2.5 New methods to identify leishmania super-spreaders in modelling targeted control

The University of Warwick (WARWICK), Coventry, United Kingdom   - INBios International, Inc., Seattle, USA   - Infectious Disease Research Institute (IDRI), Seattle, USA

Area of research: Prevention
Research programme: Translational Science

This PhD Project aims to identify efficacious intervention strategies against zoonotic visceral leishmaniasis (ZVL) in humans where domestic dogs are the reservoir host. ZVL is a neglected tropical disease (NTD) particularly of children transmitted by Phlebotomine sand fly vectors. In many endemic regions, current policy against transmission focuses on blanket culling of Leishmania seropositive dogs, and insecticide spraying against vector(s), however there is little to no evidence that these approaches have had significant impact on human or canine infection incidence. Specifically, the test-and-slaughter of seropositive dogs uses test antigens that have low specificity for disease and canine infectivity to the vector i.e. transmission potential (cf. past exposure/ infection). Consequently the mass slaughter policy is questioned on theoretical, scientific and ethical grounds, and dog-owner compliance to the national program is low. This PhD project aims to prototype diagnostic assay development and evaluate novel antigens and antigen combinations to improve the specificity of a potential “roll-out” serological test. Serum samples come from endemic cohort dog and fox populations that are well characterised for infectiousness to the vector and clinical and infection outcomes. The second part of the project will be to use these results in quantitative models to identify optimal testing regimes to impact on transmission to reduce infection burdens in dogs and humans. This work will be in close collaboration with the Warwick Infectious Disease and Epidemiology group (WIDER) http://www2.warwick.ac.uk/fac/cross_fac/wider/ and the Warwick NTD modelling consortium http://www.ntdmodelling.org. The student will spend time in the collaborating labs (IDRI and InBios) in Seattle, USA who develop and produce field diagnostic tests for Brazil and elsewhere.

Infectious Brazilian dog with advanced canine leishmaniasis (Orin Courtenay)

Expected results:

(1) Animal testing using antigen(s) more specific to infectious cf. infected hosts will greatly improve our ability to differentiate the small proportion of hosts contributing most to transmission.

(2) Mathematical modelling will identify the most efficacious test interpretations as criteria for local interventions: adopting antibody and molecular threshold-based diagnostic tests will increase specificity further, increase dog owner compliance, and reduce transmission rates, with greater efficacy than current policy protocols.

(3) Knowledge transfer to existing Brazilian partners will result in re-consideration of MoH intervention strategy.

Summary:

Background: To control transmission of Leishmaniasis from zoonotic reservoirs requires identification of the proportion of the population that is infectious to the sandfly vector. Our recent xenodiagnosis and quantitative molecular (qPCR) studies of cohorts of naturally infected dogs demonstrate that dogs contributing to >80% transmission events have significantly higher Leishmania burdens in their skin, that may be detected with high specificity and earlier on during the infection process by adopting specific qPCR and serum antibody diagnostic test thresholds. The proposed PhD project aims to test novel antigens or/and antigen combinations towards developing a more specific tests to identify “super-spreaders” in the mixed canid population. In conjunction with mathematical modelling, the performance of these tests under varying epidemiological scenarios to reduce transmission will be explored for potential field efficacy. 

Methodology: Archived sera and tissue samples from well characterised dog and fox cohort populations will be tested using current and novel Leishmania antigens (INBIOS). Used in relation to existing data for these cohorts (demographic, immunologic, parasitological, clinical and infectiousness to sandflies over 2 years follow-up), the results will be used to develop the next generation of ZVL mathematical models, specifically accounting for age-related transmission dynamics and spatial scale.