Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial

(See the editorial commentary by Kollmann on pages 859–60.) An increasing body of literature supports that vaccines have immune-modulating effects that influence host defense to other diseases than the targeted pathogen, so-called nonspecific effects of vaccines or heterologous immunity [1]. The heterologous immunity may have significant impact on overall health and for certain vaccines may be even more important than the specific protection [2]. An example is the bacillus Calmette–Guerin (BCG) vaccine; many observational studies [2–6] and recently also randomized-controlled trials (RCT) [7, 8] have shown that BCG reduces all-cause mortality more than can be ascribed to protection from Mycobacterium tuberculosis infections. Combined, 2 RCTs in Guinea-Bissau in LBW infants have shown that early BCG administration can reduce overall infant mortality up to 20% (mortality rate ratio [MRR] at 12 months of age: 0.79 [95% CI, 0.61–1.02]). Furthermore, BCG almost halved the neonatal mortality (MRR: 0.52 [95% CI, 0.33–0.82]) [7]. This dramatic reduction in the neonatal mortality seems to be mainly due to fewer cases of septicemia and respiratory infections [8]. In Guinea-Bissau, we are now conducting a new BCG trial among LBW infants with neonatal mortality as the main outcome. Nested within this trial, we performed a subgroup study to investigate the immunological effects of BCG on the responsiveness to specific and nonspecific immunological challenge, as measured by the in vitro cytokine production of blood cells after stimulation with innate immunity agonists and recall antigens.