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Objective Understanding transmission dynamics is useful for tuberculosis (TB) control. A population-based molecular epidemiological study was conducted to determine TB transmission in Ghana. Methods Mycobacterium tuberculosis complex (MTBC) isolates obtained from prospectively sampled pulmonary TB patients between July 2012 and December 2015 were characterized using spoligotyping and standard 15-locus mycobacterial interspersed repetitive unit variable number tandem repeat (MIRU-VNTR) typing for transmission studies. Results Out of 2309 MTBC isolates, 1082 (46.9%) unique cases were identified, with 1227 (53.1%) isolates belonging to one of 276 clusters. The recent TB transmission rate was estimated to be 41.2%. Whereas TB strains of lineage 4 belonging to M. tuberculosis showed a high recent transmission rate (44.9%), reduced recent transmission rates were found for lineages of Mycobacterium africanum (lineage 5, 31.8%; lineage 6, 24.7%). Conclusions The study findings indicate high recent TB transmission, suggesting the occurrence of unsuspected outbreaks in Ghana. The observed reduced transmission rate of M. africanum suggests other factor(s) (host/environmental) may be responsible for its continuous presence in West Africa. [ABSTRACT FROM AUTHOR]

• Comparative genomics studies of MTBC shows significant genomic diversity. • MTBC genomic diversity has significant implications on phenotypic profiles. • MTBC diversity is relevant in the design of new control tools. • Diversity in MTBC must be considered in choice of future clinical trial sites. The diversity in the lineages of Mycobacterium tuberculosis complex (MTBC) was initially considered insignificant. However, comparative genomics analysis of MTBC have found genomic variation among the genotypes with potential phenotypic implications. Therefore, this viewpoint seeks to discuss the impact of the identified genotypic diversity on the physiology of MTBC and the potential implications on TB control. Studies conducted in West Africa and other parts of Africa have unravelled the implications of the genomic diversity on phenotypes such as disease outcome, transmission dynamics and host immune response. The understanding of the phenotypic diversity among the different lineages of MTBC may be an important key to the fight against TB. The relevance of these differences has been observed in the design of new control tools such as diagnostics and anti-TB drugs/vaccines. This only points to the fact that the diversity in MTBC cannot be ignored in future studies especially clinical trials for new vaccines and new anti-TB drugs. [ABSTRACT FROM AUTHOR]

• Six out of the eight human adapted TB lineages circulate in Northern Ghana • The dominant sub-lineages in Northern Ghana are the Cameroon and Ghana sub-lineages • The Ghana sub-lineage of Mtbss is associated with multi drug resistance • Mycobacterium africanum lineage 6 is associated with the elderly • The Ghana sub-lineage is increasingly becoming a public health threat We conducted a cross-sectional study in the five administrative regions of Northern Ghana to determine the diversity of Mycobacterium tuberculosis complex (MTBC) sub/lineages and their susceptibility to isoniazid (INH) and rifampicin (RIF). Sputum specimens were collected and cultured from 566 pulmonary tuberculosis patients reporting to 17 health facilities from 2015 to 2019. Mycobacterial isolates obtained from solid cultures were confirmed as members of the MTBC by PCR amplification of IS 6110 and rpoß and assigned lineages and sub-lineages using spoligotyping. Of 294 mycobacterial isolates recovered, MTBC species identified were: M. tuberculosis sensu stricto (Mtbss) 241 (82.0%), M. africanum 41 (13.9%) and M. bovis four (1.4%) with eight (2.7%) unidentified. The human-adapted lineages (L) identified (N=279) were L1 (8/279, 2.9%), L2 (15/279, 5.4%), L3 (7/279, 2.5%), L4 (208/279, 74.5%), L5 (13/279, 4.7%) and L6 (28/279, 10.0%) with three unidentified lineages. Among the 208 L4, the dominant sub-lineages in the region were the Cameroon 120/208 (57.7%) and Ghana 50/208 (24.0%). We found 4.4% (13/294) and 0.7% (2/294) of the patients infected with MTBC isolates resistant to INH only and RIF only, respectively, with 2.4% (7/294) being infected with MDR strains. Whereas L6 was associated with the elderly, we identified that the Ghana sub-lineage of L4 was associated with both INH and MDR (p<0.05), making them important TB pathogens in Northern Ghana and a growing public health concern. [ABSTRACT FROM AUTHOR]

• Unresolved previous infection as major cause of recurring tuberculosis (TB) in Ghana. • Genomic epidemiology identifies high relapse among recurrent TB cases in Ghana. • 15-locus MIRU-VNTR typing is sufficient to predict the cause of TB recurrence. • Evidence of recent household-related TB transmission in Ghana. • Need for increased education by national TB control program. To retrospectively investigate the cause of recurring tuberculosis (rc TB) among participants with pulmonary TB recruited from a prospective population-based study conducted between July 2012 and December 2015. Mycobacterium tuberculosis complex isolates obtained from rc TB cases were characterized by standard mycobacterial genotyping tools, whole-genome sequencing, and phylogenetic analysis carried out to assess strain relatedness. The majority (58.3%, 21/36) of study participants with rc TB episodes had TB recurrence within 12 months post treatment. TB strains with isoniazid (INH) resistance were found in 19.4% (7/36) of participants at the primary episode, of which 29% (2/7) were also rifampicin-resistant. On TB recurrence, an INH-resistant strain was found in a larger proportion of participants, 27.8% (10/36), of which 40% (4/10) were MDR-TB strains. rc TB was attributed to relapse (same strain) in 75.0% (27/36) of participants and 25.0% (9/36) to re-infection. Our findings indicate that previous unresolved infectiondue to inadequate treatment, may be the major cause of rc TB. [ABSTRACT FROM AUTHOR]

Summary Mycobacterium africanum comprises two phylogenetic lineages within the Mycobacterium tuberculosis complex (MTBC). M. africanum was first described and isolated in 1968 from the sputum of a Senegalese patient with pulmonary tuberculosis (TB) and it has been identified increasingly as an important cause of human TB, particularly prevalent in West Africa. The restricted geographical distribution of M. africanum , in contrast to the widespread global distribution of other species of MTBC, requires explanation. Available data indicate that M. africanum may also have important differences in transmission, pathogenesis, and host–pathogen interactions, which could affect the evaluation of new TB intervention tools (diagnostics and vaccines)–those currently in use and those under development. The unequal geographical distribution and spread of MTBC species means that individual research findings from one country or region cannot be generalized across the continent. Thus, generalizing data from previous and ongoing research studies on MTBC may be inaccurate and inappropriate. A major rethink is required regarding the design and structure of future clinical trials of new interventions. The West, Central, East, and Southern African EDCTP Networks of Excellence provide opportunities to take forward these pan-Africa studies. More investments into molecular, epidemiological, clinical, diagnostic, and immunological studies across the African continent are required to enable further understanding of host– M. africanum interactions, leading to the development of more specific diagnostics, biomarkers, host-directed therapies, and vaccines for TB. [ABSTRACT FROM AUTHOR]