Public Funding for Mologic LTD.

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The current SARS-CoV-2 pandemic has highlighted the need for access to rapidly produced, reliable diagnostics with the required sensitivity and specificity at a cost that makes these widely accessible to lower and middle income (LMICs) as well as higher income countries. Protein based diagnostic development and manufacture is reliant upon the availability of key protein based reagents that are critical components of these tests. Such tests may need to be manufactured in their millions to billions a year and thus a secure and sufficient supply of authentic and low cost protein reagents is required. For example, for a simple Malaria lateral flow test, 3 different protein reagents are required in 10-500 mg quantities per million tests with an anticipated need of 400 million tests per annum. Some of these reagent proteins must be made in cultured mammalian cell systems to be correctly folded, assembled and modified in order to ensure they can function with the highest possible specificity and sensitivity in diagnostics. Although there are some protein reagent expression systems for production of recombinant proteins from mammalian cells commercially available, these have been refined and developed largely for the expression of high-value proteins to use as drugs to treat a range of diseases and conditions. Access to such systems involves prohibitively high costs that in turn make the use of these essential reagent proteins to manufacture diagnostics in the necessary high volume problematic. There is thus a massively unmet need in terms of access to mammalian cell recombinant protein reagents at a cost that allows their application into commercially viable diagnostics. The project described here will establish technologies, knowhow and systems within a leading UK diagnostics company, Mologic, for the rapid production of recombinant protein reagents in cultured mammalian cell systems, at sufficient amounts, quality and cost to be viable for application into low cost rapid diagnostics for distribution in both developed and developing countries. This will secure reagent provision for development and manufacture of diagnostics and also provide the ability to generate new essential protein reagents swiftly in response to current and emerging needs at a cost that allows their application into diagnostics.

This project addresses the need for new vaccines for global epidemics by the development of a virus-like particle (VLP) based platform technology to deliver a vaccine against Q Fever. The causal agent of Q fever, Coxiella burnetii has been identified as an agent of concern due to its low infectious dose, the ability of the organism to survive for long periods in the environment and cause significant outbreaks in both humans and animals. Outbreaks of Q fever are recorded in humans and animals on an annual basis, worldwide. Acute infection with C. burnetii usually presents as a self-limiting febrile illness often accompanied by severe headaches and in severe cases atypical pneumonia occurs. Chronic disease, typically presenting as endocarditis, occurs in approximately 5 % of cases and without treatment is usually fatal. Formed of the proteins that assemble to form the viral structure such as the capsid or envelope, a VLP mimics an invading virus but is unable to infect and cause infection as it does not contain the necessary genetic code. When used for immunisation, VLPs are recognised as foreign agents and the densely packed arrangement of antigens on the surface of the particles elicits a strong immune response. Mologic have developed a derivative of the Hepatitis B virus core VLP which allows the attachment of unrelated antigens, for example from other viruses or bacteria, to the surface of the particle such that they are displayed to the immune system with the same immunogenic characteristics as a whole virus. The SBRI funding “New vaccines for global epidemics: development and manufacture” has allowed further exploitation of this VLP technology using the causal agent of Q Fever (Coxiella burnetii) as a target and enabled collaboration with experts from Dstl, PHE and Iceni Diagnostics, without whom the project would not have been feasible. The consortium now wish to further develop the technology to test the efficacy of candidate vaccines against challenge with Coxiella burnetii. This will allow us to identify the most effective candidates for scaled up production and further studies to determine optimal formulations and dosage. The phase 2 study will fund the development of the vaccine platform to a stage that it is ready for commercialisation, manufacture and GLP pre-clinical testing.

COPD is the second most common cause of emergency admissions in the UK, responsible for one in eight (130,000) acute adult medical admissions. It is a global problem, with 210 million sufferers and 3 million deaths annually (WHO, 2009). There are 1.2M COPD patients in the UK. Patients with COPD have daily symptoms, a poorer health status, reduced exercise capacity, and impairment in lung function. The symptoms can deteriorate rapidly in response to infection or pollution. The acute and sustained worsening of the symptoms is termed an acute exacerbation of COPD. In the UK COPD exacerbations account for 15% of all medical admissions, 1 million bed days and an annual NHS expenditure of £500M [NICE 2010]. Mologic has developed two products for patient stratification. These are simple urine based tests similar to the familiar home pregnancy test kits. The first test Headstart will clearly identify or confirm the first signs of exacerbation with sufficient reliability and clarity for the patient to know when to take medication and when to seek medical attention. The second product is Rightstart, for use at home or in primary care to identify whether to use antibiotics or corticosteroids. Early identification of COPD exacerbation has the potential to reduce the severity of exacerbations by allowing faster treatment and reducing the need for GP and emergency visits to A&E. Use of Rightstart to identify the cause of the exacerbation helps ensure the correct treatment is given and also has the potential to reduce unnecessary antibiotic treatment which supports the UK governments strategies for Antimicrobial Stewardship. This project will conduct clinical trials of the Rightstart and Headstart products in conjunction with clinical experts from the Respiratory groups at Leicester Hospital and Prince Philip Hospital. The design of these trials and analysis of the results is being assisted by the Diagnostic Evidence Cooperatives (DEC) and Academic Health Science Networks (AHSN) at Oxford and Newcastle. They have developed healthcare economic models to assess the potential benefits and costs savings to the NHS from the use of Headstart and Rightstart and will use the results of the trials to further update and refine their models. In addition, they will also work throughout the project to help identify the best ways to integrate these products into existing care pathways within the NHS. Because COPD patients have multiple points of contact with the NHS including their GPs, respiratory specialists in hospital based clinics, Out of Hours Services and A&E it is important to be able to integrate and provide education on the product across a broad range of clinicians and locations with the NHS. To gain support for the product's use requires the ability to demonstrate the patient value and cost saving potential to both Clinical Commissioning Groups (CCGs) who make decisions on the Care pathways for COPD and the Prescription Pricing Agency which decides which diagnostic tests are available for prescription by GPs. The AHSN and DEC groups at Oxford and Newcastle will be providing the expertise and analysis required to support the adoption of the product by both CCGs and clinicians. In addition, patient support groups including the British Lung Foundation and Breathe Easy will be engaged to provide ongoing patient perspective and support the education and training on the products.

Reducing fungal fruit rot is a priority in strawberry production in the UK; annual economic losses due to fungal rotting are usually between £30 to £60M. Rot is mainly caused by Botrytis cinerea, Mucor spp. and Rhizopus spp., with their relative prevalence varying over time and growing site. Most strawberry production in the UK is under protection where the risk of fungal rot largely depends on the pathogen inoculum strength, and availability of susceptible tissues. Accurate risk prediction, and hence effective control of fruit rotting, is hampered by the difficulties in accurate and fast quantification of inoculum strength. This project will develop a device for semi-automatic quantification of multiple airborne strawberry pathogens and establish the relationship of both pre- and post-harvest rot risks with the quantified inoculum level. This will extend the marketable shelf life of individual strawberry lots and reduce fruit waste due to fungal rotting.

Sepsis is one of the most common deadly diseases and one of the leading causes of death in the developed world exerting a huge human and economic toll. In the UK there are over 100,000 cases and 37,000 deaths annually. Rapid diagnosis is critical to the effective treatment of the patient and offers the prospect of reduced mortality but existing diagnostic tools lack the sensitivity and/or specificity needed for effective stratification of sepsis to enable early, effective treatment. Mologic is developing an easy-to-use, 10 minute lateral flow based assay that can be used in hospital A&E, wards and intensive care units by bedside nurses to provide rapid discrimination of sepsis. This will enable faster treatment, stratification of patients by degree of risk into appropriate care areas, and financial savings in hospital systems by both reducing complications and overtreatment. The single use cartridges will be compatible with a sample of whole blood which could be obtained from a fingerprick or a venous blood sample.

Virus-like particles (VLPs) are a flexible delivery platform that provides potential for presenting multiple antigens to the immune system concurrently. Hepatitis B core antigen self assembles to form highly stable, immunogenic VLPs in a relatively low cost yeast expression system. The viral protein can be adapted to display foreign antigens on spikes that protrude from the surface of the VLPs. This technology circumvents the need for high cost, high containment production facilities, cold transportation and storage. Our goal is to produce a cost effective, second generation Q fever vaccine, using VLP technology as a production platform. In initial proof of concept studies, the Mologic-Dstl-Iceni Diagnostics consortium has successfully produced and tested Burkholderia pseudomallei vaccine candidates based on yeast-produced VLPs presenting either peptide or polysaccharide antigens. These candidates were efficacious in a mouse model of Melioidosis, demonstrating the readiness of this technology for roll out for antibacterial vaccine production. In the current proposal, we will consolidate and extend our work on this platform, applying it to Coxiella burnetii, the causative agent of Q Fever, which is listed as an agent of concern by the WHO and UN. Q fever is found worldwide and there is high prevalence in low income countries. This VLP platform bid will draw on expertise in Coxiella burnetii antigenicity to develop a vaccine against Q fever. It has been shown that C. burnetii lipopolysaccharide (LPS) provides protection against challenge, indicating that it is a key protective antigen. LPS itself is a T-cell independent antigen; conjugation to a protein carrier can improve antibody isotype development and crucially stimulate B cell memory. Therefore, to increase vaccine efficacy and develop immune memory to Coxiella, we propose conjugating native C. burnetii LPS, or synthetic fragments thereof, to VLP carriers. In parallel, we will express previously identified C. burnetii protein surface antigens on VLPs, providing material for potential blending with LPS-VLP conjugates to produce multi-antigen vaccines. The novel VLP vaccines produced in this study will be tested in our established mouse model of C. burnetii aerosol infection; immune responses will be determined and related to the vaccine efficacy. Several VLP vaccines have already been licensed for human use, demonstrating an established path to market. The opportunity to manufacture without high level containment will result in inexpensive vaccines where manufacture can be transferred to low income settings. This will serve to pave the way for future development of low-cost vaccines for other globally significant pathogens.

Our target is to develop a simple, easy to use, diagnostic system for use in the home by COPD patients to gain early warning of acute exacerbation (AECOPD) and stratify them to the most suitable and effective therapy. This will determine the use of antibiotic, anti-inflammatory or bronchodilator medication (combinations of some of these might be required). COPD is a troublesome worldwide disease with no cure, causing substantial debilitation through breathlessness that gets worse each time there is an exacerbation. Typically, the course of the disease follows periods of stability interspersed with damaging AECOPD episodes from which patients usually do not make a full recovery. Medication is needed when an exacerbation starts, rather than during the stable disease state. COPD is a large and growing world-wide problem. It is a progressively heavy burden for individual patients, carers and health services. But, despite its prevalence and impact, it is not managed well. Delays in diagnosis cause patients to miss out on prompt appropriate medication, while the lack of diagnostically guided AECOPD treatment exposes some patients to inappropriate antibiotic and/or corticosteroid therapy. Inappropriate antibiotic use should be avoided in order to minimise development of antibiotic resistance, as well as damaging side effects. There are substantial side effects of corticosteroids which also should be avoided. In July 2015, the NIHR Horizon Scanning Research & Intelligence Centre published a report on new and emerging technologies for the diagnosis and monitoring of COPD, which specifically highlighted the need for better ways to identify the cause of AECOPD, in order to guide steroid versus antibiotic treatment. The report recommended that promising technologies should be the focus of translational and clinical research funding. Moreover, the NICE Database of Uncertainties about the Effects of Treatments (DUET) highlights the use of corticosteroids and antibiotics for AECOPD as important treatment uncertainties. There is therefore a clear need for a rapid, easy and early stratification test to both identify AECOPD and to stratify sufferers into groups for treatment with antibiotics or steroids. The outcome from this project will be the development of a multiplexed, urinary biomarker diagnostic test system with integrated, personalised biomarker level interpretation algorithm for monitoring the inflammatory status of patients suffering from chronic inflammatory disease at home, with a practical simplicity and diagnostic accuracy never previously possible. This project is bold and ambitious. If successful it will have a significant positive impact on patients’ quality of life, as well as reducing health care costs, whilst representing a major business opportunity for Mologic and the UK medical diagnostics sector.

A simple, easy to use, rapid, inexpensive, effective, point of care (POC) immunodiagnostic system for early confirmation of sepsis in at-risk patients is to be developed and validated. The biomarkers will include IL-6, C-reactive protein and soluble ICAM-1. These known biomarkers will be integrated via a new algorithm with other physical/clinical indicators, and refined using a unique bank of "sepsis-risk" patient samples and controls held within the consortium, before final clinical validation. Strong pilot data gained with the markers and the sample bank gives confidence in their utility and relevance. As well as universal threshold values for each analyte, the algorithm may also be based on sequential personalised values, determined using a low-cost reader (developed outside of the proposed project) to give more accurate readings. The assay is to be based on a simple multiplexed immunoassay platform already being developed by Mologic in a parallel TSB project due to finish in April 2012.

This project aims to develop, manufacture and test ready-to-use diagnostic tests usable for the detection of clinically important phopholipase enzymes activty. It builds on a patented invention from a research team at Imperial College with a strong proven track record of innovation. Working with a UK based company, the project relies on the quality of the invention and applying it to real clinical conditions where there is a clear unmet need for more rapid diagnostic tests. Specifically, the crucial goal of this project will be the diagnosis of pancreatitis, a life threatening and difficult to diagnose condition affecting over 60,000 patients in the UK annually.

Benefiting from over 15 years extensive research, this collaboration between MaimoniDex, Mologic Ltd, Ig Innovations and Swansea University Medical School is working to develop a new biomarker for early diagnosis and confirmation of rheumatoid arthritis. MaimoniDex has identified a CDD44 isoform termed CD44vRA as a potential therapeutic target. The collaboration brings together the inventor, commercial diagnostic companies and access to patient samples and seeks to develop this biomarker as diagnostic blood test to aid, early diagnosis, early therapeutic intervention, therapeutic efficacy and clinical development of new therapies

Awaiting Public Summary

This project is a further development of the tandem core® vaccine platform which is likely to have a wide utility in the generation of powerful new vaccines. This platform has a number of advantages including high immunogenicity, good stability and decreased cost of goods due to the fact that only a single protein is made. Previously, we had shown that tandem core was capable of expressing two vaccine targets simultaneously and could generate strong immune responses. However, this material was produced in bacteria and was subsequently found not to be of a quality suitable for human use. Hence, this project sought to re-engineer the construct for expression in yeast, which are more commonly used in vaccine production and have an excellent safety record. The consortium used a combined hepatitis A and B vaccine as an exemplar and successfully transferred the system into a yeast vector. Although expression was easily achieved it was discovered that expression in yeast greatly increased the complexity of the purification process required to recover the protein. Hence, a robust purification method was developed which is suitable for all future tandem core constructs. This has now been successfully completed and the system is now ready for commercialisation in a variety of disease targets.

Awaiting Public Project Summary

The project will utilise the unique optical properties of nanosized, Surface Enhanced Raman Scattering (SERS) particles, attached to biomarker specific antibodies, to rapidly detect disease states for point-of-care (POC) applications in both the human and animal healthcare markets. The project aims to deliver a portable demonstrator using lateral flow technology containing these bio-conjugated SERS particles for sample collection and processing as well as a scaled down Infra-red Raman probe for detection. The successful development of this technology will for the first time, outside of the clinical setting, enable the user to rapidly monitor multiple analytes within turbid samples, with high selectivity and sensitivity. This capability is a holy grail of modern diagnostic testing and would have massive impact on the UK and global healthcare markets.

Awaiting Public Summary