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A novel immunity-based test for early diagnosis of Lyme disease

Periodic Reporting for period 3 - ID-Lyme (A novel immunity-based test for early diagnosis of Lyme disease)

Reporting period: 2018-07-01 to 2019-06-30

The ID-Lyme project, that started in July 2016, was all about making a novel test for the early detection of Lyme borreliosis. Lyme disease (Lyme borreliosis, LB) is the well-known infectious disease caused by Borrelia bacteria. The bacteria are transmitted by ticks from the Ixodes genus. The disease is highly prevalent in Europe. LB can be treated using cost-effective antibiotics, at least when discovered at an early stage of disease. When untreated, patients may suffer from many serious effects, including paralysis, damage to joints, heart, and nervous system. Due to difficult diagnosis, in many cases damage has already occurred before finding out what caused it.
Standard laboratory testing is often unable to give a clear answer to whether a patient has been infected or not, and whether the bacterium is still alive or not. The result is that a true infection may remain untreated, which is a significant health care concern because of the disabling effects. In later stages, diagnosis becomes more difficult and treatment more expensive and less effective. Inadequately treated LB is a significant health and economic burden for society.
With ID-Lyme, the EU has funded a four-year project that aims to deliver to the market a diagnostic test based on cell-mediated immunity (CMI) that can identify LB infections in the early stage prior to the onset of symptoms. This would enable focussed LB managemen, improve patient health outcomes and reduce LB-related healthcare costs. A better Lyme borreliosis test would have significant impact on EU healthcare and society, as currently over 2.6 million tests are performed in the EU each year on people suspected of a Borrelia infection.
The main challenge of a cell-mediated immunity test is that the test has to be performed within 12 hours from the time of blood collection. This is a logistic challenge and makes such tests very expensive and unreliable if the timelines and transport conditions are not met. To overcome this challenge, the ID-Lyme test should be performed close to the point of blood collection. For the new product, we envisaged a Point of Care device that can be sent out to the end-user. This could be a GP's office or a small diagnostic lab. Even large labs would benefit if they perform a limited number of tests per day.
In the reporting period the team came to the conclusion that a CMI test is insufficiently able to distinguish between infected and non infected individuals. Despite troubleshooting efforts Innatoss was unable to convincingly show the benefit of this approach. However disappointing, this is important information for the community since CMI tests are often claimed to outperform the classical serological tests.
In the process of designing a test for Lyme borreliosis the team developed the WOLF device that is able to be used close to point-of-care. As such the device will overcome the logistic hurdles of CMI tests in many applications including tuberculosis. The team also developed sensitive immunoassays that can be used in conjunction with such tests. During the final year of the program, the aim is to bring both the WOLF device and the immunoassays to the market.
During the first year, the consortium discussed the pros and cons of Point of Care Lyme tests with potential end-users. The conclusion was that a true Point of Care test would not be needed but that at least the first step should be close to point of blood collection. We started a Health Technology Assessment to quantify the economic burden and potential benefits for patients and society and looked at reimbursement options in the Netherlands, Sweden, Germany and Austria.
Technically, a vast amount of work was done to design and develop a technical device that would be able to perform the first step of the test close to Point of Care. In this step a blood sample is brought in contact with Borrelia proteins (antigens). We investigated the optimal antigen mixture to be used for the test and looked at stability and the storage conditions. Production of the Borrelia antigens was optimized and reproduced so we will be able to manufacture the kits once all components of the kit areready.
For analysis of the relevant biomarkers, several methods are available. The consortium is currently comparing 3 methods, looking at sensitivity and, importantly, costs, so we will be able to make the ID-Lyme test affordable to many people. Stability of reagents is tested and interference with blood components.

During the second year, the optimal mix of antigens to be used for the test was investigated by running a study on patients with an EM (Erythema migrans: the well-known red ring that becomes visible in Lyme-infected people). The design of technical device to help perform the first step of the test was completed. In addition, from the 3 methods investigated to perform the actual analysis of the blood, one was selected that proved to be sufficiently sensitive and reproducible. Potentially, this analysis method could also be used for analysing blood samples from diseases other than Lyme Borreliosis. In consultation with the EU, the activity period for the consortium was extended from three to four years. This is often necessary for projects that involve a clinical trial, since it is often difficult to attract a large enough number of patients in a short period to give statistically meaningful results.
The ID-Lyme consortium has designed and developed an innovative device that will make cellular immunity based testing more accessible to Lyme patients and their doctors. The project was delayed and the device is currently being manufactured in order to be ready for the Austrian Tick season of 2019 during which the performance of the ID-Lyme device will be clinically tested. The target launch of the ID-Lyme test has been planned for 2020.
With the new test available, it will be possible to decide in an early stage whether patients are indeed infected, so they can receive timely treatment, and which patients did not get infected after being bitten by a tick . Over-treatment with antibiotics can thus be avoided.
Initial concept of the ID-Lyme kit