In a cohort of Danish children, receipt of live MMR vs inactivated DTaP-IPV-Hib as the most recent vaccine was associated with a lower rate of hospital admissions for any infections. These findings require replication in other high-income populations.

In the current vaccine paradigm, it is usually assumed that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of mortality, and that vaccine effects are similar for boys and girls. However, epidemiological vaccine research has generated observations, which contradict these assumptions and suggest that vaccines have important non-specific effects (NSEs).We list eleven contradictory observations, including the observations that several live vaccines reduce mortality far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased female mortality.We suggest six principles, which may explain these observations: 1) live vaccines enhance resistance towards unrelated infections; 2) non-live vaccines enhance susceptibility towards unrelated infections for females; 3) the most recent vaccination has the strongest NSEs; 4) combinations of live and non-live vaccines given together have variable NSEs; 5) vaccinating with live vaccines in the presence of existing immunity enhances beneficial NSEs; and 6) vaccines may interact with other interventions affecting the immune system.These principles may characterise a new paradigm: they may help resolve the contradictory observations, they raise new questions which could not have been seen from the existing paradigm, and they correctly predict new observations, which cannot be explained within the current paradigm. Pursuing these principles could lead to an optimised understanding and use of vaccines.

Background: When vaccinations with vaccinia against smallpox and Bacillus Calmette-Guérin (BCG) against tuberculosis were phased out in some high-income countries around 1980, the impact on overall mortality was not examined. Recent studies from low-income countries have suggested that these vaccines are associated with mortality reductions, not explained by specific disease protection. We examined whether vaccinia and BCG administered in childhood were associated with long-term mortality reductions in a high-income population. Methods: In this case-cohort study, we followed 47 622 schoolchildren from Copenhagen, Denmark, born 1965 to 1976, from their first health examination to 2010. This cohort experienced the phase-out of vaccinia and BCG vaccination programmes. Results: A sub-cohort of 5 316 individuals (699 excluded) was followed for 164 450 person-years (0.2% were lost to follow-up), and 401 deaths due to natural causes (841 deaths in total) occurred in the full cohort. Compared with individuals who had not received vaccinia or BCG, those who had received both vaccinia and BCG had an adjusted hazard ratio (aHR) of 0.54 [95% confidence interval (CI): 0.36–0.81] for mortality due to natural causes of death; those who only received BCG had an aHR of 0.58 (95% CI: 0.39–0.85). Vaccinia and BCG were not associated with any protection against deaths by accidents, suicide or murder, the combined aHR being 0.94 (95% CI: 0.62–1.42). Conclusions: Vaccinia and BCG vaccinations were associated with better long-term survival, which was not explained by specific protection. Vaccines with beneficial non-specific effects may reduce overall mortality even after the target diseases are eradicated.

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BackgroundThe BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting.MethodsPregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses.Results4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15 months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics.ConclusionsBCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population.Trial registration numberNCT01694108, results.

In a nationwide Danish register-based cohort study, the live oral polio vaccine was associated with fewer admissions for lower respiratory infections compared with the inactivated DTaP-IPV-Hib vaccine. There was no difference between oral polio vaccine and measles-mumps-rubella vaccine.

BCG vaccination did not affect the rate of hospitalization for infection up to the age of 15 months in Danish children. In future studies, the role of maternal BCG-vaccination, premature birth, and cesarean delivery needs further exploration.

Smallpox vaccination is associated with a reduced risk of infectious disease hospitalization in a high-income setting.