Safety and Efficacy Assessment of Two New Leprosy Skin Test Antigens: Randomized Double Blind Clinical Study

Abstract

BackgroundNew tools are required for the diagnosis of pre-symptomatic leprosy towards further reduction of disease burden and its associated reactions. To address this need, two new skin test antigens were developed to assess safety and efficacy in human trials.MethodsA Phase I safety trial was first conducted in a non-endemic region for leprosy (U.S.A.). Healthy non-exposed subjects (n = 10) received three titrated doses (2.5 µg, 1.0 µg and 0.1 µg) of MLSA-LAM (n = 5) or MLCwA (n = 5) and control antigens [Rees MLSA (1.0 µg) and saline]. A randomized double blind Phase II safety and efficacy trial followed in an endemic region for leprosy (Nepal), but involved only the 1.0 µg (high dose) and 0.1 µg (low dose) of each antigen; Tuberculin PPD served as a control antigen. This Phase II safety and efficacy trial consisted of three Stages: Stage A and B studies were an expansion of Phase I involving 10 and 90 subjects respectively, and Stage C was then conducted in two parts (high dose and low dose), each enrolling 80 participants: 20 borderline lepromatous/lepromatous (BL/LL) leprosy patients, 20 borderline tuberculoid/tuberculoid (BT/TT) leprosy patients, 20 household contacts of leprosy patients (HC), and 20 tuberculosis (TB) patients. The primary outcome measure for the skin test was delayed type hypersensitivity induration.FindingsIn the small Phase I safety trial, reactions were primarily against the 2.5 µg dose of both antigens and Rees control antigen, which were then excluded from subsequent studies. In the Phase II, Stage A/B ramped-up safety study, 26% of subjects (13 of 50) showed induration against the high dose of each antigen, and 4% (2 of 50) reacted to the low dose of MLSA-LAM. Phase II, Stage C safety and initial efficacy trial showed that both antigens at the low dose exhibited low sensitivity at 20% and 25% in BT/TT leprosy patients, but high specificity at 100% and 95% compared to TB patients. The high dose of both antigens showed lower specificity (70% and 60%) and sensitivity (10% and 15%). BL/LL leprosy patients were anergic to the leprosy antigens.InterpretationMLSA-LAM and MLCwA at both high (1.0 µg) and low (0.1 µg) doses were found to be safe for use in humans without known exposure to leprosy and in target populations. At a sensitivity rate of 20–25% these antigens are not suitable as a skin test for the detection of the early stages of leprosy infection; however, the degree of specificity is impressive given the presence of cross-reactive antigens in these complex native M. leprae preparations.Trial RegistrationClinicalTrails.gov NCT01920750 (Phase I), NCT00128193 (Phase II)

Diagnosis of mycobacterial skin infections

“…An erythematous papule 3–4 weeks after intracutaneous inoculation of inactivated M. leprae is considered a positive reaction (Mitsuda reaction) . Currently, new leprosy skin test antigens are being developed but are not yet available to screen for delayed T‐cell hypersensitivity .…”

Diagnose mykobakterieller Hautinfektionen

“…Eine erythematöse Papel 3–4 Wochen nach intrakutaner Inokulation von inaktiviertem M. leprae gilt als positive Reaktion (Mitsuda‐Reaktion) . Derzeit werden zwar neue Antigene für den Lepra‐Hauttest entwickelt, sie stehen jedoch noch nicht zum Screening auf eine verzögerte T‐Zell‐Hypersensitivität zur Verfügung .…”

“…[5]. Derzeit werden zwar neue Antigene für den Lepra-Hauttest entwickelt, sie stehen jedoch noch nicht zum Screening auf eine verzögerte T-Zell-Hypersensitivität zur Verfügung [26].…”

Bug or no bug: challenges in diagnosing cutaneous mycobacterial infections

“…Efforts to overcome this problem include the development of improved PCR based‐gene amplification test , as well as tests to employ T‐cell‐mediated immunity. To test for T cell reactivity against M. leprae in infected individuals current research attempts focus on the improvement of intradermal skin tests measuring delayed type hypersensitivity , as well as on the development of IGRAs . Nevertheless, despite significant progress in the last years these tests are not as yet available in clinical practice.…”