Vaccination with the ML0276 Antigen Reduces Local Inflammation but Not Bacterial Burden during Experimental M ycobacterium leprae Infection

Abstract

Leprosy elimination has been a goal of the WHO for the past 15 years. Widespread BCG vaccination and multidrug therapy have dramatically reduced worldwide leprosy prevalence, but new case detection rates have remained relatively constant. These data suggest that additional control strategies, such as a subunit vaccine, are required to block transmission and to improve leprosy control. We recently identified several Mycobacterium leprae antigens that stimulate gamma interferon (IFN-␥) secretion upon incubation with blood from paucibacillary leprosy patients, a group who limit M. leprae growth and dissemination. In this study, we demonstrate that M. leprae-specific mouse T-cell lines recognize several of these antigens, with the ML0276 protein stimulating the most IFN-␥ secretion. We then examined if the ML0276 protein could be used in a subunit vaccine to provide protection against experimental M. leprae infection. Our data demonstrate that combining ML0276 with either a Toll-like receptor 4 (TLR4) (EM005), TLR7 (imiquimod), or TLR9 (CpG DNA) agonist during immunization induces Th1 responses that limit local inflammation upon experimental M. leprae infection. Our data indicate that only the ML0276/EM005 regimen is able to elicit a response that is transferable to recipient mice. Despite the potent Th1 response induced by this regimen, it could not provide protection in terms of limiting bacterial growth. We conclude that EM005 is the most potent adjuvant for stimulating a Th1 response and indicate that while a subunit vaccine containing the ML0276 protein may be useful for the prevention of immune pathology during leprosy, it will not control bacterial burden and is therefore unlikely to interrupt disease transmission.Leprosy, which is caused by infection with Mycobacterium leprae, can manifest across a wide spectrum of disease symptoms. Through the use of clinical, histopathological, and immunological diagnoses, five forms of leprosy have been characterized: lepromatous (LL), borderline lepromatous (BL), mid-borderline, borderline tuberculoid (BT), and tuberculoid (TT) leprosy (53, 56). Multibacillary (MB) patients, encompassing the BB, BL, and LL forms, are characterized as having multiple skin lesions largely devoid of functional lymphocytes. At the extreme MB pole, LL patients demonstrate high titers of anti-M. leprae antibodies but an absence of specific cellmediated immunity (53). In the absence of a strong cellular immune response, LL patients do not control bacterial replication and have high bacterial indices (BI). It is still unclear why these patients do not mount effective cell-mediated immunity, but factors such as ineffective initial antigen presentation or priming of Treg cells may contribute. In marked contrast, paucibacillary (PB) leprosy patients, encompassing the BT and TT forms, are characterized as having one or few skin lesions and granulomatous dermatopathology with a low or absent BI. At the extreme PB pole, TT patients demonstrate specific cell-mediated immunity against M. leprae and have...

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MyD88 and TRIF synergistic interaction is required for TH1‐cell polarization with a synthetic TLR4 agonist adjuvant

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Evaluation of the Safety and Immunogenicity in Rhesus Monkeys of a Recombinant Malaria Vaccine for Plasmodium vivax with a Synthetic Toll-Like Receptor 4 Agonist Formulated in an Emulsion

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