Background: One barrier to intervening in the global tuberculosis (TB) pandemic is that it is unknown whether M. tuberculosis transmission largely occurs through repeated close exposures among few contacts or many shorter-term contacts. Identifying sources of transmission is particularly urgent in congregate settings with high incidence of infection. Methods: To identify drivers of M. tuberculosis transmission within a congregate setting with extremely high incidence of TB, we conducted genomic surveillance in a prison system in Central West Brazil. We whole genome sequenced M. tuberculosis isolates and collected detailed incarceration histories, including movements between and within prisons. We integrated incarceration histories with M. tuberculosis genomes to investigate the relationship between exposures of differing proximity (cell, cell block, prison) and transmission risk, using genomic clustering as a proxy for transmission. Findings: We collected detailed incarceration histories for 595 individuals from whom we sequenced 561 high quality M. tuberculosis genomes. A month-long increase in exposure to an individual with TB within a prison cell increased the odds of pairwise genomic clustering by 7.4% (95% CI: 4.4-10.4%) and a six-month increase in exposure, by 54% (95% CI: 29.9%-82.5%). Most (89%; 528 of 595) individuals with TB had at least one potential week-long exposure in a prison cell to another individual with TB, and frequently many, with a median of 12 (IQR: 5-21) potential unique exposures to individuals in prison cells. Frequent movements by the prison system create a highly connected contact network: individuals with TB were transferred a median of 5 (IQR: 1-17) times in the 12 months before diagnosis. Interpretation: While close exposures within a prison were related to pairwise genomic clustering, most individuals with TB had multiple exposures to other individuals with TB due to frequent movements by the prison system. Our results support the urgent expansion of prison-wide mass screenings, TB preventive therapy, and structural interventions to reduce transmission risk in prisons and other congregate settings. Funding: National Institutes of Health (NIAID: 5K01AI173385, R01AI100358, and R01AI149620)

The authors have declared no competing interest.

National Institutes of Health (NIAID: 5K01AI173385, R01AI100358, and R01AI149620)

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All participants provided written consent, and this study was conducted with the approval of the Research Ethics Committee from the Federal University of Grande Dourados, Federal University of Mato Grosso do Sul and National Research Ethics Committee (CONEP) (CAAE 37237814.4.0000.5160, 2676613.3.1001.5160, and 26620619.6.0000.0021) and Stanford University Institutional Review Board (IRB-40285) and the University of Utah (IRB_00177937).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Sequence data for samples meeting quality filters are available on the Sequence Read Archive (SRA), in BioProject PRJNA671770.

https://www.ncbi.nlm.nih.gov/sra