A universal molecular diagnostic platform for low cost, room temperature, highly selective detection of TB, HIV and HCV and associated drug resistance in the European Union and Russian population

Call Reference: 
SC1-BHC-21-2018
Short description of project idea : 
After successfully reducing the prevalence of TB, HIV and HCV in the European Union and Russian population in the past, the recent rise of drug resistant infections is highly alarming. Commonly used diagnostic approaches are either limited to TB, HIV or HCV specifically and few combination tests are currently available. Furthermore, the surge of TB and HIV co-infections is concerning since a combined weakening of the immune system increases the mortality of the infections, especially in high risk groups. To combat these diseases, it is crucial that the emergence of resistant strain can be detected in the population as early as possible using devices that are cheap and robust at the same time. We propose a technological genotyping platform that promises to be the first user-friendly universal test for the diagnosis of TB, HIV and HCV, while simultaneously determining the drug resistance status for each infecting agent. Current technologies for diagnosis of infectious diseases rely on sputum smear microscopy and culture based detection (in the case of TB) or polymerase chain reaction (PCR), enzyme-linked immunosorbent assays (ELISAs) and laboratory antibody tests (in the case of HIV and HCV). Molecular methods are gaining interest due to their multiplexing capabilities, specificity and/or sensitivity. However, current assays have yet limited scaling capabilities, and require specialist instruments and performance, and controlled assay conditions. VITO in collaboration with UCF have previously developed a custom DNA hybridization based genotyping platform that allows simultaneous detection of at least 25 TB mutations associated with drug resistance as well as 20 TB mutations linked to strain type. Thanks to the unique design of mutation specific probes on a sensor chip, we can detect low abundant TB mutations present in a background of wild type sequences. Moreover, we have developed unique strategies for (i) hybridization sensors that can differentiate a single nucleotide mutation at room temperature, which often distinguishes drug-resistant from drug-susceptible strains, and (ii) a platform for visual differentiation of point mutation at room temperature. We propose to extend our platform to tackle the challenges addressed in this call by creating a new platform for highly selective, visual analysis of TB, HIV and HCV strain types at room temperature, while simultaneously determining the drug resistance status for each infecting agent.
Health
Main areas of expertise: 
Technological developments in the field of health diagnostics: - Biomarker discovery and validation - Targeted separation and detection - In vitro cell-based tests - Data science
Main objectives of the project and how will they be achieved: 
Title: 
1) Epidemiological study and statistical modelling, 2) Discovery of novel biomarkers, 3) Extension of current genotyping platform, 4) Development of point-of-care array platform for simultaneous detection of TB, HIV and HCV and drug resistance testing
Description: 
1) To detect low-abundant mutations at an early stage, we aim to greatly improve the detection of the diseases of interest and presence of any drug resistance at the same time. We will design a multiplexing hybridization platform that extends the current tuberculosis detection platform and can be combined with HIV and/or HCV to detect the presence of TB, HIV and/or HCV simultaneously. The thermodynamic platform, combined with rigorous statistical testing, will guide treatment and support epidemiological studies, including cases where co-infections dominate. Similar to the successful development of combined vaccins to protect against multiple diseases, the approach outlined in our project will enable combined detection of multiple diseases at the same time. A complete but quick detection of the pathogen, including strain type and drug resistance profile, enables diagnosis and thereby fast administration of antibiotics (in the case of TB) and anti-(retro)virals (in the case of HIV and HCV), and can be considered as a step towards personalized medicine. Biological data regarding strain type and drug resistance of TB, HIV and HCV needs to be provided by external partners. 2) Our method provides the foundation to miniaturize the currently employed microarray to a more simple device or setting that is cheaper and easier to handle. We will create a prototype platform for analysis of human blood or sputum samples for the presence of multiple infecting agents including TB, HIV and HCV, and determination of their drug resistance status. The array will consist of ~100-200 spots, each specific to a certain TB, HIV or HCV strain. Each spot on the array will operate in a broad temperature range (5-40 degrees C). It will requires simple equipment (e.g. hot plate or thermostate) and will have visual signal output. The total analysis time will be as short as 1 hour. The method will be adaptable to low-resource medical offices or even for home use. The proposed platform will make it possible to detect infectious diseases in a user friendly ‘pregnancy test-like’ format. 3) We foresee that epidemiological studies will be part of the project to investigate the dynamics and causes of the fast spread of M/DR-TB and HIV/AIDS in some regions, including the susceptibility to HIV and/or disease progression rate after infection. VITO proposes to integrate the biological and medical data obtained in this project with available socio-economic parameters in a statistical model that can predict the outcome of an epidemy. Using specifically developed algorithms, we envision that this model will allow a better understanding of how the diseases of interest can spread across the EU and Russia in high-risk group populations and specific regions. Input from epidemiology partners, preferably with previous experience in TB and/or HIV, will be necessary to set up the model. 4) The obtained samples of interest will be tested for the presence of currently known biomarkers. In collaboration with external partners, we will investigate if novel biomarkers can be identified in the biological samples obtained in this project. For example, biomarkers that are linked to co-infections are of interest here.
Challenges that may determine the impact of the project: 
Title: 
Study population and biological sample collection
Description: 
To be able to investigate epidemics of TB, HIV and/or HCV, access to relevant study populations is needed. Furthermore, collection of qualitative biological samples are a prerequisite to allow in-depth studies of epidemics and discovery of novel biomarkers. For proof-of-principle studies of the updated genotyping platform, samples containing a variety of single nucleotide polymorphisms are needed. For this sample collection we will rely on collaboration(s) with expert clinical and/or academic partners in Russia and/or other Eastern European countries.
Partners that have already expressed interest in the project and expected role: 
Title: 
VITO nv (Belgium)
Description: 
Role in 1) extending the existing DNA hybridization-based platform for mutation detection to multiplexing for simultaneous detection of TB, HIV and/or HCV and their drug susceptibility; 2) translating the concept to a user-friendly, low-cost platform; 3) statistical modelling of biological data; 4) novel protein biomarker discovery and validation
Title: 
ITMO University (Russia)
Description: 
Extension of the current DNA hybridization-based platform for mutation detection to multiplexing, and development of simplified genotyping array platform
Profile of partners sought and expected role: 
Title: 
Microbiologists, virologists
Description: 
Experts in the study of TB, HIV and/or HCV with a role in understanding their (co-)infectious behaviour, interaction with host organisms, resulting disease and therapy, in selecting biomarkers suitable for strain typing and/or drug resistance, and in culturing the micro-organisms and preparing protein and nucleic acid isolates.
Title: 
Diagnostics assay developer
Description: 
Expertise in developing nucleic acid or protein-based assays for point-of-care diagnostic purposes. Role in designing the proposed genotyping array platform, or in developing a low-cost, multiplexing assay for detection of protein biomarkers.
Title: 
Clinic, health institution
Description: 
Role in recruiting patients and collecting high-quality biological samples for epidemiological study, biomarker discovery, and/or validation of the diagnostic platforms.
Title: 
Epidemiologists
Description: 
Role in designing and organising epidemiological studies, in close collaboration with clinical partner and data scientists.
Title: 
Genetics and/or proteomics specialists
Description: 
Experts in genetics or proteomics are needed for discovery and validation of novel nucleic acid and/or protein biomarkers in biological samples of infected persons (vs. matched non-infected controls). This will be in close collaboration with the clinical partner(s) for sample collection and storage, as well as with data scientists.
Previous, relevant EU project experience: 
Title: 
Biomargin - Biomarkers of renal graft injuries in kidney allograft recipients
Programme: 
FP7-Health
Title: 
TransTechDiagnostics
Programme: 
European Regional Development Fund (ERDF), Interreg V Flanders-Netherlands
Title: 
npSCOPE - Nanoparticle scope
Programme: 
H2020-EU.2.1.2.2. - Ensuring the safe and sustainable development and application of nanotechnologies
Title: 
M3DLOC - Additive manufacturing of 3D microfluidic MEMS for lab-on-chip applications
Programme: 
H2020-NMBP-PILOTS-2017
Specific countries/regions/cities you are keen to collaborate with: 
Eastern Europe
First Name: 
Inge
Last Name: 
Nelissen
Name of the organisation: 
VITO nv (Flemish Institute for Technological Research)
Short description of organisation: 
VITO is an independent research organization that provides innovative technological solutions to industry and public authorities. It also offers scientifically based advice and support in the research domains of energy, materials, chemistry, land use and health in order to stimulate sustainable development. The research focus of the Health department is in the field of sustainable health and disease prevention, with a focus on safe, effective and/or personalized technological innovations.

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