Tuberculosis (TB) is the leading infectious disease killer globally and is largely driven by transmission in high incidence settings. Studies to date, however, have not been able to identify where the majority of transmission is occurring. TB transmission has traditionally been attributed to prolonged, close contact, but numerous studies have shown that only 9–30% of genotypically linked cases can be attributed to close contact. A compelling alternative hypothesis is that the remaining 70% of transmission occurs due to casual contact in the community, but this has never been verified. A better understanding of where transmission occurs will enable the design of more effective interventions to curb TB incidence. In the Transmission of HIV-Associated XDR TB (TRAX) study in KwaZulu-Natal province, South Africa, we demonstrated that extensively drug-resistant (XDR) TB is primarily driven by transmission, rather than acquired resistance, overturning the prevailing belief. However, similar to drug-susceptible TB, less than one-third of drug-resistant TB cases could be linked through close contact. Drug-resistant TB provides a unique opportunity to study transmission due to casual contact, as the limited caseload allows for comprehensive genotyping to identify transmission links between individuals who may name each other in a contact investigation. In the proposed study, we will test a novel hypothesis that casual contact and migration are fueling TB transmission in high incidence settings. Rising rates of urbanization and migration throughout Asia and Africa have created favorable conditions for TB transmission. Yet, to date, no studies have comprehensively studied how migration may facilitate the spread of TB from urban to rural settings. In Aim 1, we will determine the proportion of XDR TB that develops through casual contact and identify locations where transmission occurs using genomic, social network, and geospatial analyses. In Aim 2, we will characterize migration patterns among persons diagnosed with XDR TB in Durban to determine how migration creates opportunities for XDR TB dissemination. In Aim 3, we will quantify the proportion of XDR TB cases from throughout KwaZulu-Natal province that are genomically linked to cases in Durban using whole genome sequencing. The aims proposed in the CONTEXT (Casual Contact and Migration in the Transmission of XDR TB) study build upon our established research infrastructure and successful track record of combining state-of-the- art methodologies to gain insight into TB transmission. New knowledge from this study will be essential for informing evidence-based interventions to halt TB transmission and reduce drug-susceptible and drug-resistant TB incidence. This will include near real-time data on genomically linked TB cases, as well as the identification of locations that will be highest yield for targeting interventions to decrease airborne transmission. Together, the knowledge and integrated methodology created from this study will catalyze the significant declines in global TB incidence needed to achieve the global EndTB 2035 goals.

An epidemic of extensively drug-resistant tuberculosis (XDR TB) has converged with the long-standing HIV epidemic in South Africa. We have previously demonstrated that transmission is driving the spread of XDR TB, yet the majority of this transmission could not be traced to either close contacts or healthcare-associated transmission. The CONTEXT (Casual Contact and Migration in XDR TB) study will integrate geospatial, genomic, and social network data to comprehensively characterize the contributions of casual contact and migration to XDR TB transmission and generate concrete, actionable data to inform targeted public health interventions to curb the XDR TB epidemic.