child survival. Conversely, the hypothesis that MV has beneficial non-specific immune training effects is compatible with all available data. Consideration should be given to continuing MV even when measles has been eradicated.