Immunization of newborn and adult mice with low numbers of BCG leads to Th1 responses, Th1 imprints and enhanced protection upon BCG challenge

Neonatal bacille Calmette-Guerin (BCG) vaccination is widely employed to protect against tuberculosis. Predominant Th1 but not mixed Th1/Th2 responses are thought to be protective. If so, effective vaccination must cause Th1 imprints. The immune system of infants differs from that of adults and such differences could critically affect neonatal vaccination. We demonstrate that BCG infection of infant and adult mice produces similar responses. Infection with low and high numbers of BCG, respectively, leads to sustained Th1 and mixed Th1/Th2 responses. Low-dose but not high-dose infection also results in Th1 imprints, guaranteeing a Th1 response upon high-dose challenge, and resulting in optimal bacterial clearance. Our observations on low-dose Th1 imprinting are intriguing in the context of the well-known MADRAS trial. In this trial, the highest dose of BCG, which had insignificant side effects, was administered to over 250,000 human subjects. This high-dose vaccination resulted in insignificant protection against tuberculosis.