response. interactions between health interventions the non-specific effects of vaccines can be boosted or diminished when other immunomodulating health interventions such as other vaccines, or vitamins, are provided. influence of pre-existing specific immunity the beneficial non-specific effects of live vaccines are stronger with earlier vaccination, possibly due to maternal antibodies. boosting with live vaccines also seems to enhance the beneficial effects. high-income countries the non-specific effects were primarily observed in low-income countries with high infectious disease burdens, but they may not be limited to these areas. recent danish register-based studies have shown that the live attenuated measles-mumps-rubella vaccine (mmr) protects against hospital admissions with infectious diseases and specifically getting ill by respiratory syncytial virus. immunological mechanisms the findings from the epidemiological studies on the non-specific effects of vaccines pose a challenge to the current understanding of vaccines, and how they affect the immune system, and also question whether boys and girls have identical immune systems and should receive the same treatment. the mechanisms for these effects are unclear. it is not known how vaccination induces rapid beneficial or harmful changes in the general susceptibility to infectious diseases, but the following mechanisms are likely to be involved. heterologous t-cell immunity it is well known from animal studies that infections, apart from inducing pathogen-specific t-cells, also induce cross-reactive t-cells through epitope sharing, so-called heterologous immunity. heterologous t-cell immunity can lead to improved clearance of a subsequent cross-reactive challenge, but it may also lead to increased morbidity. this mechanism may explain why dtp could have negative effects. it would, however, not explain effects occurring shortly after vaccination, as for instance the rapidly occurring beneficial effects of bcg vaccine, as the heterologous effect would only be expected to be present after some weeks, as the adaptive immune response need time to develop. also, it is difficult to explain why the effect would vanish once a child receives a new vaccine. trained innate immunity the concept that not only plants and insects, but also humans have innate immune memory may provide new clues to why vaccines have non-specific effects. studies into bcg have recently revealed that bcg induces epigenetic changes in the monocytes in adults, leading to increased pro-inflammatory cytokine production upon challenges with unrelated mitogens and pathogens (trained innate immunity). in scid mice that have no adaptive immune system, bcg reduced mortality from an otherwise lethal candida infection. the effects of bcg presented when tested after 2 weeks, but would be expected to occur rapidly after vaccination, and hence might be able to explain the very rapid protection against neonatal septicaemia seen after bcg vaccine. trained innate immunity may also explain the generally increased resistance against broad disease categories, such as fevers and lower respiratory tract infections; such effects would be difficult to explain merely by shared epitopes, unless such epitopes were almost universally common on pathogens. lastly, it is plausible that the effects are reversible by a different vaccine. hence, trained innate immunity may provide a biological mechanism for the observed non-specific effects of vaccines. controversy in 2000 aaby and colleagues presented data from guinea-bissau which suggested that dtp vaccination could, under some circumstances (e.g. absence of pertussis) be associated with increases in overall mortality, at least until children received measles vaccine. in response, who sponsored the analysis of a variety of data sets in other populations to test the hypothesis. none of these studies replicated the observation of increased mortality associated with dtp vaccination. who subsequently concluded, that the evidence was sufficient to reject the hypothesis for an increased nonspecific mortality following dtp vaccination. however, aaby and colleagues subsequently pointed out that the studies which failed to show any mortality increase associated with dtp vaccination used methods of analysis that can introduce a bias against finding such an effect. in these studies, data on childhood vaccinations were typically collected in periodic surveys, and the information on vaccinations, which occurred between successive home visits, was updated at the time of the second visit. the person-time at risk in unvaccinated and vaccinated states was then divided up according to the date of vaccination during the time interval between visits. this method opens up a potential bias, insofar as the updating of person time at risk from unvaccinated to vaccinated is only possible for children who survive to the second follow-up. those who die between visits typically do not have vaccinations between the first visit and death recorded, and thus they will tend to be allocated as deaths in unvaccinated children – thus incorrectly inflating the mortality rate among unvaccinated children. this bias has been described before, but in different contexts, as the distinction between "landmark" and "retrospective updating" analysis of cohort data. the retrospective updating method can lead to a considerable bias in vaccine studies, biasing observed mortality rate ratios towards zero (a large effect), whereas the landmark method leads to a non-specific misclassification and biases the mortality rate ratio towards unity(no effect). an additional problem with the literature on the nonspecific effects of vaccines has been the variety and unexpected nature of the hypotheses which have appeared (in particular relating to sex-specific effects), which has meant that it has not always been clear whether some apparent "effects" were the result of post hoc analyses or whether they were reflections of a priori hypotheses. this was discussed at length at a review of the work of aaby and his colleagues in copenhagen in 2005. the review was convened by the danish national research foundation and the novo nordisk foundation who have sponsored much of the work of aaby and his colleagues. an outcome of the review was the explicit formulation of a series of testable hypotheses, agreed by the aaby group. it was hoped that independent investigators would design and conduct studies powered to confirm or refute these hypotheses. also, the two foundations sponsored a workshop on the analysis of vaccine effects, which was held in london in 2008. the workshop resulted in three papers. the proceedings were forwarded to who which subsequently concluded 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. the gacvs will keep a watch on the evidence of nonspecific effects of vaccination.". in 2013, who established a working group tasked with reviewing the evidence for the non-specific effects of bcg, measles and dtp vaccines. two independent reviews were conducted, an immunological review and an epidemiological review. the results were presented at the april 2014 meeting of who's strategic group of experts on immunization (sage). who/sage "concluded that the findings from the immunological systematic review neither exclude nor confirm the possibility of beneficial or deleterious non-specific immunological effects of the vaccines under study on all-cause mortality. the published literature does not provide confidence in the quality, quantity, or kinetics of impact of any non-specific immunological effects in young children after vaccination. sage considered that the non-specific effects on all-cause mortality warrant further research. sage considered that additional observational studies with substantial risk of bias would be unlikely to contribute to policy decision making and therefore should not be encouraged." the arc of the swallow in 2008, danish crime novel author sissel-jo gazan (author of the danish crime novel dinosaur feather) became interested in the work of the bandim health project and based her science crime novel the arc of the swallow (svalens graf) on the research into non-specific effects of vaccines. the novel was published in danish in 2013; it was on the best-seller list for months and won the readers' prize 2014 in denmark. it was published in english in the uk on november 6, 2014 and in the us on april 7, 2015.