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"Early detection of HIV-1 using ultra-sensitive, rapid capacitive biosensor"

Final Report Summary - CAPHIV (Early detection of HIV-1 using ultra-sensitive, rapid capacitive biosensor)

Executive Summary:
The big challenge successfully solved within the CapHIV project is certainly the step to transfer a promising biosensor concept from a lab-set to a full automated easy and safe to use Point-of-Care application. This is the step where most novel biosensor technologies fail, and in-spite of the sensational results they never leave the lab.
The CapHIV project managed exactly this step thus put with this the high-sensitive label-free biosensor technology of CAPSENZE (SME) miles ahead of the concurrent label-free biosensor concepts.
CapHIV is aimed to be a Point-of-Care diagnostic device for HIV screening, providing a result in less than an hour. The CapHIV project had two main research focuses to fulfill this need. On the one hand, the improvement and optimizing of the sensor stability to be able to manage the harsher conditions to be expected outside the lab. On the other hand, a Point-of-Care application requires easy-to-use and ease of maintenance, i.e. the ease of replacement of consumed parts of the sensor, as well as a maximum on biological safety for the user, allowing use outside controlled laboratory environment even in case of highly infectious blood samples.
In the CapHIV project the consortium developed a full automated hermetically sealed biosensor system which automatically resealing fluidic connections to the disposable replaceable parts of the sensor system, i.e. the sensor cartridge and reagent vessels. While the developed measurement control system provides an easy to use graphical user interface.
The plug-and-play type sensor cartridge and the set of required reagents can serve up to 100 measurements. The system was also extended with automated sample preparation, working directly for the fully sealed standard vacuum blood taking tubes. Thus the CapHIV device can be safely used at any general practitioner or nursing site.
A pre-validation was successfully performed. The partners are entering now the clinical validation and approval phase.

Project Context and Objectives:
One of the greatest challenges facing the HIV/AIDS research community today is the need to produce a definitive, low-cost, accurate and portable diagnostic system. Increasingly, the pandemic is affecting nations within the EU and the European Economic Area (EEA). World Health Organization (WHO) figures estimate that worldwide, 34 million people are living with HIV and 820,000 of these people live in the EU.

In theory, a rapid test would give a positive or negative indication within an hour. However, as things stand, laboratory confirmation is necessary and takes between two weeks and months. Unfortunately, current standard nucleic-acid-based tests (NATs) can deliver a false negative result during the most acute phase of the infection, which occurs during the first few weeks after exposure. This is the point at which an HIV sufferer is at his/her most infectious phase. For those who have been recently exposed, the waiting only prolongs the misery. The aim of researchers now is to reduce false negative test results during this window.
Polymerase chain reaction (PCR) blood test can be conducted to search for the virus itself rather than antibodies. But PCR testing in isolated rural areas is labour-intensive and time-consuming.

The CapHIV consortium aims to address the need for lower costs in the diagnosis and treatment of HIV and AIDS. Rather than concentrating on the presence of antibodies, the CapHIV system targets the conserved viral capsid protein, p24 antigen, looking for extremely low levels in plasma samples. CapHIV is based on an innovative high sensitive capacitive biosensor technology that CapSenze – the Swedish company behind the CapHIV project –making the need for biological amplification obsolete. This, combined with the smaller window for the targeted p24 antigens, results in a rapid, effective diagnosis.

The CapHIV concept is based on the affinity-binding of the target protein p24-specific anti-p24 antibodies attached to the sensor surface. Via the developed flow-injection system, blood samples can be consecutively analysed, which makes the technique highly suitable for screening purposes. The new technology aims to give an accurate result in 30 minutes, which could then be delivered to the patient in a point of care location.

CapHIV is aimed to be a portable Point-of-Care type screening device suitable for field use in both the inner city and rural Sub-Saharan Africa. Unlike NAT devices, CapHIV reflects its purpose as a low-labour intensive, non-time consuming solution to testing in challenging environments. The system is hermetically sealed. All consumables, as well as the biosensor itself can be changed in a plug-and-play manner. The whole system is controlled though an integrated touch screen, providing and easy to use graphical user interface. A set of consumables is planned to serve the testing capacity of a disposable biosensor cartridge which is aimed to be used in up to 100 tests.

It is hoped the system can offer low cost screening of about €10 per test, with the device priced at around €30,000. The projected costs are aimed at eventually supplying hospitals in the developing world.
The consortium also foresees new challenges emerging for its device, as it might rapidly be adapted for use in detecting other infections as new pandemics arise. In addition, the device could be used to test water supplies for infectious diseases such as cholera and to detect poisons used in biological terrorist attacks. This will create continuous new markets for SME partners.

European CE marking for IVD medical devices, as well as US Federal Drug Administration (FDA) approval is vital in opening up the market for CapHIV and the device is on course to be available internationally, having passed the rigorous first assessment. Successful results have emerged from laboratory tests; the challenge now is to gain validation via on-site praxis.

Project Results:
CapHIV is based on the innovative and high-sensitive capacitive biosensor concept owned by the SME CAPSENZE. The CapHIV project had two main research focuses with the aim to bring this novel biosensor technology from the lab to a marketable application by:
(1) Improving and optimizing the sensor stability by developing means to prevent non-specific binding, as well as by optimizing the measurement process.
(2) Building an automated easy-to-use Point-of-Care suitable device around the biosensor, which can be operated outside a lab environment.

As a result of the surface chemistry optimization the sensor can now directly manage whole blood samples in a diluted form without the need for any special sample preparation. The now required 1000 fold dilution is handled automatically by the device, thus the operator just needs to place the blood sample as obtained from the patient by the state-of-the-art fully closed vacuum tube technique. It is considered as one of the greatest achievements of the project that the non-specific binding could practically be eliminated, even at dilution factors as low as 1000 even with whole blood. In case of serum acceptable results could be achieved even at a dilution factor of 100.

The other half of the project focused on device development, with following main results:
a) Hermetically sealed disposable sensor cartridge, containing only the consumed part of the sensor, namely the sensing electrode functionalized with the antibodies.
b) A cartridge docking unit with specially developed interfacing to the cartridge, ensuring fluidic connection and all required electric connections in an all times hermetically sealed way.
c) Innovative double electrode needle.
d) plug-and-play rack for consumable reagents and calibration fluids
e) A stylish housing including all supportive hardware (pump, valve, thermostat, degasser) and electronics components (power supply, control boards, RFID reader)

In addition to the original objectives also an own auto-sampler has been developed for CapHIV, as the consortium could not find suitable OEM auto samplers on the market. In connection with the CapHIV device the auto-sampler enables automated sample dilution, which is the only required sample preparation step. The autosampler is designed to handle standard fully sealed blood taking tubes, and also comlies to the target to operate though out the process in a hermetically sealed way.

Within the project 4 final prototypes have been build, which are ready for clinical validation in the upcoming CapHIV-DEMO project. The CapHIV system has been pre-evaluated using whole human blood, infected in-vitro with HIV. CapHIV has been compared to current gold-standard.

Potential Impact:
According to a recent report by the WHO, there are more than 33.3 million people living with HIV worldwide. Of these, around 30.8 million are adults and 2.5 million are children under the age of 15. Women account for just over half of all adults living with HIV worldwide. Since 1981, almost 30 million people have died from AIDS, a figure that is increasing by approximately 1.8 million annually. Approximately 2.6 million people are newly infected each year. About 97% of these new infections occur in low- and middle-income countries. Young people less than 25 years old account for nearly half of all new HIV infections, and 71% of these cases occur in individuals between the ages of the 15 and 24 years. AIDS is the second most common cause of death among 20- to 24-year-olds. However, the overall growth of the epidemic has stabilized in the past ten years. The percentage of adults living with HIV has stayed fairly constant since 2000 and hovers around 0.8% of the global population.
The global market forecast for HIV testing, which includes both diagnostic assays and HIV-monitoring assays, is projected to grow at of 21% from $1.7 billion in 2011 to $4.4 billion by 2016. Worldwide HIV screening, which include traditional ELISA and rapid EIA tests, and confirmatory diagnostic tests are expected to increase from $1.3 billion to $3.6 billion in 2016.
The socio-cultural situation in many African and South-American countries is complex due to a large population of diverse cultures, and many social practices lend themselves to high transmission rates of infections such as HIV. Nigeria has a population of approximately 134 million and is divided into almost 400 ethnic groups. The socio-cultural factors in this country include polygyny, marital instability and remarriage, prostitution, and domestic violence. Other socially-accepted practices such as scarification, skin piercing and incision operations including circumcision allow for high transmission rates of HIV. Even the best surveillance systems and treatment options cannot limit the spread of HIV in such scenarios. The HIV prevalence rate has risen in Nigeria because of these factors. In 1987, it was less than 0.1%, but it rose to 5.8% in 2001. In 2007, the incidence rate had dropped somewhat to 3.1%. Educational programs to provide Nigerians with information on HIV and its mode of transmission have been implemented, and perhaps are contributing to the reduction in incidence rate.
In order to be able to successfully answer the above described trends, capHIV partners think that the main target countries shall be Africa and South-America. In these countries it is a typical phenomena to offer blood tests which have generally adequate accuracy to pass local regulatory requirements. The tests are often marketed at very low prices to the end-user, such as those for detection of HIV-2. Sales in South America and Africa have to be based on the idea that in these countries there are very few laboratories of specific analysis and logistic and distributor resources are even more scarce. Therefore centralizing analysis is really difficult and need of a POC (near patient) is very necessary.
South-American countries do not have a very high incidence of HIV infection but it is increasing. Considering that these are developing countries and that in many of these countries specific national programs are being implemented to detect HIV infections (including in pregnant mothers) to prevent infection to increase, a detection device to avoid new cases can be a very interesting tool. These are quickly developing countries, and therefore price (which in its first version will be may a little high and therefore a problem in some countries) will not be a limiting factor.
In Africa (except South-Africa) price could be a limiting factor. capHIV will seek to establish a market niche in the point-of-care (PoC) HIV diagnostic. In this segment currently only lateral flow test exists as a concurrent product, which however are no match in sensitivity. Similar to these tests, capHIV would also be able to operate from one drop of fingertip blood.
A second market segment envisaged would be the high sensitive screening/testing of first time blood donors by blood banks providing a significant price advantage against the concurrent PCR method. Currently there is a tendency to use high sensitivity methods (i.e. PCR) in case of blood donors who are not yet in the data base, however this initiative is currently limited by the extremely high cost of PCR tests. The PCR method is classically used only for confirmation tests.
However and considering that early detection is a key factor to low cost of future treatment (not only of AIDs but also for tuberculosis), implementing and early detection could reduce future costs, like the solution that the capHIV project offers.
The primary project result of capHIV is a pre-competitive prototype that was crafted by the RTD partners to provide an innovative, accurate and user -friendly measurement device to the participating SME partners that is able to detect HIV-1 using an ultra-sensitive, rapid capacitive biosensor, targeting the market of blood banks, clinics and point of care facilities. Based on the final results, capHIV SMEs intend to break into the HIV-detection measurement market in Europe which is estimated at several billion EUR. Thus the consortium SMEs that cover the full supply chain want to take an advantage of early market penetration and outrun the existing competition. Since capHIV is a long-term investment, the partners have analysed the benefits they expect to receive from a business perspective and based on identified exploitation opportunities, a consolidated business plan was set-up following a conservative approach. It was agreed between the SME partners that CAPSENZE will be the exclusive producer of the device and the cartridges. They will manufacture the instrument with the involvement of third party suppliers. The separate components in the device (except the measuring card) will be produced by external suppliers which are all per se CE marked, while antibody production and delivery, marketing and service are split between the partners. As manufacturer, CAPSENZE intends to verify that the capHIV product complies with all relevant essential requirements, e.g. safety, health, environmental protection requirements, of the applicable directives. In addition, in compliance with the directives, CAPSENZE intend to have the capHIV device examined by a notified conformity assessment body. This, in order to have the device assessed before being placed on the market and thereby satisfy the legislative requirements (harmonized level of safety). CAPSENZE (as a manufacturer) will pay to each partner a royalty of 2% of the net ex-works selling price after each capHIV device and capHIV cartridge kits sold. In case the cartridge or the autosampler technology developed within capHIV is used for non-capHIV purpose then CAPSENZE (as owner of the capHIV hardware technology) pays to the each partner a royalty of 2% net ex-works selling price for each given part. Sale or licensing of the rights obtained in capHIV by any of the partners is subject to the agreement of the other partners. CAPSENZE will provide the prototypes free of charge for use in the DEMO-capHIV project allowing each partners to fulfill its dedicated tasks. PHENOSYSTEMS will maintain (upgrades) and sell the capHIV laptop-software to CAPSENZE who is marketing and selling it together with the capHIV device. PHENO will grant after each soled software license a royalty of 15% to CAPSENZE (covering the marketing costs) and 2% each to ABBCN and LIO. PHENO will provide maintenance contracts to the clients and will offer special development services to the customers.

LIONEX will produce the p24 antigen and antigen based reagents for the capHIV system. ABBCN will have production rights of the antibodies developed in the capHIV project. ABBCN will pay to LIONEX a royalty of 2% net ex-works selling price of the antibodies. If for any reason ABBCN is persistently unable to produce the antibodies then the production rights are transferred to LIONEX. In such case LIONEX offers the same royalties to ABBCN. ABBCN will market the capHIV product using its logistic team, knowledge of South American market (Argentina, Brasil and Chile at present). ABBCN has the legal authorization to perform this task. In these markets ABBCN is already active and distributes its products to companies and hospitals for research. Each result owner has the right to use its own foreground, including licencing to third parties, but the agreed conditions on the royalties are applicable to any of these third parties. Each partner is responsible for that this agreement is fulfilled by its third party, unless otherwise agreed by all concerned partners. All partners have the right to use the capHIV device for their own purposes within their own laboratories. All partners can get device(s) at production price from CAPSENZE after the closure of the project. The partners intend to generate data and submit the documentation which is necessary for obtaining the CE Mark in the DEMO-capHIV project (selected for funding and under negotiation), which is pre-condition for commercialization. The planning of production, industrialization and marketing plan is scheduled within the DEMO project in light of the clinical validation results.

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