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Moving Forward in the Diagnosis of InfectiousDiseases in Resource Limited Countries:

Diagnostic Technology Advances 4th edition

Organized by Fondation Mérieux & the American Academy of Microbiology

“Les Pensières”

Fondation Mérieux Conference CentreVeyrier-du-Lac - France

September 12-14, 2011

This meeting was made possible in part through unrestricted educational grants from: Ahimsa Partners - FranceBiokit, SA - SpainbioMérieux - FranceIM ACCESS - FranceQIAGEN GmbH - Germany

Steering committee

Jean François de Lavison Ahimsa Partners

Ogobara Doumbo Malaria Research and Training Center

Keith Klugman American Academy of Microbiology

Christophe Longuet Fondation Mérieux

Souleymane Mboup Université Cheik Anta Diop

Rosanna Peeling London School of Hygiene and Tropical Medicine

Valentina Picot Fondation Mérieux

Mario C. Raviglione World Health Organization

Ann Reid American Academy of Microbiology

Giorgio Roscigno FIND Diagnostics

Amadou A. Sall Institute Pasteur of Dakar

François Simon APHP

Jan Van Erps RollBack Malaria Partnership

Guy Vernet Fondation Mérieux

Gene Walther Bill & Melinda Gates Foundation

Bernhard Weigl PATH

Welcome Letter

September 12, 2011

Dear Participant,

It is our pleasure to welcome you to the symposium entitled:

“Moving forward in the diagnosisof infectious diseases in resource limited countries:

diagnostic technology advances”

in Fondation Mérieux’s Conference Centre “Les Pensières.” We hope you will enjoy this meeting, which brings together some of the world’s foremost experts.

The format of the meeting’s programme is intended to generate discussion and interaction among participants and to foster the dissemination of new information on this topic. The conference will provide an opportunity for specialists to exchange knowledge and experiences through collaboration with researchers from around the world.

Over the next two days, the team at Les Pensières will be on hand to help you with any questions you may have and to make your stay and conference as comfortable and valuable as possible.

Benoît Miribel Director General Fondation Mérieux

For more information: www.fondation-merieux.org

Background and rationale A critical factor in reducing the infectious disease burden in developing countries is the ability to provide accurate diagnosis and monitor response to treatment. New technologies are emerging to improve the diagnosis and monitoring of infectious diseases. Rapid molecular methods and integrated diagnostic platforms are among the most promising approaches, having an important role in the global control of infectious diseases. International organizations and governments of developing countries realize that strengthening laboratory capacity both at the central and point-of care levels is necessary to reduce the burden of infectious disease and achieve the Millennium Development Goals.

In recognition of the critical constraints on the diagnosis of many infectious diseases affecting the developing world, Fondation Mérieux organizes an annual forum to discuss the current state and future potential of diagnostic technologies to address the pressing needs of developing countries.

After three successful forums “Moving Forward” on tuberculosis, malaria and HIV organized respectively with the Global Laboratory initiative of the STOP TB Partnership & the World Health Organization in 2008, with the Roll Back Malaria Partnership in 2009 and with UNAIDS in 2010, the 2011 forum co-organized with the American Academy of Microbiology will focus on Current Diagnostic Technology Advances on infectious diseases.

The format of the forum will provide with an opportunity to share knowledge and experiences, identify connectionsbetweenfieldsthatmayrarelyinteract,generatenewideas,andidentifypromisingareasfor future research and introduction of these technologies in the needed settings.

Among the questions to be addressed at the forum are: · What are the greatest challenges and problems with respect to current diagnostic technologies in the developing laboratory and point of care setting?

·Whatscientificandtechnologicaladvancesareonthehorizonthatmightallowdevelopingcountriesto ‘leapfrog’ over current hurdles and radically expand laboratory capacity?

· How to facilitate integration of new tools?

The Moving Forward Forum will provide a comprehensive look at the current state and future potential of diagnostic technologies to address the needs of developing countries.

The objectives of this annual forum are to: · Increase awareness of the importance of adequate diagnosis of infectious diseases in resource limited countries;

·Highlightthespecificneedsandthenewperspectivestoaddressappropriatelydiagnosticsinthese regions of the world;

· Learn about the diagnostic tools available and those in development;

· Exchange lessons learned from ongoing initiatives and disciplines;

· Agree on priorities and on how all actors can interact to move forward.

Scientific Programme

Monday 12 September 2011

17.30 - 18.15 Registration

18.15 - 18.30 Welcome Address Alain MERIEUX

Keynote lectures

18.30 - 19.00 Burden of infectious diseases in developing countries Kevin M. DE COCK

19.00 - 19.30 Global diagnostics landscape Rosanna PEELING

19.30 Welcome dinner

Session 1 Challenges and needs 09.00 - 12.40 Chair: Ann Reid & François Simon

Positioning of TB diagnostics within a tiered system Integrated approach from reference to district laboraroty

Giorgio ROSCIGNO

Diagnostic technologies for the point of care setting Rosanna PEELING

Grant challenge in global health: the potential role of standards in point of care diagnostics

Gene WALTHER

10.00 - 10.20 Panel discussion

10.20 - 10.50 Coffee break

Essential quality assurance measures and recommendations for resource-limited country laboratories

Niel T. CONSTANTINE

Delivery and adoption of new diagnostic technologies inresource limited settings

Oyewale TOMORI

Tuesday 13 September 2011


Business models for the developing world Jean-François DE LAVISON

TBC Georges WHITESIDES


12.40 - 14.00 Lunch

TB field experiences Fuad MIRZAYEV

Malaria field experiences Ogobara DOUMBO

HIV field experiences Avelin AGHOKENG



Lessons learnt in the evaluation of RDTs for visceral Leishmaniasis Marleen BOELAERT

Diagnostics of viral hemorrhagic fever Amadou A. SALL

Clinical trials in applied diagnostics John T. McDEVITT


19.30 Dinner

Session 2 Building from successful field experiences in applied diagnostics 14.00 - 17.30 Chair: Jan Van Erps & Souleymane Mboup


Approaching high tech affordable diagnostics in low tech settings Wendy STEVENS

The Global Health Innovation Quotient Prize: a milestone based prize to stimulate R&D for point-of-care fever diagnostics

Don JOSEPH


New approaches at the reference laboratory level:· Resistance testing· Pathogens identification

Ron BALLARDJean-Noël TELLES



New approaches at the point-of-care level:· RDTs: What is new?· TBC· POC – Molecular Diagnostics

Arman NABATIYANWilliam RODRIGUEZEllen Jo BARON


Emerging diagnostic technologies: nano / microfluidicstechnology

Robert S. MARKS

Discussion

Conclusion / Recommendations

Meeting Cloture

13.30 Lunch

Wednesday 14 September 2011

Session 3 Research & Development: new approaches in diagnostics 09.00 - 15.00 Chair: Keith Klugman & Rebecca Lackman

Keynote lectures

Burden of infectious diseases in developing countries

Kevin M. DE COCK CDC - USA

Keynote lectures

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Global diagnostics landscape

Rosanna PEELINGLondon School of Hygiene and Tropical Medicine - UK

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Session 1

Challenges and needs

Positioning of TB diagnostics within a tiered systemIntegrated approach from reference to district laboratory

Giorgio ROSCIGNOFIND Diagnostics - Switzerland

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Diagnostic technologies for point of care settings

Rosanna PEELINGLondon School of Hygiene and Tropical Medicine - UK

Many high quality diagnostic tests for infectious diseases are com-mercially available, but they are neither accessible nor affordable to most patients in the developing world, where laboratory services are often limited to major urban centres. Affordable rapid immuno-chromatographictestsinlateralflowstriporcassetteformatshavebeen available for HIV, malaria, syphilis and some neglected tropical diseases for the last decade, but a new generation of exciting new technologies may transform the diagnosis of infectious diseases in POC settings. Molecular assays with integrated platforms providing sample-in, answer-out convenience are available for tuberculosis andseveral otherdiseases. Isothermal nucleicacidamplificationtechnologies that require only a small reader and can give both a diagnostic and an antibiotic resistance result in 15-60 minutes willsoonbeavailable.Microfluidicdeviceswiththeconvenienceofrequiring ultralow specimen volume, no moving parts, and having multiplexcapabilityarenowavailable,andcanreplacelateralflowimmunoassays.

New diagnostic technologies for POC settings have the potential to improve global health but only if they are rigorously evaluated, effectively regulated and correctly used. Financing mechanisms to make them affordable and to overcome health systems constraints to ensure sustainable uptake in resource limited settings are also important before the full impact of these new technologies can be realised.

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The potential role of standards in point of care diagnostics

Gene WALTHERThe Bill & Melinda Gates Foundation - USA

The goal of the Grand Challenges in Global Heath – Point of Care (POC) Diagnostics initiative is to create a sustainable market for high-performance, low-cost, point-of-care diagnostics for the deve-loping world. Currently, there are numerous point-of-care diagnos-tic components being developed by both research institutions and companies. Each of these components is being developed to its own technical and operating standards. This poses a set of rela-ted challenges. First, for the user, there is a limited menu of tests and typically when tests do exist, the user needs to buy different equipment from different manufacturers for each indication. For the developer, when a novel biomarker or test method is discovered the developer must bear the expense and complication of developing a complete end-to-end platform, seeking regulatory approval and developing a strategy for market access. Further, for the developer, in selected cases access to critical technologies is limited by intel-lectual property barriers or is prohibitive due to excessive royalty stacking.The objective is to establish a flexible, open, standard platformarchitecture that supports an extended menu of tests of different types from different manufacturers so that we can solve this dual problem. Ideally, a future user will be able to purchase one of a number of competing platforms from different manufacturers that would reliably run an extended menu of diagnostic tests also from a variety of manufacturers. We anticipate that this platform will have a modest capital cost, but a multi-year lifetime.A properly designed set of standards will permit companies to spe-cialize and to compete in building more cost effective and more innovativeplatformsconsistentwiththestandard,confidentthatanextended menu of tests already in the marketplace would work on their platform. Perhaps one platform model would be optimized foruseinremotefieldsettingsandcapableofdoingasingletestat a time and a second model would be optimized for a small clinic capable of doing multiple tests asynchronously. We envision that this future diagnostic technology framework will be comprised of four related sets of standards: Product Standards; In-terface Standards; Regulatory Standards and Business Standards.

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Suite

Product Standards:AfutureProductStandardmustclearlydefinewho the users are, where the greatest impact can be achieved, and the value proposition. To this end, the Product Standard will define a number of use scenarios, likely specialized to differentgeographies, different clinical needs, different menus of tests and different parts of the health system. The Product Standard will also need to define the desiredmenu of tests as individual tests, asbatteries of tests or as multiplexed tests. The Product Standard will needtodefinethebasicminimumperformanceorTargetProductProfilefortheplatformaswellaseachoftheindividualtestsandaminimum set of expectations for the user interface. Interface Standards: A future Interface Standard must clearly definethephysicalinterfacebetweentheplatformandthedisposabletest elements as well as all interfaces for energy exchange (heat, cooling, pressure, electromagnetic), quality control, test menu item identification(includinganyspecialinstructionsaspecifictestmightneed to provide to the platform), and interrogation and read-out of test results. Regulatory Standards: The current state of affairs for testing and achieving regulatory approval for diagnostics in global health is sub-optimal. As part of this initiative we will seek to set a clearly definedsetofstandardsaroundpreclinicalandclinicaltestingofanextended menu of tests on a set of interoperable platforms. It will be necessary to work closely with regulatory agencies to explore the extent to which it will be possible, and under what circumstances, futureproductscanbeapprovedmoreefficiently if theymeetthestandardstobedefinedunderthisinitiative.Thiswilllikelyincludestructural reforms such as regional harmonization of registration requirements.Business Standards: The objective is the sustainable delivery of affordable point-of-care diagnostics in developing countries. We anticipate that setting Business Standards in this initiative are likely toevolve inanumberofdistinctphases. Thefirstphasewillbecomprised of a set of agreements and expectations with regard to facilitating collaboration in developing standards, sharing technical data and ensuring that we minimize barriers to future integration of components into either test menus or platforms and then the interoperability of diagnostic tests and platforms. The second phase of Business Standards will grow out of this work and will be embodied in the follow-on investment strategy to build prototypes of platforms and extended menu of tests that will be interoperable on these platforms. It is likely that this second set of Business Standards will require detailed agreements around cross licensing, information sharing, royalty sharing, distribution and service & support arrangements. Critical to success of setting Business Standards at each o f these phases will require an active engagement with industry.

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Essential quality assurance measures and recommendations for resource-limited country laboratories

Niel T. CONSTANTINEUniversity of Maryland - School of Medicine - USA

Regardless of the technology used, accurate laboratory diagnosis requires essential quality management (QM), quality assurance (QA), quality control (QC), and quality assessment programs. Knowledge to institute these effectively, as well as continuous monitoring and vigilance are of paramount importance to have a successful and sustainable outcome. Nearly all errors that occur in laboratories are preventable.Quality measures include those to address pre-analytical, analytical, and post-analytical aspects, and canbestbeinstitutedusingdedicatedqualityassuranceofficers.Assessment of laboratories and personnel in many resource-limited country laboratories has documented the need for improvement in infrastructure, training, and monitoring of performance. In Nige-ria, we developed a quality system that included didactic lectures, wet workshops, interactive exchanges with personnel, a quarterly assessment program, and established a most important tiered “QA unit” to enforce and continuous monitor all activities. Errors and non-compliance with recommended standard operating procedures were compiled from 34 laboratory sites, and revealed a number of similar issues occurring at multiple sites, as well as site-speci-ficproblems.Withsubsequentfollow-uptoaddresstheseissues,measuredimprovementsincludedareductionindeficienciesfrom13% to 2%. Our experiences clearly show that laboratory activities and perfor-manceinresource-limitedlaboratoriescanbemodifiedinapositivemanner to provide quality results, but only with a well-designed and dedicated quality system. Recommendations will be presented.

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Delivery and adoption of new diagnostic technologies in resource limited settings

Oyewale TOMORIRedeemer’s University - Nigeria

New diagnostic techniques provide accurate, rapid and reliable diagnosis, required for the prevention of, and institution of rapid response to epidemics at community level. These diagnostic tech-niques are also useful in monitoring response to treatment at the individual level. Significantlossoflifecanbeprevented,whilehugesavingsinthecost of intervention and health care delivery can also be achieved by the effective use of new diagnostic technologies. However, the effective adoption and widespread use of these techniques require the availability of a minimum level of resources – human, infras-tructural andfinancial. In resource limited settings, characterizedbyinsufficiencyandinadequacyofqualifiedandwelltrainedlabo-ratory staff, unavailability of basic infrastructures, (electricity, good qualitywater, equipment, reagentsandconsumablesand insuffi-cient funding, the adaptation and adoption of such new diagnos-tictechnologiesbecomehighlyproblematic,difficultandunsustai-nable. Therefore the delivery and adoption of these new diagnostic techniques for effective utilization in resource limited settings, must address the following:

training of laboratory personnel, provision of basic laboratory infrastructures, reagents and consumables, operating funds the integration of laboratory services with disease surveillance.

Toderivemaximumbenefitsfromthedeploymentanduseofthesenew diagnostic techniques, resource limited countries must ensure the integration of laboratory service with the disease surveillance system and rapidly strengthen laboratory capacity both at the cen-tral and point-of care levels, Otherwise, introducing new diagnos-tic techniques in existing laboratory systems in resource limited countries will be like putting new wine into old bottles. Until these new techniques are well integrated into the disease surveillance systems, older diagnostic techniques should not be abandoned, but should continue to be used as part of laboratory diagnostic system.

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Business models for the Developing World

Jean-François DE LAVISON Ahimsa Partners - France

Successful development and validation of a diagnostic device does not ensure its success in the marketplace. New sales policies, lo-gistical approaches, and technical assistance paradigms, as well as new monitoring and prevention programs will be needed. The last few years have shown an enormous and increasing openness by traditional diagnostics-related organizations and industries toget involved indiagnostics forglobalhealth.Signifi-cant hurdles remain, some related to technology, and many to the business structures that have so far prevented individual develo-pers from working together and openly sharing the best of their ap-proachestocreatediagnosticsthattrulybenefitthoseinresource-poor settings.We then need to create a community of innovators who will de-velop a new class of POC diagnostics for multiple pathogens or conditions that will be easy to use and low cost. We will have, with the contribution of all the stakeholders, to develop new business models and business environments, and engender environments that will allow all countries, rich and poor, to partner and share in diagnostic innovations and as a result improve global health for all.We need, to succeed today, where we failed, yesterday.The time is ripe—technologies have advanced tremendously in the years since the previous efforts were launched and the vision to address those issues is slowly moving. We must seize this chance.

Lecture title not confirmed

Georges WHITESIDESGeorge Whitesides Research Group - Harvard University - USA

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Session 2

Building from successfull field experiences in applied diagnostics

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TB field experiences

Fuad MIRZAYEVWorld Health Organization - Switzerland

The presentation will provide the overview of the TB diagnostics endorsedbytheWHOandfieldexperiencesimplementingsomeofthe newer diagnostics in the countries within the framework of the Expanding New TB Diagnostics Project led by the WHO and Global Laboratory Initiative together with FIND and Global Drug Facility of the Stop TB Partnership. It will also present the recent WHO policy on rapid molecular TB diagnostics and the coordinated approach to the roll out and future scale up of this technology.

Malaria field experiences

Ogobara DOUMBOMalaria Research and Training Centre - Mali

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HIV field experiences

Avelin AGHOKENGIRD - France

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Building from successful field experience: the RDTs for visceral leishmaniasis

Marleen BOELAERTInstitute of Tropical Medicine - Belgium

Access to prompt and accurate diagnosis of visceral leishmaniasis (VL) is essential for clinical prognosis and also for disease control in anthroponotic transmission areas. Treating patients on clinical presumption is inadequate, because clinical features of VL (prolonged fever, hepato-splenomegaly, anaemia and wasting) are non-specific and the chemotherapy has potentially seriousside effects. Since Leishman identified the parasite in 1901, therecommended method for diagnosis of VL has been the microscopic demonstration of amastigotes of Leishmania donovani (called LD bodies) in tissue smears or culture. Conditional on flawlesstechnicalexecution,theparasitologicaltestsareveryspecific,buttheir sensitivity varies depending on the type of tissue aspirate. Spleen tissue aspirate is close to the gold standard for diagnostic confirmation of VL as its sensitivity approaches 95% , but it isan invasive and complex technique. Spleen aspiration may be complicated by life-threatening haemorrhage in around 0.1% and therefore requires considerable expertise, as well as facilities for nursing surveillance, blood transfusion and surgery. Alternatively LD bodies can be searched for in aspirates of bone marrow or lymph nodes, with lesser sensitivity. Moreover, the accuracy of microscopic examination is subject to the ability of the laboratory technician and the quality of reagents. In 1986 a Direct Agglutination Test was developed by El Harith that was a major breakthrough as it allowed the diagnosis and subsequent treatment of thousands of VL cases in very remote areas of South-Sudan, Ethiopia, Kenya and Somalia. The diagnostic accuracy of this antibody detection test was high as shown by meta-analysis, and cost-effectiveness analysis of parasitology-based versus DAT-based diagnosis showed that the more sensitive algorithm is the preferred option in this fatal disease. More recently, antibody-detecting rapid diagnostic tests (RDT) createdanotheropportunitytosafelyandefficientlylinkdiagnosisand treatment for VL. A recombinant antigen derived from a 39-amino acid repeat in L. chagasi (rK39) proved to be very accurate in the diagnosis of VL when used in an ELISA format, and was later developed ina lateralflowformat.Since1998,severalbrandsofthislateralflowtestshavebeenstudiedindifferentendemicareasusing various study designs. Meta-analysis confirmed their highdiagnostic accuracy, though with some regional variation.

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Since 2005 these RDts have been recommended by the VL elimination initiative in the Indian subcontinent. Today there are multiple products to choose from on the market. A global comparative evaluation of commercially available rapid diagnostic tests was conducted in 2010 under leadership of WHO/TDR. Diagnostic accuracy of VL RDTs varied between the major endemic regions. Many tests performed well and showed good heat stability; however, reduced sensitivity against Brazilian and East African panels suggests that in these regions, used alone, most RDTs are inadequate for excluding a VL diagnosis. Therefore, use in combination with a more sensitive test is recommended. The results of this evaluation will be presented and the more general challenges of quality assured diagnosis by RDT in endemic regions will be discussed. Finally, the search for better VL tests is not finished. The DATand the RDTs are antibody-detection tests and suffer from two majorlimitations.Firstly,asignificantproportionofhealthypeopleliving in endemic areas with no history of VL are positive for anti-leishmanial antibodies because of asymptomatic infections. The seroprevalence in healthy population varies from below 10% in low to moderate endemic areas to above 30% in high-transmission foci or in household contacts. Therefore, antibody tests must always beusedincombinationwithastandardizedclinicalcasedefinitionfor VL diagnosis. Secondly, though antibodies decrease after successful treatment, they remain detectable up to several years after cure. Therefore, the RDTs cannot be used to monitor clinical progressorconfirmcure.Theycanneitherbeusedtodiagnoseacase of relapse of VL. Currently, R&D efforts concentrate on the development of antigen detection tests. Also, the HIV-leishmaniasis coinfections continue to pose a challenge to diagnosis.

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Diagnostics of viral hemorrhagic fever

Amadou A. SALLInstitut Pasteur de Dakar - Senegal

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Programmable bio-nano-chip sensor systems: from humanitarian to clinical applications

John T. McDEVITTRice University - USA

Clinical analysis remains one of the most important frontiers in measurement science today as an ever-increasing understanding of living systems places evolving demands on the bioanalysis laboratory. One important trend is toward miniaturized designs—for clinical systems, this can lead to medical results at the point-of-need (i.e. bedside, ambulance, pharmacies and rural locations in resource scarce settings). Medical costs consume a stageringly large fraction of the global economic output, accounting now for about 17% of the total US gross demostic product and growing at a rate of 7 to 8% each year. In African countries with only ~1% of the economic engine of the US, this problem is even more severe. Further complicating the situation is the fact that diagnostic tools, so critical to healthcare, have not kept pace with medical knowledge. Thefieldsofproteomics,genomics,andbioinformaticshaveenjoyedexplosive growth, but precious few of the biomarkers found here are translated into widespread clinical practice. More than 20,000 scientific-discoverypapersforcancerand6,000forcardiacdiseasehave been published, yet only about one biomarker per year for ALL diagnostics areas received US Food and Drug Administration approval from 1995 to 2005. Unless these biomarkers receive approval from medical regulatory bodies they can not move into widespread clinical practice. These statistics are sobering, but they also illustrates tremendous opportunity for new technologies that will enhance greatly global healthcare. Stated succinctly, today our society faces a severe technology bottleneck where we are unable to access information realted to health and wellness status, much of which is encoded in biomarker signatures. Rich biomarker data combined with microfabrication techniques can provide the means to deploy quick, affordable point-of-need diagnostics for a wide variety of ailments. Over the past 15 years the McDevitt group has pioneered the development of the Programmable Bio-Nano-Chip Sensor Systems, a universal platform that serves to extract the information content of biomakers. This platform and the information derived therefrom is now being used to establish a “biomarker highway”.

Session 3

Research & Development: new approaches in diagnostics

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Advanced diagnostic tools of this type show strong potential to impact healthcare both in developed countries as well as in resourcescarcesettingsthroughtheidentificationandmonitoringof diseases early when they are easier and less costly to treat. This presentation will feature the design, fabrication and clinical testing of the Programmable Bio-Nano-Chip Sensor technology. Also discussed here will be the use of this universal detection modality in the context of 6 major clinical trials for the areas of HIV immune function (one of the most important global humanitarian issues), cardiac heart disease (number one killer on a global basis) and three types of cancers (oral, ovarian, prostate). The ability to produce scalable and sustainable devices for use in resource poor settings by leveraging such universal platform capabilities will also be explored.

Session 3

Research & Development: new approaches in diagnostics

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Approaching high tech affordable diagnostics in low tech settings

Wendy STEVENSWits University - South Africa

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The Global Health Innovation Quotient Prize: a milestone-based prize to stimulate R&D for point-of-care fever diagnostics

Don JOSEPHBIO Ventures for Global Health - USA

BIO Ventures for Global Health has designed and is proposing the Global Health Innovation Quotient Prize (the IQ Prize), to incentivize the development of a point-of-care diagnostic platform for the diagnosis of fever in children under age 5. Such a tool would save many thousands of lives in the developing world. An open competition, funded by donor governments or other entities, would motivate engagement of the innovation and creativity of the biopharmaceutical industry for an urgent need in global health.

I. Misdiagnosed Fever is an Urgent Threat to Child Health Children brought to clinics in developing countries often present with general symptoms, including fevers that could be caused by a wide range of diseases – malaria, pneumonia and others. Clinical misdiagnoses contribute to the deaths of the nearly 3 million childrenunderfivewhoarelosttomalariaandbacterialpneumoniaeach year. The vast majority of these deaths occur in developing countries, and a significant portion could be avoidedwith timelyand accurate diagnosis. In the absence of point-of-care (POC) diagnostic tests, clinicians are unable to differentiate between all the causes of fever and cannot reliably provide the right treatment. In addition, without the aid of modern diagnostic technologies, clinicians often indiscriminately prescribe antibiotics. This trend has led to dangerous increases in antibiotic resistance.

II. A Point-of-Care Fever Diagnostic Could Save 350,000 Lives Annually BIOVenturesforGlobalHealth(BVGH)isanon-profitorganizationthat works to save lives by enabling the biopharmaceutical industry to engage in global health R&D. BVGH consulted with more than 100 leading global health and industry stakeholders to identify a POC diagnostic that could help prevent the misdiagnosis of fever. A POC diagnostic that could test for a range of diseases and differentiate the causes of fever could save the lives of hundreds of thousands of children in developing countries. BVGH estimates that such a diagnostic could reduce pediatric pneumonia deaths by up to 20%, potentially saving more than 350,000 lives per year. Despite the immense need for a POC fever diagnostic, industry investments to develop such products remain limited, largely due to alackofattractivemarketsandfinancialreturns.

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III. IQ Prize OverviewBVGHhas designed the IQ Prize, a ‘pay-for-success’, milestone-based prize to help address this challenge. This innovative approach willreimburse and rewardspecific milestones along theproduct development process (as opposed to an end prize only). The anticipated result of the IQ Prize is the development of two effective POC fever diagnostic products developed by separate biotechfirmswithin8years.Inordertoberewardedwithmilestonepayments,thetargetproductprofilewillrequireproductswhicharelow-cost, portable, simple to use and durable enough to withstand resource-poor environments. BVGH is seeking donor commitments to fund a prize competition that would lead to development of these diagnostics. It would make a particularly large impact in sub-Saharan Africa and India, where preliminary modeling indicates that up to 220,000 and 175,000 lives, respectively, could be saved.

BVGH developed the IQ Prize through consultations with more than 100 leading stakeholders, including diagnostic companies, biotechnology investors, global health leaders, clinicians in low-resource settings, and academic experts. A high-level industry working group was convened to validate the prize structure as well as key assumptions in the financial analysis. Using recognizedinflection points in diagnostic development, upon successfulcompletion of milestones, financial awards would bemade. Theend result would be two separate approved products meeting the targetproductprofile.

IV. The IQ Prize Can Encourage Additional Global Health R&D in the Future The IQ Prize can deliver significant value-for-money to donors,engage the biotech sector in global health R&D and produce products thatcanbringsignificantbenefits todevelopingcountryclinicians. There is a significant need for a wide variety of newdrugs, vaccines and diagnostics needed to meet developing country health needs. BVGH believes that milestone-based prizes are an innovative strategy to help industry meet these needs, and bring life-saving new products to those most in need.

Resistance testing

Ronald BALLARDCDC - USA

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New approaches at the reference laboratory level: pathogens identification

Jean-Noël TELLESFondation Mérieux - France

Recent advances in molecular technologies have revolutionized clinicaldiagnostics.Newdevelopmentsinthefieldsofnucleicacidsextraction, nucleic acids amplification anddetection havegreatlyimprovedthepathogensidentification.Theautomationfornucleicacid extraction allowed to process batches of clinical samples and to obtainreproduciblehighyieldofpurifiednucleicacidsfromanykindof clinical samples. The combination of the PCR multiplexing and the newly developed multi-detection technologies allow to identify multiple pathogens from a single clinical sample and to perform a syndrome based diagnostic in a single run .The integration the nucleicextraction,amplificationanddetectionstepsinasingle.

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Meeting the challenges of point-of-care: a rapid p24 antigen test for diagnosis of acute pediatric HIV infection

Arman NABATIYANNorthwestern University - USA

The need for point-of-care technologies is highlighted by the growing ratesofinfectiousdiseasessuchasHumanImmunodeficiencyVirus(HIV), pneumonia and mycobacterium tuberculosis in the developing world, and influenza and sexually transmitted diseases in thedeveloped world.Currently, the majority of HIV infected infants are found within limited-resource settings where inadequate screening for HIV, due to the lack of access to simple and affordable point-of-care tests, impedes implementation of anti-retroviral therapy. I report on our team’s development of a low-cost dipstick p24 antigenlateralflowassaythatcanfacilitatethediagnosisofHIVforinfants in resource-poor conditions. A heat shock methodologyand corresponding instrument for implementation were developed to optimize disruption of immune complexes present in the plasma of infected infants.Amembrane-based filter device for rapid andefficientcollectionof≥25µLplasmafrom80µLofheel-stickwholeblood was also developed for use with our heat shock p24 assay. The analytical sensitivity of the assay using recombinant p24 antigen is 50pg/mL (2pM) with whole virus detection as low as 42.5k RNA copies/mL plasma. In a blinded study comprising 51archived infant samples from the Women and Infants Transmission Study, our assaydemonstratedanoverallsensitivityandspecificityof90%and100% respectively. Infieldevaluationsof389freshsamples fromSouthAfricaninfants,asensitivityof95%andspecificityof99%wasachieved. The assay is simple to perform, requires minimal plasma volume(25µL)andyieldsaresultinlessthan40minutesmakingitideal for implementation in resource-limited settings.At present we are in the process of pilot manufacturing 10,000 assay test strips and plasma separator devices and 80 beta-units of the heat shock instrumentforfieldevaluationoftargetpediatricspecimensatsixsites across Africa within the coming year.

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Lecture title not confirmed

William RODRIGUEZDaktari - USA

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Point-of-care molecular diagnostics

Ellen Jo BARONStanford University - Cepheid - USA

The Cepheid GeneXpert® combines complex sample-processing steps with PCR amplification and real-time target detection in asingle sealed cartridge. Quantitative results are also possible when suitable internal controls are included. By simplifying the pre-ampli-ficationsteps,concentratingspecimenstomaximizetheavailabilityof target sequences, conducting dozens of precision pipetting steps inside the cartridge, controlling for contamination, and utilizing a unique modular platform design, PCR is made as easy and rapid as possible.Newconfigurationsmakeworkinginanaustereenviron-ment even easier, facilitating the concentration of highly skilled indi-viduals in larger referral laboratories, where they are more likely to be retained and where their expertise can be used to perform more complex tests that are not yet fully automated. Xpert® systems are already running on solar power, and mobile van applications are indevelopment.Thecartridgedesigncanbemodifiedtosuitdif-ferent sample types and targets, including RNA and DNA, bacterial cells, spores, intracellular pathogens, and enveloped and non-en-veloped viruses, which leverages the already widespread installed instrumentbase.MTB/RIFandInfluenzaassaysareneededandalready available for use in Resource Limited areas. Other assays to be developed over the next 5 years that are also relevant in this setting include Chlamydia/Neisseria gonorrhoeae, HIV viral load, Vaginitis, Hepatitis B and C quantitative viral assays, and HPV.

Speakers Avelin Aghokeng IRD

Emerging diagnostic technologies: nano/microfluidics technology

Robert S. MARKSBen Gurion University - Israel

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Speakers Avelin Aghokeng IRD

France

Ronald Ballard CDC USA

Ellen Jo Baron Stanford University - Cepheid USA

Marleen Boelaert Institute of Tropical Medicine Belgium

Niel Constantine University of Maryland USA

Jean François de Lavison Ahimsa Parners France

Ogobara Doumbo Malaria Research and Training Center Mali

Joseph Fair Global Viral Forecasting USA

Keith Klugman Emory University USA

Robert Marks Ben Gurion University Israel

Souleymane Mboup University Cheikh Anta Diop Senegal

John McDevitt Rice University USA

Alain Mérieux Fondation Mérieux France

Fuad Mirzayev World Health Organization Switzerland

Arman Nabatiyan Northwestern University USA

Rosanna Peeling London School of Hygiene & Tropical Medicine England

Ann Reid American Academy of Microbiology USA

William Rodriguez Daktari USA

Giorgio Roscigno FIND Diagnostics Switzerland

Amadou A.Sall Institut Pasteur de Dakar Senegal

François Simon APHP France

Wendy Stevens Wits University South Africa

Participants

Speakers

Jean-Noël Telles Fondation Mérieux France

Oyewale Tomori Redeemer’s University Nigeria

Jan Van Erps WHOSwitzerland

Gene Walther Gates FoundationUSA

Georges WhitesidesGeorge Whitesides Research Group - Harvard University USA

Participants

Eric AdamFIND Switzerland

Isabelle Andrieux Meyer MSF Switzerland

Alexandra Ascorra Solthis France

Anne Betrand bioMérieux France

Michel Bonnier bioMérieux Brasil SA France

Emilio Brignoli bioMérieux Brasil SA Brésil

Pau Bruguera Biokit Company Spain

Larry Buck ASM LabCap International USA

Joe Campos Children’s National Medical Center USA

May Chu CDC USA

Cecil Czerkinsky IVI Seoul

Valérie d’Acremont Global Malaria Programme - WHO Switzerland

Emmanuel de Guibert IM ACCESS France

Quentin de La Barre Mérieux Développement France

Philippe Deloron IRD France

Corinne Ducournau Institut de recherche biomedicale des armées France

Jean-Francois Etard MSF France

Olivier Flusin Institut de recherche biomedicale des armées France

Blaise Genton Swiss Tropical and Public Health Institute Switzerland

Iveth Gonzalez FIND Switzerland

Michel Goudard IM ACCESS France

Philip Gould Liverpool School of Tropical Medicine UK

Giovanni Guidotti DREAM Italy

Dhalia Gutemberg IVD Trade Association Brazil

Participants

Cristina Gutierrez FIND Switzerland

Eva Harris Berkeley University USA

James M. Hughes Emory University USA

Vibol Iem Fondation Mérieux Laos

Mike Ingerson-Mahar The American Society for Microbiology USA

Jeanne Jordan Public Health & Health Services The George Washington University - USA

Don Joseph BIO Ventures for Global Health USA

Kekeletso Kao FIND Switzerland

Cara Kosack MSF The Netherlands

Thomas Kozel University of Nevada USA

Rebecca Lackman Grand Challenges Canada

Marc Leportier IM ACCESS France

Christophe Longuet Fondation Mérieux France

Aatish Madhiwala Premier Medical Corporation India

Larry Madoff Massachusetts Department of Public Health USA

Neil Mehta Premier Medical Corporation India

Claude Moncorgé OPALS France

Francis Gabriel Moussy WHO Switzerland

Paramasivan Chinnambedu Nainarappan FIND Switzerland

Berthe Marie Njanpop Agence de Médecine Préventive France

John Nkengasong CDC USA

Anne-Laure Page Epicentre France

Tikki Pang WHO Switzerland

Debadatta Panigrahi Colleges University of Sharjah Sharjah

Participants

Participants

Mark Perkins FIND Switzerland

David Perlin Public Health Research Institute USA

Valentina Picot Fondation Mérieux France

Pau Planas Biotik - Werfen Group Spain

John Ridderhof CDC USA

Teri Roberts MSF Switzerland

Nicolas Steenkeste Fondation Mérieux Cambodia

Imamus Sultan DG Grameen Healthcare Bangladesh

Rob Taylor Bill & Melinda Gates Foundation USA

Richard Willson University of Houston USA

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