rBCG30-Induced Immunity and Cross-Protection against Mycobacterium leprae Challenge Are Enhanced by Boosting with the Mycobacterium tuberculosis 30-Kilodalton Antigen 85B

Abstract

bLeprosy remains a major global health problem and typically occurs in regions in which tuberculosis is endemic. Vaccines are needed that protect against both infections and do so better than the suboptimal Mycobacterium bovis BCG vaccine. Here, we evaluated rBCG30, a vaccine previously demonstrated to induce protection superior to that of BCG against Mycobacterium tuberculosis and Mycobacterium bovis challenge in animal models, for efficacy against Mycobacterium leprae challenge in a murine model of leprosy. rBCG30 overexpresses the M. tuberculosis 30-kDa major secretory protein antigen 85B, which is 85% homologous with the M. leprae homolog (r30ML). Mice were sham immunized or immunized intradermally with BCG or rBCG30 and challenged 2.5 months later by injection of viable M. leprae into each hind footpad. After 7 months, vaccine efficacy was assessed by enumerating the M. leprae bacteria per footpad. Both BCG and rBCG30 induced significant protection against M. leprae challenge. In the one experiment in which a comparison between BCG and rBCG30 was feasible, rBCG30 induced significantly greater protection than did BCG. Immunization of mice with purified M. tuberculosis or M. leprae antigen 85B also induced protection against M. leprae challenge but less so than BCG or rBCG30. Notably, boosting rBCG30 with M. tuberculosis antigen 85B significantly enhanced r30ML-specific immune responses, substantially more so than boosting BCG, and significantly augmented protection against M. leprae challenge. Thus, rBCG30, a vaccine that induces improved protection against M. tuberculosis, induces cross-protection against M. leprae that is comparable or potentially superior to that induced by BCG, and boosting rBCG30 with antigen 85B further enhances immune responses and protective efficacy. L eprosy, caused by the bacterium Mycobacterium leprae, remains a major global health problem. Although the reported incidence has decreased over the past few decades, the annual decline has leveled off. The World Health Organization reported 232,875 new cases in 2012 with 71% of the cases occurring in the southeast Asian region of the world (1). In many parts of the world, including Southeast Asia, the number of new cases reported increased over the previous year.Leprosy presents across a clinical and immunopathological disease spectrum ranging from multibacillary lepromatous leprosy, characterized by many skin lesions with numerous bacilli and an absence of cell-mediated immunity to M. leprae, to paucibacillary tuberculoid leprosy, characterized by few lesions and a paucity of bacilli but the presence of specific cell-mediated immunity. Infection of peripheral nerves and nerve damage are a frequent and often debilitating manifestation of leprosy. Leprosy is treated with a prolonged course of antibiotics used in combination. As in the case of tuberculosis (TB), drug resistance has emerged, although worldwide levels of resistance to the major drugs dapsone and rifampin have stabilized in recent years. Nevertheless, because of the extrem...

New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles

“…The last group ( n  = 8) (subgroup III) of IVE-TB genes consisted of Mtb genes with high homology to M. leprae (genes taxid: 1769) (Rv0468, Rv0470c, Rv0501, Rv0640, Rv1390, Rv1846, Rv1872 and Rv2215). The rationale behind the last selection was to include candidates with potential cross-protection against M. leprae infection3536. In addition, since these genes are conserved in M. leprae , which has strongly downsized its genome size compared to other pathogenic mycobacteria, these M. leprae genes could play important roles in intracellular mycobacterial survival37.…”

Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients

“…The Mycobacterium tuberculosis and Mycobacterium leprae bacilli are considered the only human exclusive pathogenic mycobacteria and they share host immune evasion similarities (8) . BCG vaccination has been associated with leprosy protection since the 1960s (9) , and due to common immunopathogenic characteristics between leprosy and TB, the cross-protection against both diseases with modifi ed BCG vaccines continues to be evaluated (10) .…”

Prospects in Mycobacterium bovis Bacille Calmette et Guérin (BCG) vaccine diversity and delivery: Why does BCG fail to protect against tuberculosis?

“…This study highlighted Ag85B antigenicity and linked it to protective immunity against TB. In this regard, rBCG30 can cross-protect against Mycobacterium leprae challenge, which is further enhanced by M.tb 30-kDa Ag85B boosting [55]. In order to address if M.tb secreted antigens are also capable of inducing a protective response, Pym et al .…”