Grants awarded: Strategic Translation Award

Medical devices

Multicentre clinical evaluation of a neonatal seizure detection algorithm

Seizures are difficult to detect in new-born babies and can be a marker of brain injury, resulting in lifelong disability. Treating seizures early is more successful than treating them at a later point, and there is evidence to show that controlling seizures can reduce brain damage.

Seizures cannot be treated unless clinicians have an accurate way of measuring them – recognising seizures by observing the baby alone is not reliable. The only way to accurately detect these events is to monitor electrical brain patterns using wires attached to the scalp (EEG). However, EEG signals are very difficult to interpret and full-time monitoring of EEG outputs by trained clinicians is not practical.

Using funding from a Translation Award, Liam Marnane and colleagues at the University College Cork have developed an automated intelligent EEG computer program that can detect seizure accurately. They will now test the system in neo-natal intensive units around the world to show its benefits for new-borns. The goal is to make the software reliable and compliant with international regulatory requirements so that it is suitable for inclusion in multiple medical monitors.

Novel test for early diagnosis of Tuberculosis

Tuberculosis (TB) is responsible for the deaths of some 1.4 million people every year - half of them children - and is the world’s eighth biggest killer, according to the World Health Organisation. Global BioDiagnostics Corporation (GBD) has received a Strategic Translation Award to develop a novel point of care test for the rapid diagnosis of tuberculosis in resource-limited settings.

TB causing bacteria produce a unique enzyme, β-lactamase or BlaC. GBD's test utilises a synthetic molecule which is enzymatically cleaved by BlaC to generate a fluorescent signal that is readily detectible by simple, low-cost, portable fluorimeters. The test is based on technology developed at of Texas A&M Health Science Center School of Medicine and Stanford University and can detect presence of the bacterium that causes TB in as little as 10 minutes.

The project builds upon 5 years of research by Texas A&M, funded by the Bill and Melinda Gates Foundation. A proof of concept study undertaken by the company with funding from the Wellcome Trust in the US and Peru has proven feasibility of the technique for the rapid diagnosis of TB using sputum samples from suspected TB patients. This further project aims to optimize the assay and to validate the test through clinical evaluation in field settings where TB is endemic.

Steering-brain-stimulation Probe Assembly Development and Engineering

Deep Brain Stimulation (DBS) is applied, amongst others, for patients with Parkinson's disease. By electrically stimulating a small region in the brain, often the Sub-Thalamic Nucleus (STN), important symptoms of the disease are suppressed and patients regain control over their movements.

The stimulation is done using a probe that is implanted in the brain and an Implantable Pulse Generator (IPG) which supplies the appropriate signals to the probe. Given that the STN is only a few millimeters in size, systems that are currently on the market often stimulate other areas as well, which then leads to sometimes severe stimulation-based side-effects. These side-effects have been a prominent barrier-to-adoption for wide scale adoption.

Sapiens BV have been awarded a Strategic Translation Award to develop a unique high-resolution probe which can be configured to steer the stimulation signals from the probe towards specific brain regions which is referred to as Steering Brain Stimulation (SBS). This radically new approach should eliminate mostly all stimulation-based side-effects and if successful will provide patients with Parkinson's Disease with a much more effective treatment.

In-room neonatal MRI scanner to be placed in the NICU anywhere in the hospital building

In neonatal units, ultrasound imaging is used today for routine imaging of the brain. Prior research has indicated that magnetic resonance imaging rather than ultrasound is optimally suited to visualise the brain conditions seen in neonates.

Key reasons for the lack of utilization of magnetic resonance in neonate imaging are that the equipment is often bulky, difficult to site and therefore usually placed in separate and often distant areas of hospitals. There is a huge need for a dedicated, bespoke magnetic resonance imager that addresses these issues.

GE Healthcare have been awarded a Strategic Translation Award to co-fund the development of magnetic resonance imaging equipment capable of being located within neonatal units. First, engineers at GE Healthcare will build three small, high-field (3T) magnetic resonance prototype systems capable of being installed in a neonatal unit. Secondly, these prototype magnetic resonance systems will be placed in a minimum of two neonatal units to understand workflow elements and the requirements for a fully functioning finished product. As such, the hope is that the project output will be able to provide high quality information in 3 years that has a high chance of changing neonatal management.

Vaccine

Development of a multivalent Shigella bioconjugate vaccine to prevent deadly diarrhea in children

 Each year 1.1 million people, mainly children in developing countries, are estimated to die from Shigella infection. Despite significant efforts to find an efficient and safe vaccine against shigellosis, still no vaccine is available on the market.

GlycoVaxyn has developed an innovative technology that enables the manufacture of bioconjugate vaccines in a cost-effective manner. Bioconjugates are immunogenic complexes of polysaccharides and proteins that are directly synthesized in vivo using appropriately genetically engineered bacterial cells (E.coli). GlycoVaxyn has been using this novel technology to obtain a multivalent Shigella bioconjugate vaccine to prevent deadly shigellosis of children in developing countries.

Dr Michael Wacker has received the Strategic Translation Award to assess if this Shigella bioconjugate is able to protect from shigellosis in healthy adults. The candidate vaccine will be produced and subsequently tested in a Phase I study for safety and immunogenicity. In a second step, in order to evaluate the efficacy of the vaccine, a human challenge model will be used. This study will allow obtaining a proof that the vaccine is protecting before tested in large complex field studies in children. This project is an important step for the clinical development of a multivalent Shigella vaccine.

Developing a Conjugated Vaccine to prevent invasive non-typhoidal Salmonella infections in infants and young children in sub-Saharan Africa

The bacteria called non-typhoidal Salmonella (NTS) are a major cause of blood infections (septicaemia) and infections of the coverings of the brain (meningitis) in sub-Saharan Africa, where 20-30% of affected children die. Currently there are no vaccines available to prevent NTS disease in humans.

Professor Myron M. Levine’s team at the University of Maryland, Center for Vaccine Development, has received the Strategic Translation Award to complete development and bring to clinical trials a conjugated injectable vaccine to protect young children and high-risk adults in sub-Saharan Africa against NTS. The University of Maryland’s vaccine technology is based on chemically linking two pieces from the bacterial cell - the sugar that coats the cell surface, and a protein derived from the flagella structure that allows the bacteria to swim. The vaccine is designed to stimulate the human body to produce antibodies (protective proteins) in blood that will prevent NTS disease.

An advantageous aspect of this project is the University’s collaboration with Bharat Biotech, contributing its expertise in vaccine manufacturing, product development and commercialization. Work funded by the current Strategic Translational Award will include testing the NTS vaccine in early clinical trials in the USA.

Acceleration of the development of vaccines and diagnostics for typhoid fever using a human challenge model

Typhoid is a serious infection which kills up to 600,000 people every year. Many children and adults are affected by the disease and it is the commonest bacterial cause of fever in children attending hospital in some parts of South Asia. It is very expensive to undertake the field studies that are needed to see if new vaccines work and this has stalled development of some new generation vaccines which might give better protection against typhoid.

In this project a research team lead by Professor Andrew Pollard from Oxford University will use a model of infection in healthy volunteers to see if a new vaccine can prevent the disease. The researchers will also use the model to understand typhoid infection better and study which components of immunity are important in vaccine protection. The team will use the model to try to develop new blood or urine tests for better diagnosis of typhoid. It is hoped that these studies will improve case management and move vaccine development more quickly to eventually save lives.

Development of a PorA / FetA protein vaccine to prevent meningococcal disease

Meningitis B is the leading cause of bacterial meningitis and septicaemia in the UK causing up to 1500 cases each year and is the leading infectious cause of death in childhood. Development of a vaccine has been hampered by the lack of immunogenicity of various antigens as well as the variability of the proteins between strains.

Professor Andrew Pollard and Professor Martin Maiden at University of Oxford with Professor Jeremy Derrick (Manchester University) and Professor Ian Feavers (National Institute for Biological Standards and Control) have been awarded a Translation Award to develop a promising meningococcal vaccine candidate based on the structuring of surface proteins within hyperinvasive lineages, taking a vaccine composed of a combination of the PorA (porin), and FetA (iron-regulated surface protein) proteins from pre-clinical studies to Phase I clinical trials in humans.

Development of an oral adenovirus-based vaccine against influenza

PaxVax has received a Strategic Award to develop an orally delivered vaccine to protect people against pandemic strains of influenza. Most influenza vaccines in use today are injections requiring needles, sterile techniques and liquids.

To develop this vaccine PaxVax has adapted an oral adenovirus vaccine that has been used safely in 10 million U.S. military personnel over 30 years to protect them against adenovirus related respiratory illness. PaxVax has modified the adenovirus component of the vaccine such that it makes influenza proteins. The vaccine is prepared as an enteric coated capsule which passes the stomach and delivers live adenovirus particles to the small intestine causing immunity to influenza.

With Wellcome Trust support PaxVax is performing a clinical trial of an influenza H5N1 (Bird Flu) vaccine. The trial is designed to assess the vaccine's safety in approximately 120 subjects and to measure antibody, cellular and mucosal immunity at a range of different doses.The potential advantages of PaxVax oral vaccines compared to traditional injectable vaccines for recipients include convenience, ease of administration and lower costs. The advantages of such flu vaccines for society at large include faster manufacturing, ease of stockpiling, more rapid distribution to the needy and lower costs.

Conjugate vaccine for typhoid fever caused by the bacteria Salmonella enterica serovars Typhi

and Paratyphi A

Currently, there are over 21 million cases of typhoid fever worldwide with no affordable vaccine available offering long-term protection. The highest incidence of cases and deaths occur in children of low- and middle-income countries, predominantly in the Indian subcontinent and in South-East Asia. Current antibiotics, once an effective means of treatment, are becoming less useful due to increasing drug resistance.

In conjunction with the Wellcome Trust, the Novartis Vaccines Institute for Global Health aims to combat that by leveraging its knowledge from research and development in conjugate vaccines for the development of a bivalent vaccine that protects against both S.Typhi and S.Paratyphi A; two very similar illness which - if left untreated - can result in complications and death, particularly in young children and the immuno-compromised. Such a vaccine will target molecules on the surface of the bacteria, which will be made more immunogenic by linking them with a protein carrier that is used in many childhood vaccines.

The NVGH research will build upon a promising prototype conjugate vaccine developed by the National Institutes of Health. The research team, led by Dr Laura Martin, aims to have a product ready for clinical trials by the end of 2010. This vaccine will be tested in Europe first and subsequently in the low- and middle-income countries where it is most needed.

Diagnostics

An automated blood based assay-system for monitoring tumour load in a routine diagnostic setting

Cancer is caused by the accumulation of genetic damage (mutations) in cells within a particular organ. These mutations are only found in the cancerous cells, and therefore could be used to monitor the tumour load during treatment, and rapidly evaluate treatment response.

This could potentially allow patients' treatment to be personalised, through making individual decisions on treatment duration and intensity. Ultimately, this could allow drugs to be targeted to only those patients who show meaningful response, reducing unnecessary side-effects and improving effectiveness. Advances in DNA sequencing allow the high-throughput identification of these mutations from any tumour tissue in a clinically relevant time-frame.

As tumour cells die, they release their DNA into the bloodstream. The new generation of genetic sequencing technologies can identify a particular class of mutations caused by the abnormal rearrangement of chromosomes in patients with cancer. From these rearrangements, personalized tests can be developed for each patient to detect tumour DNA that has been released into the bloodstream. Such tests are highly specific and sensitive, being able to isolate and detect just one molecule of tumour DNA in many millilitres of blood. To implement such tests in a real-world healthcare system requires development of new instruments and technology.

Dr Patrick van den Bogaard at Biocartis SA, in collaboration with researchers at the Wellcome Trust Sanger Institute and at Philips Research, are developing a novel diagnostic platform which will automate a blood-based assay for monitoring tumour load in the patient’s own hospital. The system will use disposable, microfluidic cartridges with digitally encoded micro particles for the rapid and sensitive detection of multiple DNA samples. The availability of this test is expected to have a major impact on personalising treatment of tumours, increasing the quality of clinical care and the quality of life for the patient.

Rapid diagnostics tests for resource-poor settings

Inexpensive, simple and high-performance tests for the simultaneous detection of hepatitis B virus (HBV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) for use in resource-limited settings. From a product development partnership between Diagnostics for the Real World Limited and Dr Helen Lee, University of Cambridge Diagnostic Development Unit, these tests will be particularly applicable to clinical settings in which a rapid and immediate test result is crucial.

Clinical trial of a Chlamydia trachomatis rapid test

Chlamydia trachomatis infections are one of the most common bacterial sexually transmitted diseases in the world. If detected early, the disease is very easy to treat with a one-off antibiotic pill.

However, undetected and untreated infections can lead to infertility, ectopic pregnancy and pelvic inflammatory disease. Efforts to control chlamydia are hampered by the fact that the majority of infected individuals are asymptomatic. In addition, sensitive methods to detect the infection are technically complicated, time consuming and expensive.

Dr Helen Lee and Diagnostics for the Real World (DRW) have developed a rapid diagnostic test, the Chlamydia Rapid Test, and FirstBurst Urine Collector. These developments together provide a 30-minute diagnostic test kit for chlamydia infection. The test procedure requires minimal instrumentation and can be carried out by individuals with basic training. The FirstBurst Urine Collector is a convenient, disposable device for collecting first-void urine that will be useful not only for improved sensitivity of detection of chlamydia but also with other STDs. The clinical trial will enable DRW to apply for regulatory approval of these products in the EU and US, allowing market entry in Europe and the US and enabling the availability of a high-quality product for developing countries.

Enabling technology

Development of A549 cells as a cell substrate for vaccine production

PaxVax proposes to develop a new way to make vaccines that is less expensive and faster than current methods. Many vaccines are still produced using archaic egg-based methods that limit vaccine supply and keep costs high.

The new method will grow viruses in the laboratory in a type of human cell called A549 rather than in chicken eggs as is currently done for many vaccines such as the influenza vaccine. The cells will be grown in a liquid suspensions that are very inexpensive compared with eggs. It will be possible to make much more vaccine in cells than can be made in eggs. Importantly, vaccines can be made in cells much faster than is feasible in eggs. Production speed for timely vaccine distribution is critical when faced with a situation such as the 2009 H1N1 swine flu pandemic.

Although several manufacturers have previously developed novel methods which replace eggs with cells grown in culture, the medicines regulatory authorities have been resistant to approving them due to uncertainty about the risks of using such cell lines in vaccine production, especially those employing live virus. Advances in biotechnology now allow for extensive genetic characterization and purity testing of vaccine candidate production cells. In Europe and the USA the EMEA and the FDA have issued guidelines for development of vaccine producing cell substrates. A549 is being developed to meet these new stringent standards. A key benefit to society will be the ability to supply life-saving vaccines to all nations regardless of their economic status due to the extremely low cost for making vaccines in A549 cells.

Therapeutics

Administration of sNN0029 (VEGF) using an implanted drug delivery system for the treatment of patients with Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a deadly disease that causes death of nerve cells (motor neurons) that are normally used to control breathing, swallowing and movements, e.g. of limbs. The disease affects 200,000–300,000 patients worldwide and approximately 90% of patients with ALS die within 5 years of diagnosis.

sNN0029 is a drug that contains a naturally occurring protein called VEGF that has been shown to have disturbed expression in the central nervous system of ALS patients, as well as promoting survival of motor neurons in relevant rodent models.

Based on these findings, NeuroNova AB – a Swedish subsidiary of Newron Pharmaceuticals in Milan, Italy – has developed a therapy to directly deliver VEGF into the brain using a drug delivery system which is placed underneath the skin. The company has completed a three month phase I/II safety and tolerability study of this therapy in ALS patients. The Wellcome Trust is now providing a programme-related investment to complete a phase I/II trial to evaluate safety and efficacy of higher doses of sNN0029 in patients with ALS.