The immunological effect of revaccination with Bacille Calmette-Guerin vaccine at 19 months of age

Background: Bacille Calmette-Guerin (BCG) vaccination has important non-specific immune effects. In a randomized trial in Guinea-Bissau, BCG revaccination was associated with significantly increased survival in children who received diphtheria-tetanus-pertussis (DTP)-booster vaccine before enrolment and in children who did not receive micronutrient supplementation (MN). Within the trial we assessed the immunological effects of BCG revaccination. Methods: Children were randomized to BCG or nothing. Blood was sampled 6-11 weeks after randomization (early sample group) or 5-9 months later (late sample group). In vitro cytokine responses (interferon (IFN)-gamma, interleukin (IL)-13, tumor-necrosis-factor (TNF)-alpha, and IL-10) were assessed in whole blood cultures stimulated with lipopolysaccharide (LPS), purified protein derivative (PPD) or phytohaemagglutinin (PHA). Effect-modification by sex, DTP-booster vaccination and MN was studied. Results: Cytokines were measured in 345 infants. BCG was associated with significantly increased IFN-gamma (geometric mean ratio (GMR) = 4.54 (95% confidence interval: 3.13-6.58)) and IL-13 (GMR = 1.43 (1.00-2.05)) PPD responses, the effect being strongest in the early sample group. Across all three conditions BCG tended to increase IL-10 (LPS, PHA, PPD: GMR = 1.20, 1.12, 1.20), most pronounced in the late sample group. BCG reduced the TNF-alpha/IL-10 ratio in boys with DTP-booster at bleeding and increased it in those without (interaction test: p = 0.03). In children without MN, BCG was associated with reduced TNF-alpha response in the early sample group (p = 0.006), and increased IL-10 in the late sample group (p = 0.03). Conclusion: BCG revaccination resulted in a strong IFN-gamma response to PPD, which waned slightly over time. BCG also affected the pro-/anti-inflammatory balance, with reduced TNF-alpha and increased IL-10 responses to LPS, PHA and PPD. This effect depended on sex, DTP-booster vaccination and micronutrient supplementation, being most pronounced in children who had received DTP-booster before enrolment and children who had not received MN, i.e. the group of children which also had lower mortality after BCG revaccination. (C) 2013 Elsevier Ltd. All rights reserved.