Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.

Background. To prepare for national introduction of a pneumococcal vaccine of restricted valency, we studied the pattern of nasopharyngeal carriage o

Mycobacterium africanum (MAF) is a common cause of human pulmonary tuberculosis in West Africa. We previously described phenotypic differences betwee

Summary: The tuberculosis (TB) vaccine Bacillus Calmette‐Guérin (BCG) was introduced 100 years ago, but as it provides insufficient protection against TB disease, especially in adults, new vaccines are being developed and evaluated. The discovery that BCG protects humans from becoming infected with Mycobacterium tuberculosis (Mtb) and not just from progressing to TB disease provides justification for considering Mtb infection as an endpoint in vaccine trials. Such trials would require fewer participants than those with disease as an endpoint. In this review, we first define Mtb infection and disease phenotypes that can be used for mechanistic studies and/or endpoints for vaccine trials. Secondly, we review the evidence for BCG‐induced protection against Mtb infection from observational and BCG re‐vaccination studies, and discuss limitations and variation of this protection. Thirdly, we review possible underlying mechanisms for BCG efficacy against Mtb infection, including alternative T cell responses, antibody‐mediated protection, and innate immune mechanisms, with a specific focus on BCG‐induced trained immunity, which involves epigenetic and metabolic reprogramming of innate immune cells. Finally, we discuss the implications for further studies of BCG efficacy against Mtb infection, including for mechanistic research, and their relevance to the design and evaluation of new TB vaccines.

To assess whether traditional measures of access to health care (distance and travel time to a facility) and non-traditional measures (social and financial support indicators) are associated with mortality among children under 5 years of age in the Gambia. We conducted a case-control study in a population under demographic surveillance. Cases (n = 140) were children under 5 years of age who died between 31 December 2003 and 30 April 2006. Each case was matched in age and sex to five controls (n = 700). Information was gathered by interviewing primary caregivers. The data were analysed using conditional logistic regression. Of traditional measures of access, only rural versus urban/periurban residence was important: children from rural areas were more likely to die (OR: 4.9; 95% confidence interval, CI: 1.2-20.2). For non-traditional measures, children were more likely to die if their primary caregivers lacked help with meal preparation (OR: 2.3; 95% CI: 1.2-4.1), had no one to relax with (OR: 1.8; 95% CI: 1.1-2.9), had no one who could offer good advice (OR: 23.1; 95% CI: 4.3-123.4), had little say over how earned money was spent (OR: 12.7; 95% CI: 1.3-127.6), were unable to cut spending for health care (OR: 2.5; 95% CI: 1.5-4.2) or had to carry out odd jobs to pay for the care (OR: 3.4; 95% CI: 2.1-5.5). A protective effect was observed when the caregiver had other children to care for (OR: 0.2; 95% CI: 0.1-0.5). Improving access to health-care for children in the Gambia and similar settings is not simply a matter of reducing travel time and distance to a health facility, but requires improvements in caregivers' support networks and their access to the financial resources they need.

It is recommended that young child contacts of sputum smear positive tuberculosis cases receive isoniazid preventive therapy (IPT) but reported adherence is low and risk factors for poor adherence in children are largely unknown.