The introduction of BCG vaccination to neonates in Northern Sweden, 1927-31: Re-analysis of historical data to understand the lower mortality among BCG-vaccinated children.

BACKGROUND: Following the introduction of oral Bacille Calmette-Guérin (BCG) a century ago, Albert Calmette suggested that BCG both provided protection against death from tuberculosis (TB) and other causes. The findings were not pursued. Today, there is considerable evidence that intradermal BCG have beneficial non-specific effects (NSEs). We re-analyzed data from BCG's introduction 1927-1931 in Sweden hypothesizing that BCG reduced infectious deaths. METHODS: In three papers published by Dr Carl Näslund, the progress of oral neonatal BCG rollout provided free-of-charge and the effects on child mortality in the highly TB-prevalent region Norrbotten was sequentially updated. We analyzed cause-specific post-neonatal mortality by vaccination status excluding deaths from congenital conditions. Due to apparent differences in effects during study years, effects were assessed overall and separately in two periods (1927-1929, 1930-1931). RESULTS: According to Näslund, TB households were slightly more likely to accept vaccination; fewer newborns that were sick or had congenital problems were vaccinated. BCG coverage was 28.3% (5659/20,012); 8.7% (1746/20,012) died. The BCG/unvaccinated Risk Ratio (RR) of post-neonatal childhood death was 0.53 (0.45-0.62). BCG was associated with 80% (49-92%) reduced mortality from TB. From 1927 to 29, BCG appeared to protect strongly against deaths from all diseases, including the non-infectious, RR = 0.09 (0.02-0.36), presumably reflecting selection bias. From 1930 to 1931, there was no protection against non-infectious deaths, RR = 0.92 (0.49-1.70) indicating less bias (p = 0.004 for same effect). During 1930-1931, BCG was associated with reductions in non-TB infectious deaths (RR = 0.75 (0.58-0.97)); 2/3 were caused by respiratory infections, against which the BCG/unvaccinated RR was 0.61 (0.43-0.84). Other causes of death were less frequent and provided no clear pattern, except that BCG was associated with more meningitis deaths, RR = 6.85 (2.20-21.4). CONCLUSION: Healthy vaccinee bias, particularly in 1927-1929, resulted in strongly beneficial overall BCG effects. However, the 1930-1931 data provided some support that BCG both protected against TB deaths and deaths from respiratory infections.

BCG skin reactions by 2 months of age are associated with better survival in infancy: a prospective observational study from Guinea-Bissau.

INTRODUCTION: Receiving Bacille Calmette-Guérin (BCG)-Denmark vaccine at birth has been associated with ~40% reductions in all-cause neonatal mortality. We evaluated determinants of BCG skin reaction characteristics by age 2 months and tested the association with subsequent mortality. METHODS: Prospective observational study amalgamating five trials providing BCG-at-birth that were conducted between 2002 and 2018 in Guinea-Bissau. The reaction status and size were evaluated at home-visits by 2 months of age among 6012 neonates; mortality from 2 to 12 months was assessed at subsequent visits. Reaction determinants were evaluated by binomial regression providing risk ratios (RRs). In Cox-models providing adjusted mortality rate ratios (aMRRs), we assessed the association between (1) having a 2-month reaction (yes/no) and (2) reaction size tertiles and subsequent all-cause mortality risk. A subgroup had their BCG reaction evaluated and were bled at age 4 weeks; their samples underwent in vitro analysis for specific and non-specific cytokine responses. RESULTS: The BCG strain was the main determinant for developing a 2-month reaction and the reaction size: the BCG-Russia/BCG-Denmark RR for large-reaction was 0.38 (0.30-0.47) and the BCG-Russia/BCG-Japan RR was 0.61 (0.51-0.72). 5804 infants (96.5%) were reactors by age 2 months; 208 (3.5%) were non-reactors. The 2-12 months mortality risk was 4.8% (10/208) for non-reactors, 2.9% (64/2213) for small reactors, 1.8% (30/1710) for medium reactors and 0.8% (15/1881) for large reactors. The reactor/non-reactor aMRR was 0.49 (0.26-0.95) and there was a linear trend of decreasing mortality with increasing reaction size (p for trend <0.001). BCG reactors had higher 4-week specific and non-specific cytokine responses, responses that were highest among those with large reactions. CONCLUSION: Among BCG-vaccinated infants, having a BCG skin reaction by age 2 months was associated with markedly better survival, as was the reaction size. Our findings thus support that BCG has substantial effects on all-cause mortality. Emphasising at-birth vaccination with immunogenic BCG strains and revaccinating non-reactors and small reactors could have major public health benefits. TRIAL REGISTRATION NUMBERS: NCT00146302, NCT00168610, NCT00625482, NCT01989026 and NCT02447536.