Final Report Summary - NANOMAL (Development of a handheld antimalarial drug resistance diagnostic device using nanowire technology)
Executive Summary:
Malaria is a global health priority that has been targeted for elimination in recent years. Attaining the goals that define elimination of malaria in different countries depends critically on provision of effective antimalarials and further that these antimalarials are used appropriately in individual patients. Drug resistance is a major threat to malaria control and has important global public health implications. Over the past decades the genetic bases for resistance to most of the antimalarial classes currently in use has become defined. For some drugs and combinations, these mutations are the most important predictors of treatment failure. This proposal has innovated new technologies to confirm malaria diagnosis and detect drug resistance status in malaria parasites by analysis of mutations in nucleic acids, using nanowire technology, and has resulted in the development of a simple, rapid and affordable point-of-care handheld diagnostic device. The device will be useful at many levels in malarial control by:
1. Optimising individual treatments for patients
2. Assessing the epidemiology of drug resistance in malaria endemic areas
3. Assessing population impacts of antimalarial interventions
The development programme has capitalised on highly original and proprietary advances made by QuantuMDx in the field of point-of-care diagnostics. This has been complemented by academic expertise that has made major contributions to the understanding of antimalarial drug resistance mechanisms in laboratory models, as well as parasites obtained directly from patients. The impact of this proposal will be extended rapidly to other established and emerging infectious diseases.
Project Context and Objectives:
Malaria is a global health priority that has been targeted for elimination in recent years, with an estimated 200 million cases worldwide and approximately 600,000 deaths in 2013. Attaining the goals that define elimination of malaria in different countries depends critically on provision of effective antimalarials and further that these antimalarials are used appropriately in individual patients. Drug resistance is a major threat to malaria control and has important global public health implications. Over the past decades, the genetic basis for resistance to most of the antimalarial classes currently in use have become defined. For some drugs and combinations, these mutations are the most important predictors of treatment failure.
The NanoMal consortium is led by St George’s, University of London and the Newcastle-based QuantuMDx Group, with the Karolinksa Institutet in Sweden and Tübingen University in Germany. Over 3 years, the €5.2 million project, supported with €4 million in funding from the EU's seventh research framework programme, will develop a simple-to-use, affordable, handheld diagnostic device to swiftly detect malaria infection and parasites' drug resistance status by identifying associated genetic mutations. The device will use a range of novel technologies to rapidly analyse parasite DNA from just a finger-prick of blood. It will then provide a malaria diagnosis, speciation and drug resistance information in less than 20 minutes, allowing a course of personally tailored treatment to be given by the end of the process. The smartphone-like diagnostic device will allow healthcare workers in remote, rural areas to deliver effective drug treatments, potentially saving lives and enabling efficient allocation of limited resources. Furthermore, it will have the ability, through communications technology, to allow collected drug resistance information to become centrally available, so that drug resistance markers can be assessed at a community through to international level.
Project Results:
The overall aim of the ground-breaking NanoMal project is to develop a handheld, point-of-care device for fast diagnosis and treatment of malaria infections, the objectives for the three year project were to i) develop and characterise the individual components of the device, ii) design an initial malarial parasite assay able to identify an infection, the species of infecting Plasmodium parasite and whether resistance-associated mutations in the parasites’ DNA are present (and provide the necessary DNA samples for its development), iii) optimise and integrate device components, iv) put in place resources for device testing, v) miniaturise and optimise the integrated device, vi) test the integrated device in both the laboratory and the field and vii) put in place management, promotional, regulatory and commercial structures to aid the project to completion.
The individual elements of the NanoMal device are i) sample lysis and DNA extraction, ii) PCR, iii) sample detection and iv) a hand-held reader incorporating an intuitive user interface. The first involves producing purified DNA from blood by breaking up a sample and removing all debris except for the DNA, while flowing through a microfluidics chamber, all within 5 minutes. The second involves the use of a simple microfluidic channel and a complex arrangement of heating elements to amplify the DNA by the technique of PCR. 35 cycles of PCR are possible in less than 5 minutes, with the amount of DNA doubling with each cycle. The third is state-of-the-art, highly innovative and uses a novel nanowire-based biosensor to detect the binding of DNA of interest to probes immobilized on the surface of an array of nanowires. The fourth is a robust and simple to use handheld reading unit into which is placed a single-use, disposable cartridge (formed from the first three elements) and which provides an interface to input patient information and provide the result and treatment options. Each of the elements has been fully integrated into a working pre-alpha prototype, including both disposable cartridge and handheld reader. Furthermore, the device has undergone an extended period of optimisation and miniaturisation to improve utility and performance. Thus the underlying technology is now close to commercialisation.
The NanoMal consortium has also devised a basic malaria assay for use in the device’s cartridges. This has been designed and tested to detect all 5 species of human malaria, including the most dangerous, Plasmodium falciparum, the most widespread, Plasmodium vivax, and the newest member, Plasmodium knowlesi. Furthermore, this assay has been optimised to detect carefully chosen mutations associated with drug resistance in Plasmodium falciparum, which can be used to demonstrate the clinical utility of this ground breaking device. Testing will continue to use a range of carefully characterised and curated parasite DNA samples and parasite strains that have been acquired by St George’s, University of London. This will be followed by laboratory testing, using a library of clinical samples collected and held at the Karolinksa Institutet, near patient testing at Tübingen University and in Gabon and finally demonstrations projects with our networks of clinical collaborators. Furthermore, the Team has developed a road map to commercialisation for the device. This initially involved our external advisory board and establishment of key links with external bodies, such as the Foundation for Innovative Diagnostics, FIND. More recently, regulatory and quality control measures have been put in place and production and distribution partners identified. NanoMal’s efforts have not gone unnoticed with the Guardian Global Development Professionals Network naming the device as the number one innovation in malaria elimination.
Potential Impact:
At the end of the project, NanoMal will have produced a robust, field tested, rapid (sample to result time of < 20 minutes) and affordable point-of-care handheld diagnostic device with a malaria speciation and drug resistance status disposable cartridge. The simple-to-use, handheld NanoMal device will provide prompt diagnosis of malaria, to allow appropriate treatment and reduce both morbidity and mortality, and bring complex drug resistance analysis to the remotest global areas, where malaria often goes undetected because of the lack of suitable healthcare facilities. The latter technological advance will provide a step change to present day diagnostic tools for malarial infection by providing drug susceptibility testing data in a clinically useful timeframe. This will enable appropriate patient prescribing and treatment and reduce the risk of further drug resistance development (and thus spread of infection of this important global disease burden).
In addition, QuantuMDx will have developed a mobile application to enable health professionals to offer patients ongoing support and education during and after treatment. This technology will also have an immediate impact on resistance monitoring, when coupled with mobile technologies incorporated into the device. NanoMal, in time, will provide real-time global mapping of drug resistance that could be exploited and fed directly into policy. Thus, the NanoMal device will be useful at many levels that are fundamental to effective malarial control and eventual eradication, by i) optimising individual treatments for patients (“right first time prescribing”), ii) assessing the epidemiology of drug resistance in malaria endemic areas and iii) assessing population impacts of antimalarial interventions.
List of Websites:
http://www.nanomal.org/
Malaria is a global health priority that has been targeted for elimination in recent years. Attaining the goals that define elimination of malaria in different countries depends critically on provision of effective antimalarials and further that these antimalarials are used appropriately in individual patients. Drug resistance is a major threat to malaria control and has important global public health implications. Over the past decades the genetic bases for resistance to most of the antimalarial classes currently in use has become defined. For some drugs and combinations, these mutations are the most important predictors of treatment failure. This proposal has innovated new technologies to confirm malaria diagnosis and detect drug resistance status in malaria parasites by analysis of mutations in nucleic acids, using nanowire technology, and has resulted in the development of a simple, rapid and affordable point-of-care handheld diagnostic device. The device will be useful at many levels in malarial control by:
1. Optimising individual treatments for patients
2. Assessing the epidemiology of drug resistance in malaria endemic areas
3. Assessing population impacts of antimalarial interventions
The development programme has capitalised on highly original and proprietary advances made by QuantuMDx in the field of point-of-care diagnostics. This has been complemented by academic expertise that has made major contributions to the understanding of antimalarial drug resistance mechanisms in laboratory models, as well as parasites obtained directly from patients. The impact of this proposal will be extended rapidly to other established and emerging infectious diseases.
Project Context and Objectives:
Malaria is a global health priority that has been targeted for elimination in recent years, with an estimated 200 million cases worldwide and approximately 600,000 deaths in 2013. Attaining the goals that define elimination of malaria in different countries depends critically on provision of effective antimalarials and further that these antimalarials are used appropriately in individual patients. Drug resistance is a major threat to malaria control and has important global public health implications. Over the past decades, the genetic basis for resistance to most of the antimalarial classes currently in use have become defined. For some drugs and combinations, these mutations are the most important predictors of treatment failure.
The NanoMal consortium is led by St George’s, University of London and the Newcastle-based QuantuMDx Group, with the Karolinksa Institutet in Sweden and Tübingen University in Germany. Over 3 years, the €5.2 million project, supported with €4 million in funding from the EU's seventh research framework programme, will develop a simple-to-use, affordable, handheld diagnostic device to swiftly detect malaria infection and parasites' drug resistance status by identifying associated genetic mutations. The device will use a range of novel technologies to rapidly analyse parasite DNA from just a finger-prick of blood. It will then provide a malaria diagnosis, speciation and drug resistance information in less than 20 minutes, allowing a course of personally tailored treatment to be given by the end of the process. The smartphone-like diagnostic device will allow healthcare workers in remote, rural areas to deliver effective drug treatments, potentially saving lives and enabling efficient allocation of limited resources. Furthermore, it will have the ability, through communications technology, to allow collected drug resistance information to become centrally available, so that drug resistance markers can be assessed at a community through to international level.
Project Results:
The overall aim of the ground-breaking NanoMal project is to develop a handheld, point-of-care device for fast diagnosis and treatment of malaria infections, the objectives for the three year project were to i) develop and characterise the individual components of the device, ii) design an initial malarial parasite assay able to identify an infection, the species of infecting Plasmodium parasite and whether resistance-associated mutations in the parasites’ DNA are present (and provide the necessary DNA samples for its development), iii) optimise and integrate device components, iv) put in place resources for device testing, v) miniaturise and optimise the integrated device, vi) test the integrated device in both the laboratory and the field and vii) put in place management, promotional, regulatory and commercial structures to aid the project to completion.
The individual elements of the NanoMal device are i) sample lysis and DNA extraction, ii) PCR, iii) sample detection and iv) a hand-held reader incorporating an intuitive user interface. The first involves producing purified DNA from blood by breaking up a sample and removing all debris except for the DNA, while flowing through a microfluidics chamber, all within 5 minutes. The second involves the use of a simple microfluidic channel and a complex arrangement of heating elements to amplify the DNA by the technique of PCR. 35 cycles of PCR are possible in less than 5 minutes, with the amount of DNA doubling with each cycle. The third is state-of-the-art, highly innovative and uses a novel nanowire-based biosensor to detect the binding of DNA of interest to probes immobilized on the surface of an array of nanowires. The fourth is a robust and simple to use handheld reading unit into which is placed a single-use, disposable cartridge (formed from the first three elements) and which provides an interface to input patient information and provide the result and treatment options. Each of the elements has been fully integrated into a working pre-alpha prototype, including both disposable cartridge and handheld reader. Furthermore, the device has undergone an extended period of optimisation and miniaturisation to improve utility and performance. Thus the underlying technology is now close to commercialisation.
The NanoMal consortium has also devised a basic malaria assay for use in the device’s cartridges. This has been designed and tested to detect all 5 species of human malaria, including the most dangerous, Plasmodium falciparum, the most widespread, Plasmodium vivax, and the newest member, Plasmodium knowlesi. Furthermore, this assay has been optimised to detect carefully chosen mutations associated with drug resistance in Plasmodium falciparum, which can be used to demonstrate the clinical utility of this ground breaking device. Testing will continue to use a range of carefully characterised and curated parasite DNA samples and parasite strains that have been acquired by St George’s, University of London. This will be followed by laboratory testing, using a library of clinical samples collected and held at the Karolinksa Institutet, near patient testing at Tübingen University and in Gabon and finally demonstrations projects with our networks of clinical collaborators. Furthermore, the Team has developed a road map to commercialisation for the device. This initially involved our external advisory board and establishment of key links with external bodies, such as the Foundation for Innovative Diagnostics, FIND. More recently, regulatory and quality control measures have been put in place and production and distribution partners identified. NanoMal’s efforts have not gone unnoticed with the Guardian Global Development Professionals Network naming the device as the number one innovation in malaria elimination.
Potential Impact:
At the end of the project, NanoMal will have produced a robust, field tested, rapid (sample to result time of < 20 minutes) and affordable point-of-care handheld diagnostic device with a malaria speciation and drug resistance status disposable cartridge. The simple-to-use, handheld NanoMal device will provide prompt diagnosis of malaria, to allow appropriate treatment and reduce both morbidity and mortality, and bring complex drug resistance analysis to the remotest global areas, where malaria often goes undetected because of the lack of suitable healthcare facilities. The latter technological advance will provide a step change to present day diagnostic tools for malarial infection by providing drug susceptibility testing data in a clinically useful timeframe. This will enable appropriate patient prescribing and treatment and reduce the risk of further drug resistance development (and thus spread of infection of this important global disease burden).
In addition, QuantuMDx will have developed a mobile application to enable health professionals to offer patients ongoing support and education during and after treatment. This technology will also have an immediate impact on resistance monitoring, when coupled with mobile technologies incorporated into the device. NanoMal, in time, will provide real-time global mapping of drug resistance that could be exploited and fed directly into policy. Thus, the NanoMal device will be useful at many levels that are fundamental to effective malarial control and eventual eradication, by i) optimising individual treatments for patients (“right first time prescribing”), ii) assessing the epidemiology of drug resistance in malaria endemic areas and iii) assessing population impacts of antimalarial interventions.
List of Websites:
http://www.nanomal.org/