Longitudinal Changes in CD4+ T-Cell Memory Responses Induced by BCG Vaccination of Newborns

Recent estimates of the global tuberculosis burden indicate reductions in the number of persons with tuberculosis, the incidence of tuberculosis, and deaths due to tuberculosis [1]. Despite this, approximately 8.8 million new tuberculosis cases were diagnosed in 2010; 1.45 million individuals died from tuberculosis [1]. BCG vaccination in infancy is routine in tuberculosis-endemic countries. However, BCG confers reliable protection against severe forms of tuberculosis in infancy only [2]. Protection against pulmonary disease at all ages is variable and mostly poor. Epidemiological modeling suggests that a new tuberculosis vaccine or vaccination strategy that has greater protective efficacy than the current BCG strategy is critical for tuberculosis elimination [3]. Most investigators agree that future vaccination against tuberculosis would involve a heterologous prime-boost regimen, with BCG or an improved live mycobacterial vaccine as a prime, followed by an adjuvanted subunit or viral vectored boost [4, 5]. A major hurdle to designing novel vaccination strategies is our limited knowledge of key T-cell response characteristics induced by BCG. The kinetics of T cells induced by neonatal BCG vaccination have not been studied in humans; in particular, we do not know when this immune response peaks. This is a critical knowledge gap, because studies of CD8+ [6, 7] and CD4+ [8, 9] responses in viral infection models suggest that the best time for boosting is after the peak effector phase, when effector T cells have transitioned into an established memory population. Vaccine boosting during the primary effector phase, when cells are activated, may lead to T-cell exhaustion or activation-induced cell death [6, 9, 10]. Another unresolved question is whether BCG vaccination consistently induces long-lived central memory cells. Cross-sectional studies in infants have suggested that BCG may induce primarily effector T cells [11–13]. This is supported by studies of murine BCG vaccination, which induces a predominant effector T-cell response that fails to establish a long-lived central memory response [14, 15]. These data led to the hypothesis that the short-lived nature of BCG-induced effector T cells underlies the limited duration of BCG-induced protection against tuberculosis [15]. However, BCG vaccination of infants and adults induces immunological memory [16–18], and a recent retrospective analysis of long-term efficacy of BCG given between 1935–1938 suggests that BCG induces long-lived protection [19]. A comprehensive longitudinal study of memory phenotype following human newborn BCG vaccination, particularly a study that yields clarity about the induction of central memory T cells, is required. Therefore, we characterized the kinetics, function, and phenotype of BCG-specific T cells in a longitudinal study of infants routinely vaccinated with BCG at birth. Expansion and contraction of the primary BCG-specific T-cell response occurred within 3 months of vaccination, and the magnitude of specific CD4+ T cells peaked 6–10 weeks after vaccination. After peak, BCG-specific CD4+ T cells displayed a phenotype of classic central memory T cells but retained functional characteristics more consistent with effector T cells.