Longitudinal assessment of anti-PGL-I serology in contacts of leprosy patients in Bangladesh.

BACKGROUND: Despite elimination efforts, the number of Mycobacterium leprae (M. leprae) infected individuals who develop leprosy, is still substantial. Solid evidence exists that individuals living in close proximity to patients are at increased risk to develop leprosy. Early diagnosis of leprosy in endemic areas requires field-friendly tests that identify individuals at risk of developing the disease before clinical manifestation. Such assays will simultaneously contribute to reduction of current diagnostic delay as well as transmission. Antibody (Ab) levels directed against the M.leprae-specific phenolic glycolipid I (PGL-I) represents a surrogate marker for bacterial load. However, it is insufficiently defined whether anti-PGL-I antibodies can be utilized as prognostic biomarkers for disease in contacts. Particularly, in Bangladesh, where paucibacillary (PB) patients form the majority of leprosy cases, anti-PGL-I serology is an inadequate method for leprosy screening in contacts as a directive for prophylactic treatment. METHODS: Between 2002 and 2009, fingerstick blood from leprosy patients' contacts without clinical signs of disease from a field-trial in Bangladesh was collected on filter paper at three time points covering six years of follow-up per person. Analysis of anti-PGL-I Ab levels for 25 contacts who developed leprosy during follow-up and 199 contacts who were not diagnosed with leprosy, was performed by ELISA after elution of bloodspots from filter paper. RESULTS: Anti-PGL-I Ab levels at intake did not significantly differ between contacts who developed leprosy during the study and those who remained free of disease. Moreover, anti-PGL-I serology was not prognostic in this population as no significant correlation was identified between anti-PGL-I Ab levels at intake and the onset of leprosy. CONCLUSION: In this highly endemic population in Bangladesh, no association was observed between anti-PGL-I Ab levels and onset of disease, urging the need for an extended, more specific biomarker signature for early detection of leprosy in this area. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN61223447.

Clinical manifestations of leprosy after BCG vaccination: an observational study in Bangladesh.

BACKGROUND: Although BCG is used as a vaccine against tuberculosis, it also protects against leprosy. Previous evaluation over 18 years of an intervention of two doses BCG for 3536 household contacts of leprosy patients showed that 28 (23%) out of 122 contacts diagnosed with leprosy, developed symptoms 2-10 months after vaccination. This study describes contacts of leprosy patients in Bangladesh who developed leprosy within 12 weeks after receiving a single BCG dose. METHODS: A cluster RCT in Bangladesh aims to study the effectiveness of the BCG vaccine versus BCG in combination with single dose rifampicin (SDR) given 2 to 3 months after BCG, in the prevention of leprosy among contacts of newly diagnosed leprosy patients. During the first 1,5 years of this ongoing trial we identified contacts who developed leprosy within the first 12 weeks after receiving BCG vaccination, the timeframe before SDR is given. RESULTS: We identified 21 contacts who developed leprosy within 12 weeks after BCG vaccination among 5196 vaccinated contacts (0.40%). All 21 cases presented with paucibacillary (PB) leprosy, including children and adults. About half of these cases had previously received BCG vaccination as indicated by the presence of a BCG scar; 43% presented with signs of nerve function impairment and/or Type 1 (reversal) reaction, and 56% of the index patients had multibacillary (MB) leprosy. CONCLUSION: An unexpectedly high proportion of healthy contacts of leprosy patients presented with PB leprosy within 12 weeks after receiving BCG vaccination, possibly as a result of boosted cell-mediated immunity by homologues of Mycobacterium leprae antigens in BCG. Various immunological mechanisms could underlie this phenomenon, including an immune reconstitution inflammatory syndrome (IRIS). Further studies are required to determine whether BCG vaccination merely altered the incubation period or actually changed the course of the infection from self-limiting, subclinical infection to manifest disease.

The combined effect of chemoprophylaxis with single dose rifampicin and immunoprophylaxis with BCG to prevent leprosy in contacts of newly diagnosed leprosy cases: a cluster randomized controlled trial (MALTALEP study).

BACKGROUND: Despite almost 30 years of effective chemotherapy with MDT, the global new case detection rate of leprosy has remained quite constant over the past years. New tools and methodologies are necessary to interrupt the transmission of M. leprae. Single-dose rifampicin (SDR) has been shown to prevent 57% of incident cases of leprosy in the first two years, when given to contacts of newly diagnosed cases. Immunization of contacts with BCG has been less well documented, but appears to have a preventive effect lasting up to 9 years. However, one major disadvantage is the occurrence of excess cases within the first year after immunization. The objective of this study is to examine the effect of chemoprophylaxis with SDR and immunoprophylaxis with BCG on the clinical outcome as well as on host immune responses and gene expression profiles in contacts of newly diagnosed leprosy patients. We hypothesize that the effects of both interventions may be complementary, causing the combined preventive outcome to be significant and long-lasting. METHODS/DESIGN: Through a cluster randomized controlled trial we compare immunization with BCG alone with BCG plus SDR in contacts of new leprosy cases. Contact groups of around 15 persons will be established for each of the 1300 leprosy patients included in the trial, resulting in approximately 20,000 contacts in total. BCG will be administered to the intervention group followed by SDR, 2 months later. The control group will receive BCG only. In total 10,000 contacts will be included in both intervention arms over a 2-year period. Follow-up will take place one year as well as two years after intake. The primary outcome is the occurrence of clinical leprosy within two years. Simultaneously with vaccination and SDR, blood samples for in vitro analyses will be obtained from 300 contacts participating in the trial to determine the effect of these chemo- and immunoprophylactic interventions on immune and genetic host parameters. DISCUSSION: Combined chemoprophylaxis and immunoprophylaxis is potentially a very powerful and innovative tool aimed at contacts of leprosy patients that could reduce the transmission of M. leprae markedly. The trial intends to substantiate this potential preventive effect. Evaluation of immune and genetic biomarker profiles will allow identification of pathogenic versus (BCG-induced) protective host biomarkers and could lead to effective prophylactic interventions for leprosy using optimized tools for identification of individuals who are most at risk of developing disease. TRIAL REGISTRATION: Netherlands Trial Register: NTR3087.