The Use of Molecular Methods in Subclinical Murine Models of Leprosy to Examine the Efficacy of Proposed Post-Exposure Prophylaxis (PEP) Regimens

Project coordination
IHRC, Inc,
National Hansen’s Disease Program

Aim: This study saught to determine which rifampin-containing treatment modality is the most effective leprosy PEP regimen regardless of a) the immune status of the host and b) whether the leprosy infection is caused by M. leprae or M. lepromatosis.

Final project summary:
Although multidrug therapy (MDT) has greatly reduced the global burden of leprosy, new cases continue to occur each year. This suggests that transmission of the disease is still ongoing despite the availability of effective treatment. People with early, symptom-free (subclinical) infections—often acquired through contact with someone who has leprosy—are thought to play an important role in sustaining transmission, particularly in high-burden areas.

One strategy to reduce transmission is post-exposure prophylaxis (PEP): preventive treatment given to people who have been exposed to leprosy. By reducing subclinical infections, PEP has the potential to lower the risk of disease development and limit further spread within communities.

This study evaluated different PEP regimens to determine which approaches are most effective. Researchers established low-level leprosy infections in three mouse strains with different levels of immune function (Balb/c, Interferon-γ knockout [IFNγ KO], and athymic nude mice). These models represent different points along the leprosy disease spectrum and provide a valuable platform for testing preventive treatments. The effectiveness of the drug regimens was assessed using highly sensitive and specific genetic testing methods.

The study had three main objectives:

1. To develop a robust pre-clinical model for evaluating PEP regimens.
2. To identify the most effective PEP regimen across different levels of host immune function.
3. To compare the effectiveness of PEP treatments against infections caused by Mycobacterium leprae and M. lepromatosis, the two bacterial species known to cause leprosy.

The results showed that RC-3X was the most effective of the regimens tested. This was expected, as it combines two drugs administered over three treatment rounds. However, multi-dose preventive regimens may be difficult to implement on a large scale and can place additional demands on both recipients and healthcare providers. Furthermore, some contacts may perceive repeated treatments as therapy rather than prevention, potentially increasing feelings of stigma.

Importantly, SHDR proved to be more effective than DDR, even though both regimens delivered the same total amount of rifampin. This finding suggests that optimizing the dosage within a single-treatment regimen may improve its effectiveness while maintaining the practical advantages of a simple preventive intervention.

The study also demonstrated that the athymic nude mouse model is a valuable tool for evaluating PEP regimens because of its high sensitivity, broad inoculation range, and ability to support long-term bacterial growth. Together, these findings provide important experimental evidence to guide the design and evaluation of future clinical trials aimed at improving leprosy prevention.

Impact

Lenz, S. M., Collins, J. H., Ray, N. A., Hagge, D. A., Lahiri, R., & Adams, L. B. (2020). Post-exposure prophylaxis (PEP) efficacy of rifampin, rifapentine, moxifloxacin, minocycline, and clarithromycin in a susceptible-subclinical model of leprosy. PLoS neglected tropical diseases, 14(9), e0008583.