Contribution of remote M.tuberculosis infection to tuberculosis disease: A 30-year population study.

Background: The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.

BCG re-vaccination in Malawi: 30-year follow-up of a large, randomised, double-blind, placebo-controlled trial.

Background: A large, double-blind, randomised, placebo-controlled trial of repeat BCG found 49% efficacy against leprosy but no protection against tuberculosis after 6-9 years' follow-up in 1995. We report here additional follow-up, which resulted in greatly increased tuberculosis case numbers, and allowed subgroup analysis.

Methods: Nearly 47 000 individuals of all ages living in northern Malawi with a BCG vaccine scar were randomly assigned (1:1) between 1986 and 1989 to receive a second BCG or placebo.

Evaluation of Host Serum Protein Biomarkers of Tuberculosis in sub-Saharan Africa.

Accurate and affordable point-of-care diagnostics for tuberculosis (TB) are needed. Host serum protein signatures have been derived for use in primary care settings, however validation of these in secondary care settings is lacking. We evaluated serum protein biomarkers discovered in primary care cohorts from Africa reapplied to patients from secondary care.

Risk of Mycobacterium tuberculosis transmission in an antiretroviral therapy clinic.

Objective: The risk of transmission of Mycobacterium tuberculosis in antiretroviral therapy (ART) clinics is recognized, particularly, when HIV and tuberculosis services are unified, but the degree of potential exposure to patients with infectious tuberculosis has not been measured. We aimed to quantify this clinic exposure.

Methods: Over 1 year, we recorded all visits to a clinic in northern Malawi that offers HIV testing and counselling, HIV care, ART, and TB diagnostic and treatment services.

Whole Genome Sequencing Shows a Low Proportion of Tuberculosis Disease Is Attributable to Known Close Contacts in Rural Malawi.

Background: The proportion of tuberculosis attributable to transmission from close contacts is not well known. Comparison of the genome of strains from index patients and prior contacts allows transmission to be confirmed or excluded.

Methods: In Karonga District, Malawi, all tuberculosis patients are asked about prior contact with others with tuberculosis.

Control of (multi)drug resistance and tuberculosis incidence over 23 years in the context of a well-supported tuberculosis programme in rural Malawi.

Background: The rise in tuberculosis (TB) incidence following generalized HIV epidemics can overwhelm TB control programmes in resource-limited settings, sometimes accompanied by rising rates of drug resistance. This has led to claims that DOTS-based TB control has failed in such settings. However, few studies have described the effect of a sustained and well-supported DOTS programme on TB incidence and drug resistance over a long period.

Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.

We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.

CD209 genetic polymorphism and tuberculosis disease.

Background: Tuberculosis causes significant morbidity and mortality worldwide, especially in sub-Saharan Africa. DC-SIGN, encoded by CD209, is a receptor capable of binding and internalizing Mycobacterium tuberculosis. Previous studies have reported that the CD209 promoter single nucleotide polymorphism (SNP)-336A/G exerts an effect on CD209 expression and is associated with human susceptibility to dengue, HIV-1 and tuberculosis in humans.

Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi.

Twenty-seven polymorphisms from 12 genes have been investigated for association with tuberculosis (TB) in up to 514 cases and 913 controls from Karonga district, northern Malawi. Homozygosity for the complement receptor 1 (CR1) Q1022H polymorphism was associated with susceptibility to TB in this population (odds ratio [OR] = 3.12, 95% Confidence interval [CI] = 1.

Large-scale candidate gene study of leprosy susceptibility in the Karonga district of northern Malawi.

We present a large case-control candidate gene study of leprosy susceptibility. Thirty-eight polymorphic sites from 13 genes were investigated for their role in susceptibility to leprosy by comparing 270 cases with 452 controls in Karonga district, northern Malawi. Homozygotes for a silent T-->C change in codon 352 of the vitamin D receptor gene appeared to be at high risk (odds ratio [OR] = 4.

Mycobacterial purified protein derivatives stimulate innate immunity: Malawians show enhanced tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-10 responses compared to those of adolescents in the United Kingdom.

To investigate the role of innate immunity in variable efficacy of Mycobacterium bovis BCG vaccination in Malawi and the United Kingdom, we examined 24-h tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-10 responses to mycobacterial purified protein derivatives (PPDs). The rank order in stimulatory potency for different PPDs was the same for all three cytokines. Before vaccination Malawians made higher pro- and anti-inflammatory responses than did United Kingdom subjects.

Gamma interferon responses induced by a panel of recombinant and purified mycobacterial antigens in healthy, non-mycobacterium bovis BCG-vaccinated Malawian young adults.

We have previously shown that young adults living in a rural area of northern Malawi showed greater gamma interferon (IFN-gamma) responses to purified protein derivatives (PPD) prepared from environmental mycobacteria than to PPD from Mycobacterium tuberculosis. In order to define the mycobacterial species to which individuals living in a rural African population have been exposed and sensitized, we tested T-cell recognition of recombinant and purified antigens from M. tuberculosis (38 kDa, MPT64, and ESAT-6), M.

Kinetics of delayed-type hypersensitivity to tuberculin induced by bacille Calmette-Guérin vaccination in northern Malawi.

During 1986-1989, a bacille Calmette-Guérin (BCG) vaccine trial was carried out in northern Malawi. The effects of age, sex, and prevaccination delayed-type hypersensitivity (DTH) on the time course of the DTH response over 1-36 months after vaccination were studied in 2418 persons. DTH response increased rapidly, to peak at 31-90 days after vaccination, when most persons had a measurable response.

BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies.

Background: The efficacy of BCG vaccines against pulmonary tuberculosis varies between populations, showing no protection in Malawi but 50-80% protection in the UK. To investigate the mechanism underlying these differences, randomised controlled studies were set up to measure vaccine-induced immune responsiveness to mycobacterial antigens in both populations.

Methods: 483 adolescents and young adults in Malawi and 180 adolescents in the UK were tested for interferon-gamma (IFN-gamma) response to M tuberculosis purified protein derivative (PPD) in a whole blood assay, and for delayed type hypersensitivity (DTH) skin test response to tuberculin PPD, before and 1 year after receiving BCG (Glaxo 1077) vaccination or placebo or no vaccine.