Tuberculosis (TB) now ranks as the leading infectious disease cause of mortality in the world. About 1.7 billion people are currently infected with Mycobacterium tuberculosis (Mtb) and are at risk of developing active TB disease. The challenge to eliminate TB remains as relevant and urgent as ever. Unfortunately, efforts to control this global epidemic have been hampered by inadequate understanding of the underlying epidemiology and biologic mechanisms and lack of effective interventions to prevent TB transmission. Identifying the key drivers of transmission and developing interventions has thus far remained unattainable, particularly in many high-burden TB settings that also have a high incidence of HIV co-infection. The large reservoir of sub-clinical infections, the HIV co-epidemic, and a rise in TB drug resistance make public health efforts to battle this disease complex. In HIV-endemic settings, such as in Southern Africa, TB incidence is highly correlated with HIV prevalence. In this region, high rates of HIV infection are key drivers of the TB epidemic and create a complex clinical situation with unique difficulties in diagnosis, and in tracking infectious individuals. These limitations seriously hamper TB elimination in the region. Additionally, TB disease incidence appears to be driven more by recent transmission rather than by reactivation events, particularly among latently infected HIV-infected individuals. To understand how HIV co-infection affects TB transmission, studies in high-incidence settings with low rates of HIV co-infection are also needed to determine whether universal or targeted interventions may be required to lower TB transmission.
The TB transmission cycle is extremely complex with multiple contributing host and pathogen factors. In order to identify research gaps to inform novel interventions and strategies that may effectively halt TB transmission, especially in HIV-endemic settings, NIAID/NIH supported two workshops. One was held in 2016, titled “Towards Zero New TB infections”, followed by another in 2017 titled “Halting TB transmission in HIV endemic settings.” These workshops brought together global experts in the field and greatly informed this initiative. The following are some of the identified research gaps: (1) developing improved identification methods and better characterization of the source cases, including increased understanding of the contributing lung pathology, (2) defining the roles of Mtb strain diversity, (3) characterizing the bio-aerosols, (4) characterizing the environment where transmission occurs, and (5) developing host-based markers for recent exposure and infection (The Journal of Infectious Diseases, Volume 216, Issue suppl_6, 3 November 2017, pages S627-S668).
This initiative will provide an improved understanding of where, when, and how TB transmission occurs; the transmissibility of Mtb strains (especially drug resistant); and the complex effects of HIV and anti-retroviral therapy (ART) on transmission. Currently, a renewed focus is placed on reducing person-to-person transmission between the infected person (Transmitter (T)) and others in shared air spaces, referred to as Transmitter-Recipient Cluster Chains (TRCCs). This initiative will support multidisciplinary studies of TRCC members to characterize host/pathogen/microenvironment interactions, and the effect of HIV co-infection that affect Mtb transmission in high-burden settings. “High-burden setting” is defined as a TB incidence of 100 cases per 100,000 people per year. High-transmission settings are where transmission originates largely from specific and identifiable populations (e.g., young adult men), where reactivation is common in high-risk groups (e.g., HIV-prevalent populations, people with risk factors such as diabetes or malnutrition, elderly populations), and congregate settings (e.g., prisons or healthcare institutions). With improved knowledge of these interactions, efficacious approaches for preventing TB infections and subsequent disease could be developed or improved and adapted for a broad scale-up.
Research will be supported to characterize TB transmission events within the TRCC in high-burden settings, including elucidating the impact of HIV co-infection on transmission rates, specifically in terms of:
Aerobiology: Studies elucidating the infectious aerosol microenvironment and overall environmental aspects that promote transmission.
Environmental factors: Development of new methods and studies to measure transmission in a variety of high-risk environments, which could include structural and institutional amplifiers.
- Identification of biomarkers of recent TB exposure/infection.
- Inherent susceptibility: underlying genetic or epigenetic factors, signaling pathways, and changes in immune cells functions that play a role in effectiveness of host responses determining transmission.
Mtb strain diversity and the nature of contagion: characteristics of Mtb strains/subpopulations inclusive of drug-resistant strains that facilitate efficient transmission.
Roles of HIV infection and effects of ART in transmission (both effects on the transmitters [e.g., aerosol infectious loads] and those at risk of becoming infected).
New interventions: Development and studies of potential new interventions to decrease human-to-human transmission that are targeted to regions with high versus low HIV endemicity. Studies of nosocomial transmission and high-risk groups (e.g., healthcare workers) are encouraged. Although clinical trials are not allowed in response to this FOA, applicants may choose to use samples (biological or other data) obtained from human subjects as part of previous or ongoing clinical trials.
Deadline: November 5, 2018 (letters of intent); December 5, 2018 (full proposals)
Filed Under: Funding Opportunities