Commentary: BCG has no beneficial non-specific effects on Greenland. An answer to the wrong question?

Our group has spearheaded research into the ‘non-specific effects’ of vaccines in West Africa. Many observational studies and lately randomized trials have shown that BCG lowers all-cause mortality, particularly from septicaemia and respiratory infections. These beneficial non-specific effects are seen as long as BCG is the most recent vaccine. For this reason, a WHO-commissioned review of the nonspecific effects of vaccines specifically selected results for the shortest period of follow-up, and where possible with censoring for subsequent vaccines. In a meta-analysis of the included studies, BCG versus no BCG was associated with a 47% [95% confidence interval (CI) 1⁄4 28-60%] reduction in all-cause mortality. The other live vaccine under review, measles vaccine, was likewise associated with large reductions in mortality; in contrast, most studies suggested that the non-live diphtheria-tetanus-pertussis (DTP) vaccine was associated with increased all-cause mortality. In 2014, WHO recommended further research into the potential non-specific effects of vaccines. Haahr et al. used a transient or temporary discontinuation of neonatal BCG vaccination from 1991 to 1996 in Greenland to compare BCG-vaccinated and BCGunvaccinated birth cohorts with respect to infectious disease hospitalizations (the vast majority being due to respiratory infections) up to 3 years of age. They assumed that the only potential birth cohort effect was the possible BCG effect. This may not be correct; there were changes in the timing of subsequent non-live vaccines, which were also associated with birth cohort. Nonetheless, from 3 days to 3 months when BCG was the dominating vaccine, having received neonatal BCG was associated with a 28% (95% CI 1⁄4 -6-51%) reduction in the risk of infectious disease hospitalizations, corroborating the findings from the WHO review. Haahr et al. did however not emphasize this result; instead they focused on the period from 3 months to 3 years of age. What is studied in this age group is not the effect of neonatal BCG versus no BCG, but the effect of receiving first neonatal BCG and then non-live vaccines versus receiving non-live vaccines only. In this period, BCG was associated with a 7% (-4-20%) increased risk of infectious disease hospitalisation (test for similar BCG effect between 0-3 months and 3-35 months, P 1⁄4 0.05) (Table 1). The findings from Greenland are similar to the findings from a recent cohort study in Finland using hospital admission data from before and after neonatal BCG vaccination was stopped in 2006. The incidence rate ratio for hospital-treated pneumonia for BCG-vaccinated children was 0.73 (95% CI1⁄4 0.55-0.96) from birth and up to 3 months (before non-live vaccines were provided), versus 1.04 (0.89-1.20) from 3-12 months (test for interaction 0.03). The findings are also similar to the results of a recent randomized trial in Denmark where the incidence rate ratio for GP visits for suspected infection was 0.88 (95% CI1⁄4 0.79-0.98) from birth to 3 months (again emphasizing the period before non-live vaccines were given), versus 1.03 (0.97-1.09) from 3-13 months (test for interaction 0.01). The tendency for an age-differential effect of BCG was also seen for parental-reported infection, strongest for parent-reported fever [0.78 (0.52-1.03) before versus 1.05 (0.95-1.16) after 3 months] and pneumonia [0.50 (0.17-1.46) versus 1.26 (0.99-1.60)]. Thus, in the three studies from highincome settings, which have data on the effect of neonatal BCG on infectious diseases from birth to 3 months and from 3 months onwards, there are striking similarities: the effect of BCG was beneficial in the first months, but this effect disappeared after the children received non-live vaccines. International Journal of Epidemiology, 2016, Vol. 45, No. 6 2131