Innovations Flagships: funded projects

Development of a live-attenuated non-transmissible Salmonella vaccine

Dr Sharon Tennant, University of Maryland

Non-typhoidal Salmonella (NTS) such as Salmonella Typhimurium and Salmonella Enteritidis generally cause self-limiting gastroenteritis. However, in sub-Saharan Africa, clones of these Salmonella serovars cause invasive disease, particularly in infants and toddlers.

Our overall goal is to develop vaccines to provide broad protection against invasive non-typhoidal Salmonella (iNTS) disease. The main goal of the project is to show that we can develop live oral Salmonella vaccines with improved safety due to reduced transmission, designated here as Live Attenuated Non-Transmissible (LANT) vaccines. We will complete pre-clinical safety and efficacy studies assessing the in vivo persistence, immunogenicity and protective efficacy of candidate S.Typhimurium and S. Enteritidis LANT vaccines in mice. At the conclusion of this project, we anticipate demonstrating that iNTS LANT vaccines are only shed in faeces for a short duration but are still immunogenic and can protect animals against challenge with wild-type iNTS. 

If we are successful, these results will pave the way for initiating future Phase I clinical trials using safe, live attenuated Salmonella Typhimurium and Salmonella Enteritidis vaccines.  

Novel Shigella truncated mutant vaccine platform for oral immunisation of infants and children

Dr Lou Bourgeois, PATH

The goal of the project is to develop a novel oral, inactivated whole-cell, cross-protective vaccine against Shigella, a major cause of diarrhoea among children in low-resource settings. 

The vaccine candidate, the Shigella truncated mutant (STM), will be delivered with   a mucosal adjuvant, which can improve immune responses. The vaccine candidate’s inactivated Shigella flexneri 2a whole-cell strain is genetically engineered to maximally expose conserved surface antigens by shortening O-polysaccharide sidechains (O-PS), which typically mask certain, often conserved, antigens on the cell surface. The unmasking of surface antigens could allow the STM to also express and maximally present antigens of other pathogens. Therefore, the project will also assess this property of the STM using a novel conserved heptasaccharide antigen of Campylobacter jejuni, another leading cause of diarrhoea.

Development of a rapidly active live-attenuated cholera vaccine

Professor Matthew Waldor, Brigham and Women's Hospital

The objective of this study is to test the safety and immunogenicity of HaitiV – a novel live-attenuated cholera vaccine. Pre-clinical data suggests that HaitiV can provide rapid (within a day), single-dose, long-lived protection from cholera. 

The key goals of the study are: 

1. creation of a GMP lot of HaitiV for use in human studies, and development and approval of an investigator-sponsored Investigational New Drug application to conduct a first-in-human Phase I trial of HaitiV
2. determination of the maximum tolerated dose and safety profile of HaitiV
3. identification of the most immunogenic HaitiV dose. 

These studies will provide the pivotal data required for future development of this vaccine, including human challenge studies and field trials in cholera endemic regions.

Determining preferred product characteristics to support uptake of innovative antibodies

Shelly Malhotra, IAVI

Through this project, IAVI and the World Health Organization (WHO) department on Immunizations, Vaccines, and Biologicals (IVB) will harness input from a broad network of stakeholders to produce a Preferred Product Characteristics (PPC) technical document for forthcoming monoclonal antibodies (mAbs) for HIV prevention. 

Created early in clinical development, and with attentiveness to end-user and health systems perspectives, this PPC document will provide strategic guidance on preferences for new HIV preventative antibodies to inform clinical development and support eventual integration into WHO policy. 

It is anticipated that the acceptability, suitability and feasibility criteria identified through this process can inform product design, clinical development and access considerations for a broad array of antibody-based products for infectious and neglected diseases in the pipeline.

Entervax: clinical evaluation of a bivalent Typhoid-Paratyphoid enteric fever vaccine

Dr Kristen Albright, Prokarium Ltd

Enteric fever is caused by two pathogens, Salmonella enterica serovar Typhi (S. Typhi) and Salmonella enterica serovar Paratyphi A (S. Paratyphi A). It is a significant contributor to infectious disease mortality and morbidity in low- and middle-income countries. A growing number of S. Typhi and Paratyphi strains are antibiotic resistant, which complicates treatment and increases mortality rates.

Entervax is a bivalent vaccine against S. Typhi and Paratyphi. It is a combination of Salmonella enterica serovar Typhi ZH9 and an additional strain that expresses key antigens from S Paratyphi A (SPA). Ten clinical studies of ZH9 have evaluated measures of immunogenicity associated with protection against typhoid fever by detecting gut-derived antibody-secreting cells (ASCs). ZH9 was shown to produce higher levels compared with the current licensed typhoid vaccine. The studies show that these aroC plus ssaV mutations are effective at attenuating Salmonella for live vaccine applications.

We will enroll volunteers to a Phase 1 trial for a dose escalation of SPA followed by Entervax. We will evaluate the safety and tolerability of the ZH9+SPA vaccine and the volunteers’ immune responses against key antigens.

Our overall aim is to produce a vaccine that can be delivered orally at reduced cost to improve uptake and prevent illness in populations across the world.

Process development and pre-clinical toxicity study for trivalent Typhi/iNTS vaccine

Dr Jerome Kim, International Vaccine Institute

Invasive non-typhoidal salmonella (iNTS) may cause up to 680,000 deaths a year, mostly in resource-poor settings in sub-Saharan Africa. Treatment is difficult, expensive and in many cases, inaccessible. The emergence of antimicrobial resistant strains makes treatment more complex – increasing the risk of death, duration of hospitalisation and cost of care. There is no vaccine available to prevent NTS infection and efforts are underway to develop one, most probably in combination with a typhoid conjugate vaccine (TCV).

We are developing a trivalent S.Typhi, S. Typhimurium and S. Enteritidis vaccine. This project will complement and accelerate the early development of two NTS conjugated vaccines along with our Vi-DT vaccine that is entering a Phase III clinical trial.

This project will accelerate vaccine development through the pre-clinical toxicity study and allow us to prepare for human trials.

GlycoShig3: age-descending phase 2a study into target population with the SF2a-TT15 synthetic carbohydrate-based vaccine

Dr Armelle Phalipon, Insitut Pasteur

Diarrhoeal diseases are the second leading cause of death in children under five years old and are responsible for killing about 525,000 children every year. About 80% of the deaths occur in south Asia and sub-Saharan Africa, with a burden cost of more than 7 million disability-adjusted life years (DALYS). Institut Pasteur has developed a monovalent vaccine candidate against Shigella. flexneri 2a (SF2a), one of the most prevalent S. flexneri serotypes worldwide. The SF2a-TT15 vaccine has been shown to be safe and highly immunogenic in a Phase I clinical trial.

We will carry out a Phase IIa age-descending study starting with an adult cohort, then children aged 2–5 and infants aged nine months. Moving from one cohort to the other will be based on safety data and approval.

This clinical study combined with the ongoing controlled human infection model study will provide proof of concept of safety and immunogenicity of SF2a-TT15 in the target population.

Manufacturing and clinical development of a 4-valent bioconjugate Shigella vaccine

Dr Ennio De Gregorio, GlaxoSmithKline Biologicals SA

Shigellosis is a global health threat that disproportionally affects the most vulnerable in low-income countries, particularly children. There are 600,000 deaths attributed to Shigella each year. In 2015, we acquired the technology that allows the manufacture of conjugate vaccines in vivo. These immunogenic complexes of polysaccharides and proteins, called bioconjugates, are synthesised in vivo with genetically engineered E. coli cells.

A proof-of-concept human challenge trial with a monovalent Shigella bioconjugate vaccine has delivered satisfactory results. We will now develop the Shigella bioconjugate vaccine to generate a tetravalent formulation that can expand vaccine coverage in endemic countries. The multivalent Shigella vaccine is expected to be composed of O-antigens from the four most epidemiologically relevant Shigella strains.

Working with LimmaTech, we will assess the safety and immunogenicity of the multivalent Shigella vaccine in a dose-finding age-descending clinical trial in endemic regions. The project will enable the move to a Phase I/II clinical trial.

Clinical development of a novel, live, attenuated oral combination Shigella/ETEC vaccine

Dr Frank Malinoski, EveliQure Biotechnologies GmbH

More than 500 million cases of diarrhoeal diseases and up to 0.5 million deaths each year are caused by infection with two bacteria, Shigella and Escherichia coli (ETEC), mainly affecting children under five years old living in low-income countries. These infections also leave many children with growth disorders and cognitive dysfunction. These two pathogens also cause a significant proportion of diarrhoeal illness for travellers, military personnel and foreign workers living in low-income countries.

ShigETEC is a novel vaccine that has been developed to prevent these infections. It can be given orally and is based on a weakened Shigella bacterium that does not invade cells of the intestine and should not cause illness. ShigETEC induces immune responses that deliver broad protection against all Shigella species and it also neutralises ETEC toxins.

The aim of our project is to evaluate the safety and immune response in adult volunteers. This data will be pivotal for further developing ShigETEC for children living in disease-endemic countries, as well as travellers to those countries.

Development of a cholera rapid diagnostic test that targets both Vibrio cholerae and vibriophage

Professor Eric Nelson, University of Florida

Rapid diagnostic tests (RDTs) for Vibrio cholerae are essential tools to help control and eliminate cholera. Unfortunately, one of the most common RDTs is negatively affected by viruses, called bacteriophage, that kill V. cholerae. This is associated with inconsistent performance of the test and likely underestimation of disease burden.

We propose to address this problem by including an antibody that will detect the virus as a proxy for V. cholerae detection.

This improved RDT will be clinically evaluated to assure high performance for diagnosing cholera with and without the presence of the bacteriophage.

Validation and feasibility of a novel, simple and rapid assay to detect cholera in resource poor settings and outbreak situations

Dr Subrha Chakrobarty, John Hopkins University

Prompt identification of cholera cases facilitates rapid outbreak responses in the short term, while providing reliable surveillance data to guide long-term policies and interventions. The microbiological stool culture, the current recognised gold standard for the diagnosis of cholera, has significant limitations.

Rapid diagnostic tests (RDTs) may be used as an alternative for the diagnosis of cholera in areas with limited laboratory infrastructure. Despite their advantages, there are also significant limitations to current RDTs for cholera. Most studies conducted with the current RDTs have shown suboptimal performance with wide variation in sensitivity and specificity. We have developed a simple, rapid, sensitive, specific, inexpensive and easy-to-interpret test C-RLDT. We will evaluate and test the feasibility of implementing the C-RLDT to detect cholera from stool and water samples in resource-poor endemic countries and during outbreaks in Africa and Asia.

We will develop recommendations on how to integrate the C-RLDT testing in resource-poor countries using existing diagnostic algorithms for case detection in cholera.

Hub for Neglected Tropical Diseases Network

The overarching goal of the flagship is to drive the adoption of emerging technologies that enable better drugs to be discovered and developed for neglected tropical diseases (NTDs), faster.

The flagship has formed a virtual network of partners and technology innovators from not-for-profit organisations and industry that we support. 

This currently includes teams from:

• the University of Dundee: Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit and Mode of Action group
• Novartis Institute for Tropical Diseases
• Calibr, a division of Scripps Research
• the Drugs for Neglected Diseases initiative 
• GSK.

The hub is at the heart of the flagship strategy, bringing together the experience and learnings of the network of parties by enabling data sharing and collaborations that will drive a faster accumulation of knowledge, streamline efficiencies and reduce duplication of efforts in the NTD area where resources are scarce. It will also provide the critical volume of assets needed to attract technology innovators and new, multi-disciplinary talent, and for technologies to be adapted, tested and validated across several NTDs and parties, to maximise their impact for NTD research.

NTDs of interest are: leishmaniasis, Chagas disease, cryptosporidiosis, schistosomiasis and dengue.

Innovative therapeutics for Chagas disease and cryptosporidiosis

Dr Thierry Diagana, Novartis Institute for Tropical Diseases

Since its launch in 2003, the Novartis Institute for Tropical Diseases has become a world-leading drug discovery centre of transformative medicines for neglected tropical diseases – delivering a robust pipeline of drug candidates to treat malaria, visceral leishmaniasis, sleeping sickness and dengue. In this award, we propose to strengthen the pipeline by targeting two of the most neglected tropical diseases, Chagas disease and cryptosporidiosis. 

An estimated 8 million people are infected by the Trypanosoma cruzi parasite, the causative agent of Chagas disease. Current therapeutics are widely considered to be poorly effective and toxic. We aim to deliver a portfolio of highly effective and safe new chemical entities with proven sterilising activity in Chagas disease animal models.

Cryptosporidiosis causes an estimated 200,000 deaths in children aged under 24 months each year. With support from the Bill & Melinda Gates Foundation, and together with our partners, we have identified drug candidates with a remarkable safety profile, novel mechanism of action, and unprecedented efficacy in cryptosporidiosis animal models. In this award, we aim to establish a cryptosporidium controlled human infection model for a proof-of-concept trial with healthy adult volunteers, followed by definitive trials in the vulnerable paediatric population.

An integrated drug discovery consortium for neglected tropical diseases

Dr Peter Schultz, Scripps Research Institute/Calibr

As the drug discovery division of Scripps Research, Calibr has established a robust infrastructure and experienced team, focused on the development of new medicines for unmet medical needs. We propose to draw upon this expertise and infrastructure, as well as a network of collaborators and prior investment of over $80million in global health drug discovery, to create the Integrated Drug Discovery Consortium for Neglected Tropical Diseases (IDDC-NTD).

The IDDC-NTD will leverage innovative approaches and enabling technologies to tackle some of the most challenging neglected tropical diseases, aiming to create new drug candidates for schistosomiasis, leishmaniasis, Chagas disease, cryptosporidiosis and dengue. By exploring multiple parallel approaches, we aim to deliver several drug candidates that could progress into patient studies, including the potential to accelerate such development using a novel drug repurposing resource called ReFRAME.

In summary, by leveraging our considerable investment, scale, and momentum in preclinical drug discovery, including significant expertise and enabling technologies in global health, our IDDC-NTD is expected to have a major impact on this flagship's objectives toward creating new technologies and medicines to impact neglected tropical diseases.

A platform for drug target deconvolution and exploitation

Professor Ian Gilbert and Dr Susan Wyllie, University of Dundee

The University of Dundee Mode of Action (MoA) group works on finding and confirming the molecular targets of compounds that have biological activity against a variety of different pathogens. We have a toolbox of multiple orthogonal technologies to undertake this work, and will be determining the mode of action of compounds coming from the drug discovery programmes supported by Wellcome’s neglected tropical diseases Flagship, including those in leishmaniasis, Chagas’ disease, cryptosporidiosis and schistosomiasis. We will also characterise some of the novel molecular targets identified through this work.

We will work in collaboration with Professor Karl Hoffmann at the University of Aberystwyth and Professor Rolf Muller at the Helmholtz Institute in Saarbruken.

21st century treatments for the sustainable elimination of leishmaniasis

Dr Charles Mowbray, Drugs for Neglected Diseases initiative (DNDi)

Leishmaniasis is currently treated with toxic, painful injections of antimonial therapies. We have been working with partners – including GlaxoSmithKline, the University of Dundee, Novartis, Pfizer, Takeda Pharmaceuticals and Celgene – to build a portfolio of possible alternatives that can be used on their own or in combination against Leishmania parasites. This could transform treatment to a simple oral, well-tolerated drug that would be easy to use in resource-poor settings.

We will evaluate ten of the new orally-active chemical entities (NCEs) and select two to test in combination in Phase II studies with patients. We will maintain a back-up option of a combination of one NCE to be used with an existing oral drug, miltefosine.

An oral combination of two co-administered drugs could maximise efficacy, reduce dose and duration of treatment, minimise side-effects, improve affordability, and prevent or delay the emergence of drug resistance. The treatment could potentially be extended to cutaneous leishmaniasis.

The SCOPE study: Studying the Contexts of recent Onset Psychoses in Ethiopia to develop interventions to improve outcomes

Dr Charlotte Hanlon, King's College London

A major barrier to innovation in treatment and care for people with psychosis in low-income countries is the absence of rigorous epidemiological research into the aetiology, presentation, social context, associated physical health conditions and early course of psychosis. 

Through SCOPE, we will produce high quality, contextual evidence and use it to design innovations in detection and treatment, to improve the lives of people living with psychosis in a low-income country.  

Our key goals are to:

1. determine the rate of new cases of psychosis in rural and urban settings in Ethiopia; identify possible risk factors for onset; and characterise the needs of people with psychosis and the factors that affect early course and outcome.
2. use this evidence to co-develop innovations to improve early detection and optimise the recovery of people with psychosis. The innovations will be applicable to rural, urban and homeless populations in Ethiopia, with potential generalisability to other low- and middle-income countries. 

We will pilot test interventions, develop strategies to overcome implementation challenges and identify key intervention components to inform adaptation for other contexts.  
 

IMPETUS: Investigating Markers derived from Proteomics for Estimation of Transition from the Ultra high-risk State to psychotic disorder

Professor David Cotter, Royal College of Surgeons in Ireland

Early identification and intervention are associated with improved outcome for psychotic disorders such as schizophrenia. This is facilitated by targeting people at clinical-high-risk (CHR) for psychosis. 

There is growing evidence on the involvement of the immune system and inflammation in psychotic disorders. We have added to the literature by demonstrating that the complement pathway – the blood plasma component of the innate immune system – is dysregulated in blood samples of individuals at age 11. This is many years before individuals report symptoms in keeping with psychotic disorder (PD) at age 17. Based on our own plasma proteomic data and machine learning analyses we have evidence for a set of biomarker proteins which can predict transition from CHR to PD with a high degree of accuracy. We now seek to refine and replicate these findings.

Using state-of-the-art proteomic methods and machine learning approaches we will replicate and refine this biomarker signature of transition from CHR to PD in: 

• three distinct international samples
• one longitudinal cohort with a total sample size of more than 1,000 CHR subjects. 

We will also undertake functional assays that measure plasma protein levels of the complement and coagulation pathway and their activation fragments as indicators of complement and coagulation dysregulation. 

LAMP: learn, assess, manage, prevent for relapse in early psychosis

Dr John Torous, Beth Israel Deaconess Medical Centre

Smartphone Health Assessment for Relapse Prevention (SHARP) is an international, digital health study with the broader goal of reducing the access gap to mental health education and treatment in low-resource settings.

This research study will measure the feasibility of using an open source smartphone application (LAMP), to prevent relapse among individuals diagnosed with schizophrenia spectrum disorders. Insights from focus groups and feedback from study participants will inform adaptations to LAMP. The resulting app code will be shared to build a scalable, global mental health solution.

Automated analysis framework for FDOPA PET imaging as a biomarker for treatment stratification in psychosis

Dr Mattia Veronese, King’s College London

Psychotic disorders affect 1 in every 100 people and are among the top causes of disease burden in working-age adults. Treating psychosis is possible but almost a third of patients show limited or no response to first-line antipsychotic treatments. There is an urgent clinical need for a biomarker to identify non-responders early to guide treatment choice.

Several lines of evidence suggest that brain dopamine synthesis represents a neurochemical basis to stratify psychosis and predict non-response to antipsychotic treatment. Brain dopamine synthesis can be measured safely by a neuroimaging technique called Positron Emission Tomography (PET), following the injection of a radiotracer called FDOPA.

In this work we aim to develop an analysis approach to transfer FDOPA PET imaging from experimental medicine into clinical use. It has the potential to become a screening test and generate informed, individualised treatment plans.

BRAINCHART: normative brain charting for predicting and stratifying psychosis

Dr Andre Marquand, Radboud University

Psychiatric illnesses such as schizophrenia often start early in life and have an enormous impact on the people affected, their families and society. Despite much research, it is still very difficult to predict which individuals will develop their first psychotic episode and to predict the course of their illness afterwards – some individuals recover immediately, while others experience symptoms their whole lives.

We aim to solve this problem by developing normative ‘growth charts’ for the brain from approximately 40,000 people. This will enable us to identify individuals that follow an ‘atypical’ trajectory early, and to stratify individuals according to how likely they are to become unwell.

In the short term, this will assist scientists with planning future studies. In the long term, this will allow medical professionals to target preventative medical attention to the people that need it most, and to provide treatments tailored to the needs of individual patients.

Optimising AVATAR therapy for distressing voices: a multicentre randomised controlled trial

Professor Philippa Garety, King’s College London

AVATAR therapy is a brief intervention aimed at reducing the frequency of auditory verbal hallucinations (AVH or ‘voices’). Phase 1 of the therapy involves using a digital simulation (an avatar) of the entity the person believes is the source of the voice for a three-way discussion between participant, avatar and therapist, focusing initially on managing anxiety and helping the participant to stand up to the avatar. Phase 2 involves a realistic enactment of the ascribed character of the voice, targeting processes that are specific to an individualised formulation. The first fully powered randomised controlled trial (RCT) found AVATAR therapy resulted in a rapid and substantial fall in frequency of voices and associated distress that was superior to a supportive counselling control at 12 weeks.

We will carry out a multicentre RCT to examine the effects of high and low intensity AVATAR therapy, where high intensity involves both phases and low intensity only phase 1. We will compare each phase to standard treatment and we will identify who would be likely to benefit from the high intensity therapy compared with those for whom low intensity therapy would be sufficient. We will then examine the relative cost-effectiveness of the two levels of AVATAR therapy and routine treatment and broaden the availability of AVATAR therapy by expanding the number of staff trained in geographically dispersed NHS settings. Finally, we want to provide the evidence on effects and cost-effectiveness necessary to gain a recommendation for the therapy by guideline bodies such as the National Institute for Health and Care Excellence.   

The vulnerable self: a neurophenomenological model of the onset of schizophrenia spectrum disorders

Professor Barnaby Nelson, University of Melbourne

It remains unclear what the ‘core’ disturbances of schizophrenia are. This hampers early identification and intervention strategies. Findings from recent phenomenological, neurocognitive and neuroscience research converge around the concept of disturbed ‘basic’ self-awareness as a core feature of schizophrenia spectrum disorders.

This study will assess the relationship between phenomenological, neurocognitive and neurophysiological measures of basic self-disturbance in patients at clinical high risk (CHR) of psychosis, patients with non-psychotic disorders, and health controls. 

The relationship between these measures will be analysed, as well as their prognostic implications in the CHR for psychosis population. 

The research will enhance understanding of the core cross-domain features of schizophrenia, result in a clinical tool for improved identification of young people at high risk of progressing to psychotic disorders, and point towards mechanism-based treatment targets.

The cannabidiol early psychosis project – a randomised controlled trial

Professor Paul Amminger, University of Melbourne

The cannabidiol study aims to address whether subthreshold psychotic manifestations can be treated with cannabidiol (CBD), a non-psychoactive compound of the plant Cannabis sativa. CBD is a promising treatment for testing due to its encouraging safety and tolerability profiles, and strong preliminary evidence for its ability to reduce psychotic symptoms. In this study, CBD will be tested for the first time in the clincial high risk (CHR) phase of psychotic disorder. 

The study design encompasses a three-arm randomised controlled trial – with a placebo arm and two discreet drug doses. 

The primary outcome of the study is the improvement of positive psychotic symptoms on the Comprehensive Assessment of At-Risk Mental States (CAARMS) at 12 weeks. 

The key deliverable outcome is to provide a novel biological treatment for young people at CHR of psychosis that can be used in a wide variety of settings – from primary care to specialist – and be easily extended and translated to longer-term treatment. 

Australian Early Psychosis Collaborative Consortium Clinical Registry (CR) and Clinical Trial and Translation Network (CTTN)

Dr Andrew Thompson, University of Melbourne

Psychotic illnesses such as schizophrenia and bipolar disorder are a major cause of premature mortality and disability in Australia and globally. These disorders generally have their onset in adolescence and young adulthood. A dedicated clinical registry and research network to facilitate, support and conduct large clinical trials in this space is absent internationally and urgently required. 

In combination with a number of key foundation member early psychosis clinical services nationwide, we aim to create the Australian Early Psychosis Collaborative Consortium (AEPCC) network and registry, focusing on the critical early stages of psychotic disorders in young people and emerging adults. The platform aims to catalyse, cohere and enhance the development, evaluation and translation of new and existing treatment strategies in early psychosis – across Australia and beyond – to improve key outcomes, including remission and recovery. 

The specific key deliverables involve the development of both a clinical registry (CR) and Clinical Trial and Translation Network (CTTN), starting with Orygen and six headspace Youth Early Psychosis Programmes in major capital cities. This includes establishing the organisational and governance structures, and translational activities. Through the CTTN we aim to facilitate the approval of up to two multicentre clinical trials in accordance with regulatory requirements.

KarXT: a potential novel mechanism antipsychotic and procognitive therapeutic 

Dr Stephen Brannan, Karuna Pharmaceuticals, Inc

We are developing a portfolio of new interventions and treatments for psychosis. One of these is a drug called KarXT which uses a novel mechanism of action and has been shown to cause far fewer side-effects than traditional antipsychotics. KarXT is composed of xanomeline, a muscarinic receptor agonist, and trospium chloride, a well-established muscarinic receptor antagonist. In a Phase I study, KarXT reduced the side-effects typically seen with xanomeline alone. Trospium chloride's inhibition of peripheral muscarinic receptors improved xanomeline’s tolerability.

We funded a phase II study designed to demonstrate the efficacy and tolerability of KarXT in schizophrenia patients with acute psychosis. The results from the trial show that KarXT is effective in reducing the symptoms patients experience during an acute episode of psychosis – which can include hallucinations, delusions and paranoia – and may also reduce associated negative symptoms. The study also replicated the findings that KarXT is well tolerated. 

Spot Sepsis

Professor Yoel Lubell, Mahidol-Oxford Research Unit (MORU), Thailand

Spot Sepsis is a multi-site prospective observational cohort study, conceived by the Mahidol-Oxford Tropical Medicine Research Unit (MORU) and Médecins Sans Frontières Spain (MSF Spain). The project is co-funded by MSF Spain and Wellcome.

Over 15 months, we will enrol a minimum of 4,900 children between the age of one month and five years with acute febrile illness presenting to six regional hospitals across Asia (Indonesia, the Philippines, Cambodia, Laos, Vietnam and Bangladesh). We will collect key historical variables, record presenting clinical features, measure host biomarker profiles, and determine fever aetiology for key target pathogens. We will follow up with the children at 48 hours and 28 days to ascertain clinical outcome. Using this data, we will derive and perform external validation of a risk stratification algorithm, to predict progression to severe disease.

The project is motivated by a shared translational research vision: a desire to improve identification of children with acute infections at risk of progressing to severe illness or sepsis. This will in turn allow more efficient and effective referral choices in remote contexts, particularly those affected by conflict, where the decision to refer a child to higher care carries substantial risk or burden. We will benefit from the collaboration with our project partners, who have considerable experience in biomarker discovery/validation and clinical prediction rule derivation and validation.

Collaboration for Research, Implementation and Training in Intensive Care in Asia (CRITIcal CARE Asia)

Professor Arjen Dondorp, Mahidol-Oxford Research Unit (MORU), Thailand

The project’s primary objective in phase 1 is to network a large number of intensive care units (ICUs) in the Southeast and South Asia regions by implementing a setting-adapted, real-time, clinician-led electronic registry. The information captured through the registry will directly benefit patient care by evaluating the quality of care currently delivered in each ICU and the bottlenecks to quality care delivery. Phase 2 will provide a platform for quality improvement interventions and clinical trials within the network.

This project unites with the proposal led by OUCRU to evaluate technology innovations in critical care. Collaborating countries include Bangladesh, India, Laos, Malaysia, Nepal, Pakistan, Sri Lanka, Thailand and Vietnam. The resulting international ICU network will enable high-impact multi-site evaluation of setting-adapted interventions to improve critical care delivery and patient outcomes.

Integrated COVID-19 response: leveraging community health strategy, youth and technology to flatten the curve and improve case detection, isolation and management in Western Kenya

Dr Neema Kaseje, Surgical Systems Research Group, Kenya

To respond to the COVID-19 pandemic, we will be deploying community health workers, equipped with mobile technology, and accompanied by young people, to visit households door to door to screen for symptoms, and isolate, test and manage suspected cases.

The community health workers and young people will educate households about preventive measures, including frequent handwashing and home management of mild cases. They will also work with nurses, doctors and clinical officers to test and treat more severe cases of COVID-19 in health facilities.

The goals are to visit every household in Siaya county – covering a population of nearly 1 million – and to train and support health workers working in the 32 health facilities in Siaya.

POETIC-COVID: provision of essential treatment in critical illness in COVID-19

Dr Tim Baker, London School of Hygiene & Tropical Medicine, UK

As COVID-19 lacks a definitive treatment, critical care is the primary therapeutic means for reducing mortality. How the world effectively scales up critical care will be a fundamental determinant of the overall impact of the pandemic. Advanced critical care may be difficult or impossible to scale up in many settings, and instead, essential, life-saving treatments should be provided to all who need them.

Essential Emergency and Critical Care (EECC) is the basic, low-cost care required by critically ill patients, such as oxygen and intravenous fluids, and the system-wide requirements for their provision. This project will assess the cost-effectiveness of EECC and advanced critical care in Tanzania and Kenya, and analyse the impact of global and national response strategies to COVID-19 on critical care services. The project aims to guide COVID-19 responses in low- and middle-income countries towards scalable strategies with the greatest potential for increased survival of critically ill patients during the pandemic and beyond.

Innovative biomedical engineering and computational science to improve the management of critical illness in resource-limited settings

Professor Guy Thwaites, Oxford University Clinical Research Unit (OUCRU), Vietnam

The demand for improved care for critical illness is increasing rapidly in Vietnam along with other low- and middle-income countries. Models of care used in high-income countries are not sustainable in these settings, and so an alternative model is needed, which promotes high quality clinical care at a lower cost and needing fewer specialists. New technology can provide low-cost solutions for monitoring critically ill patients, assisting in their rehabilitation and generating clinical decision support systems that will improve diagnosis, treatment, and compensate for the lack of specialised staff.

We will develop an inter-disciplinary ‘innovations for critical care’ team of Vietnamese and international clinicians, biomedical engineers and computational scientists at the Oxford University Clinical Research Unit in Vietnam. It will be linked to biomedical engineering groups at Oxford University, King’s College London, Imperial College London and Eidgenössische Technische Hochschule, Zurich.

The team will develop and test technologies that have the potential to save lives, prevent disability and improve rehabilitation from the common causes of critical illness in Asia.

South and South-east Asian Community-based Trials Network: rural fever

Professor Yoel Lubell, Mahidol-Oxford Research Unit (MORU), Thailand

We will establish the South and South-east Asian Community-based Trials Network (SEACTN) to monitor the incidence, causes and outcomes of febrile illness in rural communities in the region. It will also enable the trialling of interventions, such as new diagnostic tests or health monitors, by village health workers (VHWs) and rural clinics directly within the community.

The network will cover 750 villages in three South and South-east Asian countries. We will provide mobile devices with data collection applications to VHWs and healthcare staff for them to record the incidence and outcomes of patients with febrile illness. Samples from patients will also be investigated to better understand the causes of febrile illness, and test for markers to identify those patients that may need urgent or specialised care. Health-seeking behaviour surveys will also be carried out and health facilities and services in the region will be mapped.

Our findings will provide an account of the incidence and associated morbidity and mortality of febrile illness in rural settings in South and South-east Asia, and support the development of better tools to triage and treat fever in the community.

Developing model applications to support national malaria elimination strategies

Dr Sheetal Silal, University of Cape Town

We will support national and regional policy design aimed at malaria elimination in South Africa, Bangladesh, Ghana and Namibia.

We will use disease transmission models and costing tools to turn national surveillance data into strategic information to support policy makers when making funding decisions. We will develop user-friendly computer applications designed to allow policy makers to run simple mathematical models and navigate the output of millions of simulations of more complex models with the aid of interactive graphs. We will focus on the implementation and translation of the results to allow policy makers to design an elimination/control strategy incrementally by combining interventions to predict the desired impact and cost.

A mathematical model of malaria transmission will be calibrated for each country. We will incorporate the model into an application that can be used to estimate the impact and cost of policy interventions and help malaria strategy design. We will also train people in the countries’ ministries of health to use and update the tool.