Full project title:
Field evaluation of novel immunodiagnostic tools for early detection of leprosy in a BCG vaccination field trial amongst contacts of leprosy patients (INDIGO)

Project coordination
Erasmus MC, University Medical Center Rotterdam (The Netherlands)

Partners
Leiden University Medical Center (The Netherlands)
The Leprosy Mission International (Bangladesh)

Aim: This study aimed to identify compounds of the immune system that are characteristic for the occurrence of leprosy and may differentiate between persons affected by leprosy, their contacts and healthy controls. Such compounds are called leprosy-specific biomarkers. 

Final project summary
Although a combination of antibiotics (multidrug therapy) is very effective at curing clinical leprosy, it is insufficient to reduce transmission of M. leprae, the causative agent of leprosy, in endemic populations as witnessed by stable new case detection rates in many leprosy endemic countries. It is therefore important to identify risk factors, transmission patterns and preventive measures that may be used as tools for early detection and prevention of leprosy. The aim of the study was to understand in more detail how people respond immunologically to the presence of M. leprae, in order to obtain insight into which immunological responses in people indicate that they are developing leprosy disease. In addition, since the BCG vaccine can induce protection against leprosy, BCG vaccination of contacts of leprosy patients will allow identification of immune responses that reflect protection against leprosy.

This was a long-term project to test many leprosy patients, their contacts, and people from the general population in Bangladesh on the presence of infection with M. leprae and the effect of BCG vaccination and treatment with an antibiotic (rifampicin) of contacts on host biomarker profiles. In a separate (non-LRI funded) project, field-friendly tests were developed to detect leprosy disease and M. leprae infection in endemic areas. This field-tests were based on differences in immune- biomarkers between those who have or developed disease and healthy contacts (exposed but remain healthy) and controls from the same area. Early diagnosis followed by (prophylactic) treatment of people who will otherwise develop leprosy will prevent transmission of the bacteria and possibly life-long disabilities in many of these people.

The researchers have identified several compounds in blood that were present in different levels in people with leprosy and contacts thereof likely infected with the bacterium compared to people who did not have any known contact with leprosy patients.

Among contacts receiving BCG and single dose rifampicine (SDR), one third of new cases were detected in the window between BCG vaccinatino and SDR. Therefore,  BCG vaccination followed by single dose rifampicine (SDR) cannot be recommended as routine intervention in leprosy control. Alternatively, focus on field trials of new candidate leprosy vaccines is a possibility. However, the research group advises contact surveys followed by SDR to eligible contacts of new leprosy cases - in line with tje recent recommendation by the World Health Organisation (WHO).

With respect to the differences in serum proteins between the test groups in this study, several new biomarkers were detected in stimulated whole blood that can discriminate MB and PB leprosy patients from contacts and healthy controls. Importantly, leprosy-associated biomarkers were identified in plasma (i.e. without overnight stimulation), offering potential for application in fingerstick blood-based tests for low resource settings.

Impact

Van Hooij, A, EM Tjon Kon Fat, R Richardus, SJF van den Eeden, Louis Wilson, CJ de Dood, R Faber, K Alam, JH Richardus, PLAM Corstjens and A Geluk. 2016. Quantitative lateral flow strip assays as user-friendly tools to detect biomarker profiles for leprosy. Sci. Rep. 6:34260;doi:10.1038/srep34260

Van Hooij, A, EM Tjon Kon Fat, SJF van den Eeden, L Wilson, M Batista da Silva, CG Salgado, JS Spencer, PLAM Corstjens, and A Geluk. 2017. Field-friendly serological tests for determination of M. leprae-specific antibodies. Scientific Reports 2017;7(1):8868.

Richardus, RA, K van der Zwet, A van Hooij, L Wilson, L Oskam, R Faber, SJF van den Eeden, D Pahan, K Alam, JH Richardus and A Geluk. 2017. Longitudinal assessment of anti-PGL-I serology in contacts of leprosy patients in Bangladesh. PLoS NTDs 2017, 11(12):e0006083.

Richardus RA, van Hooij A, van den Eeden SJF, Wilson L, Alam K, Richardus JH, Geluk A. 2018. BCG and Adverse Events in the Context of Leprosy. Front Immunol. 2018;9:629.

Blok DJ, SJ de Vlas, A Geluk, JH Richardus. 2018. Minimum requirements and optimal testing strategies of a diagnostic test for leprosy as a tool towards zero transmission: A modelling study. PLoS Negl Trop Dis 12(5): e0006529.

Geluk A. 2018. Correlates of immune exacerbations in leprosy. Seminars in Immunology. 39:111-8.

Van Hooij, A, EM Tjon Kon Fat, M Batista da Silva, R Carvalho Bouth, ACC Messias, AR Gobbo, T Lema, K Bobosha, J Li, X Weng, CG Salgado, JS Spencer, PLAM Corstjens, and A Geluk. 2018. Evaluation of immunodiagnostic tests for leprosy in Brazil, China and Ethiopia. Scientific Reports 8:17920.

Tio-Coma M, Wijnands T, Pierneef L, Schilling AK, Alam K, Roy JC, Faber WR, Menke H, Pieters T, Stevenson K et al. 2019. Detection of Mycobacterium leprae DNA in soil: multiple needles in the haystack. Scientific reports. 9(1):3165.

Corstjens P, van Hooij A, Tjon Kon Fat EM, Alam K, Vrolijk LB, Dlamini S, da Silva MB, Spencer JS, Salgado CG, Richardus JH, van Hees CLM, Geluk A. 2019. Fingerstick test quantifying humoral and cellular biomarkers indicative for M. leprae infection. Clinical biochemistry, Volume 66, pp. 76-82.

Richardus RA, Alam K, Kundu K, Chandra Roy, J, Jafar T, Chowdhury AS, Kahn D, Nieboer D, Faber R, Butlin CR, Geluk A, Richardus JH. Effectiveness of single dose rifampicin given after BCG vaccination in preventing leprosy in close contacts of patients with newly diagnosed leprosy: a cluster randomized controlled trial. 

Presentations: 
- Quantitative lateral flow assay for detection of leprae infection using fingerstick blood. EDCTP forum, Lisbon, Portugal. 18^th September 
    2018.
- Laboratory aspects (training, quality control, consumables, procedure harmonization. Kick-off meeting EDCTP PEOPLE project. Antwerp,
   Belgium. 2^nd October 2018 Title: POC test for childhood TB. NIH Pediatrics TB annual meeting. Cape Town, South Africa. 6th November
   2018.
- Host Biomarker-based POC tests for Leprosy Diagnosis in Hyperendemic Regions. Brazilian Leprosy Congress 2018. Palmas, Brazil. 17^th
   November, 2018.
- High tech at low complexity: development of POC tests for Leprosy & TB. Hôpital Lariboisière, Paris, France. 10^th December, 2018.