Abstract
Tuberculosis (TB) and leprosy still represent significant public health challenges, especially in low- and lower middle-income countries. Both poverty-related mycobacterial diseases require better tools to improve disease control. For leprosy, there has been an increased emphasis on developing tools for improved detection of infection and early diagnosis of disease. For TB, there has been a similar emphasis on such diagnostic tests, while increased research efforts have also focused on the development of new vaccines. Bacille Calmette–Guérin (BCG), the only available TB vaccine, provides insufficient and inconsistent protection to pulmonary TB in adults. The impact of BCG on leprosy, however, is significant, and the introduction of new TB vaccines that might replace BCG could, therefore, have serious impact also on leprosy. Given the similarities in antigenic makeup between the pathogens Mycobacterium tuberculosis (Mtb) and M. leprae, it is well possible, however, that new TB vaccines could cross-protect against leprosy. New TB subunit vaccines currently evaluated in human phase I and II studies indeed often contain antigens with homologs in M. leprae. In this review, we discuss pre-clinical studies and clinical trials of subunit or whole mycobacterial vaccines for TB and leprosy and reflect on the development of vaccines that could provide protection against both diseases. Furthermore, we provide the first preclinical evidence of such cross-protection by Mtb antigen 85B (Ag85B)-early secretory antigenic target (ESAT6) fusion recombinant proteins in in vivo mouse models of Mtb and M. leprae infection. We propose that preclinical integration and harmonization of TB and leprosy research should be considered and included in global strategies with respect to cross-protective vaccine research and development.
Highlights
Tuberculosis (TB) and leprosy are major infectious diseases that are caused by highly related mycobacterial pathogens, Mycobacterium tuberculosis (Mtb) and M. leprae
New routes of Bacille Calmette–Guérin (BCG) administration, such as aerosol or intranasal immunization, are tested to initiate mucosal immunity and promote homing of immune cells to the lung mucosa [44, 45]. Another shortcoming of BCG is that its protective effects against TB as well as leprosy wanes over time, dropping to 14% efficacy after 10–20 years [46], indicating a suboptimal induction of long-term immune memory responses as discussed above [47, 48]
Alternative clinical trial designs have been developed using alternative biologically relevant endpoints, such as prevention of recurrence (POR) in cured TB patients, which evaluate whether relapse rates can be reduced by post-therapy vaccination; or shortening of treatment trials, which evaluate whether treatment length can be reduced by complementary immunotherapy with TB vaccines during the last phase of TB treatment
Summary
Tuberculosis (TB) and leprosy are major infectious diseases that are caused by highly related mycobacterial pathogens, Mycobacterium tuberculosis (Mtb) and M. leprae. An extensive BCG revaccination trial of household contacts of leprosy patients in Brazil showed that the protection conferred by a booster BCG vaccination was 56% and was independent of previous BCG vaccination [29] Notwithstanding, this lack of BCG boosting effects in TB and its beneficial effects on leprosy, BCG vaccination can have less favorable effects, such as increasing the numbers of paucibacillary leprosy cases within the first months after BCG immunization [51]. POD require extensive longitudinal studies due to the long incubation times (years) in TB and leprosy (years-decades), and the limited incidence rates in most populations studied For these reasons, alternative clinical trial designs have been developed using alternative biologically relevant endpoints, such as prevention of recurrence (POR) in cured TB patients, which evaluate whether relapse rates can be reduced by post-therapy vaccination; or shortening of treatment trials, which evaluate whether treatment length can be reduced by complementary immunotherapy with TB vaccines during the last phase of TB treatment.
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