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Department of Science, Innovation and Technology
Determining the Role of Mass Drug Administration in the Emergence of Anthelminthic Resistance of Soil-Transmitted Helminths in Southeast Asia
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Our aim is to discover how the mass administration of anthelminthic drugs to children in Southeast Asia is causing reductions in anthelminthic efficacy against soil-transmitted helminths (STHs), altering the population genetic structure of STHs, and selecting STH genomes for anthelminthic resistance. This work will leverage a “natural experiment” that is happening in Southeast Asia, comparing STHs where there is mass drug administration (Indonesia and the Philippines) with STHs where there is not (Malaysia). STHs are one of the World Health Organization’s-defined 20 Neglected Tropical Diseases, infect 1.5 billion people globally, and cause more Years Lost Due to Disability than malaria, TB or HIV/AIDS. Because of the harm caused by STHs, many countries have national programmes of Mass Drug Administration (MDA) where children in high-risk populations are treated at least annually with anthelminthic drugs. These MDA programmes bring health and wider benefits to infected children and to their families. The continued success of anti-STH MDAs depends on the sustained efficacy of anthelminthics, However, there is already evidence of reduced anthelminthic efficacy against STHs. The long-term and widespread use of anthelminthics is predicted to lead to STHs developing anthelminthic resistance. There is extensive evidence of widespread, anthelminthic resistance in nematodes infecting livestock to the same drug classes used to treat STHs, a portent of the future for human STHs. MDA programmes are at a major risk of failure if there are widespread reductions in anthelminthic efficacy. The nature and extent of anthelminthic efficacy in STHs in Southeast Asia is unknown and a major evidence gap that our work will fill, generating information which is directly relevant to stakeholders, policymakers and users. Our central hypothesis is that the use of anthelminthics in MDA programmes is selecting STHs and driving the evolution of anthelminthic resistance. From this we predict that: (1) Repeated use of anthelminthics will lead to lower anthelminthic efficacy. We will test this by measuring anthelminthic drug efficacy in areas with (Indonesia and the Philippines) and without (Malaysia) MDA programmes, our Work Package 1. (2) Repeated anthelminthic use will change the STH population structure, by repeatedly bottlenecking their populations. We will investigate this by whole genome analysis of STH genetic diversity in MDA and non-MDA regions, our Work Package 2. (3) STH genomes are being selected by the repeated use of anthelminthics. We will investigate this by doing genome scans for sites of selection, our Work Package 3. The outputs and benefits of this work are: (a) ascertaining anthelminthic efficacy against STHs, which will feed into policy and practice in Southeast Asia; (b) determining the genetic effect of anthelminthic selection on STHs; (c) building a sustainable Southeast Asia–UK research network; (d) capacity strengthening a generation of researchers in state-of-the-art bioinformatics analyses of genomic data applied to improving human health and wellbeing.
Anthelmintic resistance in Southeast Asia (AHR-SEA): implications for control and elimination of intestinal helminths
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Soil-transmitted helminth (STH), or intestinal worm infections, are a major health burden worldwide, particularly in rural and poor urban areas of low- and middle-income countries, including in Southeast Asia. They infect over 1 billion people worldwide, causing considerable disease including anaemia and stunting and wasting in children. They can also significantly exacerbate poverty, particularly in marginalised communities. In the Philippines nearly 30% of school-aged children are infected with STHs, whereas in Malaysia and Thailand infections are particularly common in indigenous communities, refugees and migrants. The diseases caused by STHs are classified as Neglected Tropical Diseases by the World Health Organization (WHO). In its Roadmap for Neglected Tropical Diseases, WHO targets STH diseases for elimination as a public health problem by 2030. The main approach for STH control is regular distribution of deworming drugs to individuals living in endemic areas. However, there are concerns that resistance will arise to deworming drugs in human STHs, as is common in similar worm infections in animals, thus jeopardising control programmes. Therefore, there is an urgent need to understand how effective deworming drugs are in treating STHs, what the impacts would be on WHO elimination targets if resistance does emerge and explore alternative control approaches. Our project brings together an interdisciplinary team of expert researchers from Malaysia, the Philippines, Thailand and the United Kingdom and aims to address current knowledge gaps in relation to performance of deworming drugs in treatment of STHs and to identify alternative control strategies for STHs which are acceptable to communities. We will do this by undertaking field studies to assess performance of deworming drugs in treatment of STHs in areas of the three countries where high levels of STHs persist despite deworming treatment. We will use cutting edge genomics approaches to determine whether there are genetic variations associated with resistance to deworming treatment in the STHs circulating in the study sites. We will also investigate interactions between STHs and deworming treatment and people’s gut microbial community (microbiome) to propose alternative STH treatment options and to explore if gut microbes might influence treatment responses. Furthermore, we will employ machine learning methods to predict emergence of resistance to deworming drugs and use mathematical modelling and health economics approaches, informed by preference, symptoms and health-related quality-of-life data collected during the field studies, to determine what impact emergence of resistance will have on STH control and identify alternative control approaches which are acceptable to communities. Finally, we will design a strategy to monitor for emergence of deworming resistance. Integrated into the project will be a programme of knowledge exchange and research capacity building activities including training courses, researcher exchanges and field-based training. By embracing a collaborative interdisciplinary approach, this project will shed new light on the issue of STH resistance to deworming drugs and the effect that emergence of resistance will have on STH control and elimination. Ultimately, the project will deliver evidence-based strategies to monitor for resistance emergence and minimise the impact of resistance emergence on achieving the WHO 2030 targets, crucial information for public health policy makers.
Designing effective adjunctive chemotherapy against drug-resistant tuberculosis (TB) and TB-like respiratory diseases
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Overview and rationale: Antimicrobial resistance (AMR) threatens the control of an ever-increasing range of infectious diseases. We risk impeding drug research and offering therapy for drug-resistant tuberculosis (TB) caused primarily by Mycobacterium tuberculosis and TB-like respiratory diseases (such as asthma, chronic obstructive pulmonary disease/COPD, and cystic fibrosis) caused by opportunistic non-tuberculous mycobacteria (NTM) unless we refocus immediately. Mycobacteria are unique in their physiology, endogenous metabolism, immune evasion, dormancy and resuscitation, and they have proven to cause extreme drug resistance. HIV-TB co-infections further aggravate the TB pandemic amongst HIV-positive patients. Therefore, it is critical to accelerate the development of more effective combination therapy regimes. Context of the research: AMR in tuberculosis (TB) and TB-like respiratory diseases pose challenges in combating lung infections through existing treatment. Failure to treat a patient effectively with first-line anti-tubercular drugs mandates the use of a gruelling regimen with second-line drugs, with drawbacks including inflammation and tissue damage at the site of infection. Repurposing drugs presents an effective alternative to the time-consuming and expensive task of discovering new compounds. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) generally used as anti-inflammatory agents, have been reported to show anti-tubercular activity. Carprofen demonstrated good chemotherapeutic potential in shortening TB chemotherapy due to its additional bactericidal mechanisms of antibiotic action. Furthermore, our recent research has identified several prospective targets of carprofen on mycobacteria including efflux pump inhibition and biofilm disruption, key intrinsic mechanisms of antimicrobial resistance in mycobacterial infections. The promise of effective, shorter treatment regimens using first-line drugs in conjunction with carprofen is thus enticing. The primary aim of this proposal is to integrate multidisciplinary research expertise to accelerate the development of new antibiotic treatments to tackle drug-resistant infections. This will be achieved through defined tasks assigned under interconnected work packages to (a) investigate carprofen's anti-tuberculosis mechanisms of bactericidal action to validate its therapeutic potential as an adjunctive to first-line anti-TB drugs and its ability to reverse AMR; (b) design, synthesise and optimise lead carbazole-carboline scaffolds with improved bactericidal efficacy; (c) develop carprofen into nanosized formulation lung-delivery systems for enhanced targeted distribution and therapeutic efficacy with minimum metabolism and dose requirement; (c) conduct pharmacokinetics, pharmacodynamics and toxicity studies on infected mice model to advance the selected lead for further drug development. Potential applications and immediate benefits: The outcomes will be applied to disseminate and manage the multidisciplinary project with outreach, and impact activities on a global scale. Identification of new chemical leads with potent anti-tuberculosis activity and/or the ability to reverse AMR will accelerate further research into lead optimisation and provide a pipeline for clinical trials. Formulation of these molecules to a lung-targeted delivery system will provide direct reach; and will serve as an adjunctive chemotherapy for TB and related infections. This approach is consistent with the WHO's "End TB Strategy", which seeks to reduce TB incidence by 90% by 2035 and with the UKRI's mission to combat infectious diseases worldwide.
Multi-target DNA binding: A novel approach to combat foodborne and AMR bacteria
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Salmonella spp., a Gram-negative bacterium, is a leading cause of global foodborne bacterial infection. Symptoms include fever, diarrhoea, vomiting and abdominal cramps, however the infection has become life-threatening to people with weakened immune systems. The majority of worldwide non-typhoidal foodborne Salmonellosis is caused by S. enteritidis and S. typhimurium. In Southeast Asia, Thailand and Malaysia in particular, Salmonella infections have remained a crucial health burden due to rapid antimicrobial resistance (AMR) in the region. Tackling these problematic infections is aligned with the WHO’s Global Action Plan on the AMR. Strathclyde Minor Groove Binders (S-MGBs) are an anti-infective platform that has successfully delivered molecules that are potent against a wide range of pathogenic organisms, including bacteria, fungi, parasites and viruses. The molecule class has been externally verified as ‘novel’ according to WHO criteria, which is an important aspect of dealing with AMR. However, until now S-MGBs have demonstrated limited activity against Gram-negative bacteria. Recently, researchers from the University of Strathclyde have identified several promising, and novel, S-MGB molecule types with improved activity against Gram-negative pathogens, including Salmonella spp. In this project, we aim to enhance the capability of newly developed S-MGB molecules against Salmonella spp. and to increase awareness of global AMR though STEM education. Specific objectives to achieve these goals include : 1) to design and make improved S-MGB molecules, and test their effectiveness against Gram-negative pathogens, principally Salmonella spp., and their cytotoxicity against mammalian cells. 2) to gain insight into how these new S-MGB molecules kill bacterial pathogens by looking for differences in the gene expression of Salmonella spp. after exposure to S-MGB molecules, and by monitoring their uptake into bacteria using microscopy. 3) to deliver a sustained programme of STEM outreach to school students in Scotland, Malaysia and Thailand.
Development of host-directed therapy for targeting Mycobacterium tuberculosis persisters
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Antimicrobial resistance (AMR) is a significant global challenge. It is estimated that nearly 10 million people will die from infection with multi-drug resistant bacteria by 2050 if novel antimicrobials and advanced control measures are not introduced. While mechanisms of acquired AMR are well established the biology of persisters, drug-sensitive bacteria that survive exposure to bactericidal drugs and result in treatment failure, remains poorly characterised. Persisters are particularly important in tuberculosis (TB) which is the main cause of mortality from infection in Southeast Asia. Indonesia has the world’s second highest TB burden which is further complicated by the low rate of treatment coverage, low successful treatment rate of multi-drug resistant (MDR)TB and high number of TB re-treatment cases. The TB relapse rate in Indonesia is nearly 4 times higher than TB reoccurrences in Leicester, indicating that a higher proportion of patients are not cured or do not adhere to prescribed regimens. This challenging situation has a negative impact on Indonesian health system, people well-being and economy. Thus, reducing TB recurrence by improving TB treatment and educating patients is the key need in Indonesia. TB requires prolonged chemotherapy with a combination of drugs. Mycobacterium tuberculosis (Mtb), the causative TB agent survives in infected patients by adopting a special difficult-to-culture (DC) persister-like state. These drug recalcitrant DC Mtb persisters are believed to cause TB relapse and failed TB treatment. DC Mtb are highly abundant TB patients and can be recovered from sputum. Host immune factors associated with the inflammatory response trigger formation of DC Mtb, while anti-inflammatory drug dimethyl fumarate (DMF) removes DC Mtb from infected animal tissue. The central hypothesis of this proposal is that DC Mtb can be eliminated via host-directed therapy by altering the immune response and the niche that promotes their formation and survival. This collaborative project between the University of Leicester (UoL) and Hasanuddin University (UNHAS) is aimed to investigate the biology of DC Mtb persisters and to develop new chemotherapeutic for rapid eradication of DC Mtb in patients. This will be achieved by completing the following objectives: (1) discovery of drugs with dual anti-mycobacterial and anti-inflammatory activities suitable for elimination of DC Mtb; (2) determination of the factors that affect abundance of DC Mtb in infected patients; (3) exploration of the molecular mechanisms underpinning bactericidal effects of the new drugs on Mtb persisters; (4) to increase public awareness about the importance of adhering to treatment and eliminating Mtb persisters. The proposal applicants will embrace a collaborative multidisciplinary approach supported by complementary expertise in clinical TB research, generation and assessment of Mtb persisters, infection studies, omics technologies. Research activities will be enhanced by interactions with key stakeholders, clinicians, researchers, patients. These interactions will be directed on identification of further health and research needs concerning TB treatment and management, formulation of innovative solutions and increase of public awareness about the importance of AMR, TB and Mtb persisters. The proposed project will strengthen research in both institutions by enabling exchange of materials, protocols, and knowledge, provision of training, publishing of research finding and exploring translational opportunities. The development of host directed anti-persister therapy will have a direct impact on improvement of TB treatment and management in Indonesia and will stimulate expansion of the existing collaboration for controlling major infectious diseases.
One Health Rationale to Investigate the emerGence of AMR related to chicken Meat and Egg consumption (OHRIGAME)
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
With growing demand for protein from animal origin, the poultry industry is experiencing an unprecedented intensification in Southeast Asia. Industrialisation of livestock farming is accompanied by an overuse/misuse of antimicrobial drugs (AMD) which is believed to be a significant driver of antimicrobial resistance (AMR). AMR is a major threat for human and is reported to be responsible for close to a million deaths, yearly. The team assembled in this project has worked together within the UKRI GCRF One Health Poultry Hub, to generate robust evidence of excess AMD use in poultry production systems within Vietnam, using a holistic One Health approach that integrates studies from biological and social science disciplines. This foundation has generated knowledge on the overall structure and vulnerability of poultry production systems in Vietnam, with insights into the lives of farmers and other actors, including differences in the roles, responsibilities and behaviours of men and women working across the network. It also highlighted an alarming prevalence of food-borne pathogens in chickens, showed that chicken gut bacteria and microbial communities have high levels of AMR genes resulting in resistance to many AMDs, and that AMD residues over the maximum residue limit (MRL) are present in ~ 9% of meat on sale to the public. This project will continue the interdisciplinary approach to generate new knowledge on the dynamics of AMR acquisition during the production cycle, to understand the drivers of high AMD use in Vietnam chicken production, and to investigate potential impacts of unintentional exposure to AMD and resistant bacteria by ingestion of contaminated water (chickens) of food (chickens and humans). The objectives of the OHRIGAME project (One Health Rationale to Investigate the emerGence of AMR related to chicken Meat and Egg consumption) are to: Through longitudinal sampling, evaluate AMR in chicken gut bacterial populations during their breeding until sale Use forensic investigative analyses to identify underlying reasons for the high level of veterinary drugs in meat, by analysis eggs, chicken feed and drinking water, and relate this to AMR profiles within the same chickens. The Vietnamese government’s ban of prophylactic antimicrobial use, coming into place in 2025, will constitute a natural intervention. Use questionnaire based research to understand farmers’ motivations for under-reporting use of AMD. We will also sample chicken meat imported from Vietnam and hospital-grade food in the UK to evaluate the risk of that AMD residues and AMR genes could pose to clinical populations of patients at risk of gut bacteria dysregulation. From the start in Vietnam we will work with local and national stakeholders from government, particularly the Department of Animal Health within the Ministry of Agriculture and Rural Development, with whom we have a well-established relationship, and with the One Health Partnership secretariat, agencies, NGOs and the poultry sector. With expansion of analysis capacity, we will propose a framework to increase Vietnam capability to screen AMD residue and AMR in chicken meat production to protect the national consumers, a key priority of the Vietnam’s Decision No. 4 14 /QD-TTg (Strengthening capacity to manage and control animal diseases and diseases transmitted between animals and humans).Our international One Health approach includes AMR diplomacy actions which will benefit people locally in Vietnam and is completely aligned with the UK National Action Plan on AMR.
Emergence, Persistence and Control of Avian Influenza Zoonotic Risk
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Highly pathogenic avian influenza (HPAI) persists in poultry in several countries around the world, with Africa and Asia most severely affected by the disease. The H5 subtype is a major public health concern, with 889 human cases reported to April 2024, approximately half of which were fatal. Poultry to human transmission is especially prevalent in regions where smallholder poultry farming is commonplace, with Indonesia previously being most severely affected by human disease. Additionally, since 2019, there has been a significant increase in cases of H5N1 in poultry and wild birds in Europe and North America and reports of spillover cases to mammalian populations, including recently in cattle farms in the USA, resulting in the World Health Organisation (WHO) declaring that H5N1 poses a risk to humans. The overall aim of this project is to develop an understanding of the demographic, management and behavioural characteristics that affect transmission risk of avian influenza viruses (AIV) within and between poultry farms and between poultry and humans. This will allow us to provide critical information for farmers, government authorities and the general public in Indonesia to implement appropriate surveillance and interventions for reducing the risk of human exposure to HPAI. Our project will consist of three work packages (WPs). In WP1 we will undertake a human behavioural survey and a field study of poultry farms in Indonesia. Using a questionnaire, we will collect information on human behaviour, farming habits, temporal changes in farm/flock sizes, and syndromic detection of disease (e.g. flock death records). Laboratory samples for virological and serological analysis will be taken to detect the presence of current HPAI viruses and antibodies against AIV in poultry and humans. In order to obtain accurate data on circulating H and N subtypes, pseudotyped virus (PV) will be used in neutralisation tests. These biological data will be used in WP2 and WP3. Information will also be collated on the human population, the distribution of poultry farms in Indonesia and case reporting data in the region. In WP2 we will construct a mathematical model to simulate the spread of HPAI within and between poultry farms and at the poultry-human interface. The model will utilise the data from WP1 to determine transmission parameters and the spatial pattern of transmission risk. This will provide information regarding regions that should be targeted for surveillance to reduce the likelihood of future poultry outbreaks and consequently lower the human health risk. In WP3, the model will be used to determine the effectiveness of active surveillance and intervention strategies and their impact upon zoonotic disease transmission. We will employ an adaptive management framework that will enable surveillance and control strategies to be modified during outbreaks as more information becomes available. The key deliverables of this grant will be an increased understanding of the human health implications of HPAI outbreaks in Indonesia, an identification of high-risk regions and an exploration of appropriate adaptive strategies for future outbreaks. The Indonesian team has a proven track record of working with local policy makers which will ensure that our policy recommendations are communicated to appropriate national authorities and local practitioners. The project investigators also collaborate closely with the WHO and the Food and Agriculture Organisation and will liaise closely with these agencies during the project, thereby maximising both the regional and global impact of this research.
A One Health framework to assess the risks of antimicrobial resistance in aquatic ecosystems in North-East Thailand and inform mitigation strategies
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
The rapid global rise in antimicrobial resistance (AMR) is a critical public health crisis. It is widely acknowledged to be a One Health challenge, with aquatic environments playing a role of in the development and spread of AMR to people and animals. Aquaculture is an essential food production sector in South-East Asia; however, overuse of antibiotics and poor adherence to antibiotic treatment regimes are considered key contributors to rapid AMR development in the aquatic environment. This includes several classes of antimicrobials essential to treat human infections that are delivered to fish through medicated feed directly in shared waterbodies. Despite these concerns, the risks associated with environmental AMR – including the relative contribution of aquaculture – are poorly characterised and quantified, making it challenging to devise appropriate mitigation strategies or assess their effectiveness. This study will apply a One Health approach to elucidate the contribution of aquaculture production to environmental AMR and the subsequent risks for people, using the Pao River watershed in north-eastern Thailand. In this region, tilapia farming in open cages is commonly practiced and our team has documented high levels of unregulated antimicrobial use, wherein farmers frequently use products with unknown formulations or products not necessarily developed for use with fish. The risks that this poses for driving the selection for AMR are unknown. Moreover, antibiotic-treated feed is commonly prepared without the use of appropriate personal protective equipment such as masks and gloves, representing a potential risk for heightened AMR in fish farmers. Also in this watershed, our previous study revealed high levels of multi-drug resistant E. coli in banteng – a species of wild cattle – compared with local domestic cattle. This has led us to hypothesise that wildlife and people are at risk of acquiring AMR through this shared water source as a consequence of antibiotic use in aquaculture. To characterise and quantify these risks, we will: Assess the relative contribution of different sources of AMR to the Pao River watershed, and determine the degree of sharing of AMR bacteria/genes across the One Health spectrum. This will be done by i) measuring concentrations of antimicrobial residues and types/levels of resistant bacteria up- and down-stream of fish farms and compared with control sites without aquaculture; and ii) determining the AMR profiles of two key indicator bacterial species isolated across the One Health spectrum within the watershed (i.e. from samples collected from people, livestock, wildlife, fish) to assess for the specific contribution of aquaculture amongst other potential sources of AMR. This will be investigated through a combination of phylogenomic approaches and source attribution modelling. Characterise the practices and risks related to antimicrobial use in aquaculture as a potential driver for AMR in the aquatic environment. This will include measuring the quality and quantity of antimicrobials used, how they are administered, and what is driving these treatment decisions. We will assess likely uptake of different intervention options for improving antimicrobial stewardship through a stated-preference choice experiment. Based on the key risks identified, potential interventions to reduce the development and spread of AMR will be co-developed with multiple stakeholders, incorporating regulatory, political, economic and social dimensions. Overall, this study will generate new knowledge on AMR risks from aquatic food production and lead to an intervention pathway.
Protecting high risk groups from Plasmodium knowlesi malaria
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Malaria, an infection caused by Plasmodium parasites transmitted through infective mosquito bites can cause severe illness and remains a significant global health concern. In Southeast Asia, while progress has been made against major human malaria parasites, simian malaria parasites, including Plasmodium knowlesi, have emerged as a major source of zoonotic infections. In Malaysia, P. knowlesi now accounts for all malaria cases and together with recent outbreaks also reported in Thailand this parasite presents a major challenge to malaria elimination in the region. P.knowlesi is not affected by standard malaria control approaches and Malaysia, which has made exceptional progress in reducing P.vivax and P.falciparum is unable to be certified malaria free by WHO because it has P.knowlesi cases. Currently WHO guidlines are that P.knowlesi should be at ‘negligible’ risk, which will require a significant reduction in the number of zoonotic malaria cases in Malaysia. This proposal aims to facilitate that reduction. Our previous work has identified areas of rapid land use and land cover change as areas associated with both the primate host and mosquito vectors host of P.knowlesi. Thus individuals who work in these areas such as loggers and plantation workers are at highest risk of infection and developing disease. Our work will comprise of 3 aims. Firstly, we will work with partners to refine the P.knowlesi risk maps to identify using contemporary environmental and case report data. We will focus on the identification of specific sites for this study but the approach will provide a national and regional resource for future surveillance and control activities. Secondly, using the sites in aim 1 we will identify high risk populations withon these areas and evaluate control methods to reduce the incidence of infection in these people. The primary intervention for which the study will be be powered is a cross-over chemoprophlatic study monthly using Dihydroartemisinin piperaquine in individuals. Infection will be assessed by a novel Loop-mediated isothermal amplification (LAMP) which has emerged as a promising tool for molecular malaria diagnosis due to its simplicity and rapidity. Our preliminary studies suggest LAMP's effectiveness in diagnosing simian malaria species. We will also evaluate the accpetability and utility of personalised vector control namely insect repellent (DEET)-impregnated anklets and wristbands. These have shown promise in reducing mosquito bites, however, their effectiveness against zoonotic malaria vectors remains unexplored and we therefore aim to evaluate this personal-level protection in high risk workers. Thirdly, we will work with local and national stakeholders (local small scale farming communities, plantation owners, MoH) to understand if and how the approaches can be adopted and used more widely. We will examine different potential delivery and funding scenarios to advise regional and national control programmes on optimal methods to reduce P.knowlesi in these high risk groups. Together these aims will reduce the burden of P.knowlesi at individual and community levels in Malaysia and allow wider adoption in affected areas.
DNA-launched Nipah virus vaccines and therapeutics
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Background: Despite the significant threat Nipah virus poses to both human and animal populations across Southeast Asia, neither vaccines nor therapeutics are currently available to prevent or treat infection. If the delivery challenge could be overcome, DNA-launched approaches have advantages over other platforms (including mRNA) for vaccines and therapeutics, such as low production cost, time-to-impact, and enhanced stability for transportation/storage. We have generated an injectable DNA vaccine platform which we are exemplifying as a Zika vaccine (IUK, SBRI funding), which is currently being tested in mouse and non-human primate models. Translating the gains of the effective delivery system with DNA-encoded antigens or therapeutics would be transformative for tackling Nipah virus. Study aims: We propose to exploit our recently established DNA-delivery platform to advance the development of effective, affordable, and scalable Nipah virus vaccines and therapeutics. Our platform is based on polymer/peptide nanoformulations that are vectors for DNA delivery. Due to the simplicity of formulation this opens up the possibility of a tractable and deployable method to vaccinate and treat Nipah in a ‘One Health’ approach tackling both human and animal disease. This study aims to generate the pre-clinical efficacy data needed to support the further translation of the approach. The approach: Whilst the protective antigens from the Nipah virus are well defined and could be readily engineered into the DNA vaccine platform, there are a limited number of human monoclonal antibody (mAb)-based therapeutic candidates, with only one in clinical testing. We therefore propose to isolate new therapeutic candidate mAbs from human volunteers in Malaysia, who previously recovered from Nipah virus infection. Both DNA-encoded vaccine and therapeutic mAb candidates will be evaluated in preclinical animal models. After initial optimisation using a mouse model, vaccine and therapeutic candidates will be assessed evaluated for immunogenicity and pharmacokinetics, respectively, in pigs. And their efficacy to protect against Nipah virus infection will be tested in hamsters. We will also compare plasmid and synthetic DNA systems (dbDNA) which will improve low and single-dose efficacy, with more rapid and deployable manufacture. Outputs: The major gain here is the discovery and preclinical testing of DNA encoded Nipah virus vaccine and therapeutic candidates, supporting their further clinical development. Furthermore, the livestock testing of the platform could be transformative as a route as an agricultural vaccine, which could prevent and contain Nipah virus outbreaks in affected areas of Southeast Asia
Comprehensive Monitoring System for Tackling the Resurgence and Persistence of Malaria and Priority Diseases for Elimination in the Philippines
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
The Philippines has set a visionary goal of attaining zero or significantly reduced infections with malaria, several vaccine-preventable (VPDs), and neglected tropical diseases (NTDs) through an effective healthcare system by 2030. Yet, the country faces challenges in realising this goal. Malaria elimination initiatives are threatened by sub-patent infections that are missed by conventional diagnostics and sustain transmission, antimalarial drug resistance prevalent in Southeast Asia, increasing worldwide vector resistance to insecticides, and diagnostic failure. After years of consistent progress in defeating malaria, with only the province of Palawan reporting cases, the Philippines is currently experiencing a resurgence of Plasmodium falciparum and P. vivax. Consequently, many VPDs and NTDs persist, and in some cases result in outbreaks or re-emergence, despite effective measures. Although the Philippines has relatively low burdens of these diseases, achieving the ambitious goal of elimination necessitates building and, equally importantly, maintaining robust monitoring and surveillance systems for co-endemic diseases. Additionally, training a cadre of scientists who embrace innovations in laboratory, epidemiological, and data sciences is essential to support the country's determination to create a future free from the burden of many of these diseases. Our project, CoSTaR, rises to the challenge of disease elimination by developing sustainable and scalable solutions for malaria and priority infectious diseases in the Philippines. We will employ and refine effective molecular and serological platforms to measure residual malaria transmission in the population (WP1/2). Our serological platform for malaria is flexible and adaptable, permitting the simultaneous assessment of exposure to VPDs and NTDs that may persist in a population. We will develop this platform to address the country’s need for a first-of-its-kind integrated multi-disease monitoring system (WP5). Representing a paradigm shift in elimination efforts, this platform offers an evidence-based solution to understand population immunity against these diseases, define disease-specific transmission dynamics, and identify demographic and spatial risk factors associated with pathogen exposure, thereby complementing the government’s elimination initiatives. Solutions are also warranted to determine the biological factors that may affect residual malaria transmission. Thus, we will define the genetic structure and antimalarial drug resistance profiles in persisting parasites (WP3). Additionally, we will analyse the human host response enabling parasite persistence (WP4). In a supplementary study, we will provide baseline data on markers of vector resistance to insecticides currently being used in the country (SS). Our innovative solutions leverage the equitable and enduring partnership between the Department of Health’s (DOH) Research Institute of Tropical Medicine (RITM) and London School of Tropical Medicine and Hygiene (LSHTM) – lead teams in this project. Capacity strengthening and knowledge exchange, complemented by community engagement and stakeholder outreach, constitute the cornerstone of our project strategy (Cores). Along with Palawan State University (PSU), we will empower researchers and communities to be actively involvement in disease awareness initiatives. We will further enhance capacity in laboratory investigations and applied epidemiological analysis, nurture leadership and collaborative efforts among our researchers, and optimise the impact of our initiatives through close engagement with the local Municipal Health Office (MHO), and a wide range of local, regional, and national stakeholders. Ultimately, our efforts aim to strengthen the resilience and sustainability of disease monitoring in the Philippines, improve health outcomes, and leave a legacy of innovative and impactful research, along with well-trained researchers who will advance global health practices.
INTERCEPT: INTerrupting prolifERation of Carbapenem resistance in Indonesia: clinical and genomic Evaluation of Pathways of Transmission
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Bacteria that are resistant to last-line antibiotics of the carbapenem class are a global public health threat, and classified as critical priority pathogens by the World Health Organisation. In Indonesia, they are a serious problem and common disease-causing bacteria are frequently resistant to carbapenems. The routes by which people acquire these bacteria are unknown, but scarce data from Indonesia and experience in other settings suggests that transmission in hospitals is likely common: strategies to block transmission are needed. Infection prevention and control (IPC) and antimicrobial stewardship provide tools to do just that; the principles of these disciplines have been established in high-income settings since the 1950s, yet despite sporadic attempts to deploy them in Indonesia, carbapenem resistance has emerged and proliferated. This mirrors the earlier rapid spread of extended-spectrum beta-lactamase (ESBL) producing bacteria: these bacteria – problematic to treat in their own right - confer resistance to older antibiotics of the beta-lactam class. Carbapenems are commonly used to treat, which in turn has driven carbapenem resistance. To break this vicious cycle, new interventions to block transmission of resistant bacteria that are locally-adapted and sustainable are required. But understanding transmission is complex. Bacteria can resist antibiotics by acquiring genes that confer resistance, but these acquired genes can be transported by many vehicles, often nested, like a Matryoshka Russian doll: “jumping genes” (transposons) can jump to and from bacterial chromosomes and replicating genetic fragments (mobile genetic elements like plasmids), which can themselves jump between bacteria. Bacteria can move between animals, the environment, and humans, living harmlessly in the human gut (so-called colonisation) prior to causing invasive disease when they escape into (for example) the bloodstream. At the health system level, humans carry resistance genes with them as they move between health facilities and the community; travel disseminates them globally. INTERCEPT brings together UK and Indonesian researchers to tackle this problem, using cutting-edge techniques to identify key transmission routes across this complex system, then co-designing and piloting interventions to block them. At different levels of the Indonesian health care system, we will test humans and the environment for colonisation with carbapenem-resistant bacteria, as well as community members and hospital wastewater, defining flow of resistance genes into and out of health facilities. We will recruit a cohort of patients with bloodstream infection to properly define current treatments and outcomes of people with carbapenem-resistant infection, and identify and interview key stakeholders to understand perceived barriers to the implementation of effective antimicrobial stewardship and IPC interventions. Whole-genome sequencing techniques will fully describe bacteria and resistance genes and mobile genetic elements, tracking them through this system; mathematical models will identify key transmission routes. We will take clinical strains into the laboratory where molecular biology techniques developed at the Liverpool School of Tropical Medicine will allow us to understand mechanisms of resistance and the capability of carbapenemase genes to transfer within and between bacteria. Ultimately, insights from these analyses will inform design of locally-adapted interventions. We will convene workshops of key institutional and government stakeholders to co-design interventions, and pilot them whilst ongoing sampling assesses the impact on transmission. INTERCEPT will provide practical data to guide interventions aligned with national and international AMR-control priorities, suitable for scale-up and larger scale assessment, but also insights into transmission of carbapenem resistance that will benefit hospitalised patients in Indonesia, and worldwide.
Tackling antimicrobial resistance in Aspergillus fumigatus in South East Asia
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Pulmonary aspergillosis is a severe lung infection due to a green mould called Aspergillus fumigatus. We all inhale between 100 and 1000 Aspergillus spores daily, which can cause infections with mortality of around 40%, mostly in people with chronic lung diseases or weakened immune systems. There are estimated to be 4 million cases of pulmonary aspergillosis globally per annum, but very little is known about rates in South-East Asia. Antifungal resistance to the main class of drugs used to treat these infections, the triazoles, is rising. Environmental resistance rates of up to 90% have been detected in Vietnam, and 30% in Thailand. Resistance has been shown to double mortality. Work in Europe has shown that the increase in resistance is due to dual-use effects of triazole fungicides used in agriculture, as fungi are major crop pathogens. Resistant strains of Aspergillus fumigatus are emerging in the environment and causing infections in patients. As a consequence, the pharmaceutical industry is developing novel antifungal classes, however equivalent fungicides with the same mechanism of action are now being developed, and cross-resistance has been shown to occur experimentally. Fungicide usage is rapidly escalating in South-East Asia, but whilst composting has been identified as a major amplifier of azole-resistant Aspergillus fumigatus (ARAf) in Europe, composting is not routinely performed in South East Asia. However the higher temperatures in this region mean that amplification may occur independently of compost. Therefore understanding the agricultural drivers and hotspots for amplification of Aspergillus resistance and the impact on human health in South East Asia is urgently required. This will allow us to develop rational interventions to mitigate the risk of high mortality pulmonary aspergillosis infections whilst ensuring that food security is not compromised. Aims 1: Develop novel point-of-care technologies to enable field testing for fungicide concentrations and levels of ARAf in South East Asia We will use low-cost “Delta Traps to sample air and “eco sensors” to capture water samples from soil. Fungicides will be detected using innovative point-of-care tests and ARAf identified using portable DNA tests. Techniques will be validated using Mass Spectrometry and Metabarcoding. 2: Field studies in Thailand, Vietnam and Laos to determine the extent of antifungal usage in the environment and the relationship to ARAf. Capacity building in local laboratories at specific hub sites in Bangkok, Hanoi and Vientiane to enable field testing and accurate diagnosis of pulmonary aspergillosis. We will then undertake field studies across one health aimed at understanding the extent of rural and urban anfungal use in the environment, the relationship to ARAf in the environment, the burden of pulmonary aspergillosis and the degree of resistant infections 3: Develop an appropriate interventional strategies to try to mitigate the risk of ARAf. We will assess local practices for fungicide use, undertake further experimental work to better understand the safe levels of fungicide usage in the environment. The evidence we generate will enable us to engage the agricultural industry, end-users, and policy makers to develop just interventions to mitigate the risk of ARAf. Together, these studies will deliver training and capacity building for South East Asian partners to be able to track Aspergillus resistance, identify its underlying causes, and be able to determine the impact of resistant Aspergillus infections on human health. A international framework will be developed to tackle the underlying causes.
Targeting Thai-invasive malaria vectors by novel parasite metabolite bait trap
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Malaria is an infectious disease that poses a significant threat to public health. It has a major impact on the mortality and morbidity rates of children under the age of five, as well as pregnant women, and it also reduces labour productivity. In Thailand, malaria remains a significant public health challenge, with varying prevalence across regions. This parasitic disease is transmitted by Plasmodium-infected Anopheles mosquitoes and continues to burden affected populations. Thailand has malaria-receptive Anopheles mosquito species. The current malaria control and elimination program in Thailand relies mainly on two vector intervention tools: long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), which use insecticides to mitigate malaria transmission. The emergence of Anopheles strains resistant to currently used insecticides pose a critical challenge to achieving malaria elimination by 2030 in Thailand. Therefore, vector control is an essential aspect of combating malaria transmitted by Anopheles. The metabolite HMBPP (E-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate), produced by the malaria parasite P. falciparum, has a significant impact on the host-seeking and blood-feeding behaviour of African malaria mosquitoes such asAnopheles gambiae complex, both in laboratory and field settings. Our research has demonstrated that HMBPP acts as a direct attractant and also triggers the release of a blend of volatile organic compounds from human blood, which serves as a powerful attractant. The discovery of HMBPP and its effects make it a promising candidate for the development of a targeted mosquito control tool. Since P. falciparum is the primary malaria parasite transmitted by Anopheles vectors in Thailand, we propose that bait traps containing HMBPP could serve as a novel vector control tool in the country. Therefore, the main purpose of this research proposal is to evaluate a novel, environmentally friendly parasite metabolite bait trap for mass trapping of Thai vectors in malaria-affected regions of Thailand. In this regard, a specific aim is to evaluate the behaviour and fitness of local Thai mosquito vectors after exposure to and feeding on blood containing HMBPP. Another aim is to determine the behaviour and death rates of Thai mosquito vectors using different natural based toxins in metabolite bait traps. Finally, the effects of the candidate metabolite bait trap will be assessed on vector population suppression in a semi-field setting in Thailand.
AI-powered Diagnostic Workflow for Predicting Transmissibility and Drug Resistance in Avian Influenza Viruses
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Emergent diseases such as COVID and avian influenza presented formidable challenges to global public health. To survive and spread, pathogens evolve through genetic mutations which allow them to jump from one host to another or develop resistance to antiviral drugs. Traditional methods for identifying these mutations are slow, costly, relying on detection of actual cases to trigger analysis and response efforts. Alternatively, gain of function studies present biosafety concerns and risks. By contrast, computational methods offer a faster, safer and more cost-effective way to detect mutations underlying phenotypes such as increased transmissibility or antiviral resistance(AVR), providing a proactive approach to combating emerging zoonotic threats. While structure-guided machine learning techniques exist for predicting impacts of mutations, they typically handle single-point mutations, whereas often multiple mutations are required for full phenotypes. Additionally, these existing techniques do not yet employ Protein Language Models (pLMs), which have revolutionised our understanding of protein sequences and structures. These models are trained on vast amounts of protein data and encode evolutionary, structural, and functional information. In this project, we will leverage pLM embeddings, structural information and other features to produce two AI-powered predictors reporting the impacts of mutations likely to induce changes in the affinities of host-viral interactions and AVR. We will use the avian influenza virus as our test target. Avian influenza is carried in wild birds but can be transferred into domestic poultry. Recent outbreaks of H5N1 avian influenza have occurred in 67 countries, leading to the loss of over 131 million chickens and drawing attention to avian-to-mammal and potential mammal-to-mammal transmission. Indeed the first documented cases of cow-to-human transmission in the US in April 2024, highlight the growing risk of zoonotic spillover. Additionally, AVR has already been observed for almost all antivirals against influenza, underscoring the need for proactive intervention and improved understanding of the evolutionary potential of this virus. Our project has six aims to address key challenges in understanding and combating emerging avian influenza viruses, giving computational approaches which can then be extended to other pathogens- Develop a computational pipeline for collating all structural data on pathogen strains and host-pathogen interactions. Build two AI-based predictors exploiting structural/physicochemical properties and pLM Host-viral interaction predictor reporting mutations that facilitate cell entry, replication etc. AVR predictor for resistance to the licensed antiviral drugs Validate the AI based predictors using surrogate viral systems Sialic acid binding assay using pseudotyped viruses, expressed HA protein and cell-cell fusion assay Polymerase assays using minigenome reporters performed in human cells (viral polymerase with human ANP32 proteins) AVR to antiviral drug by performing surface plasmon resonance experiment and minigenome polymerase assay Establish a diagnostic portal, reporting impacts and thereby aiding in the identification of novel threats Organise a Southeast Asia stakeholder workshop to demonstrate the diagnostic portal and engage with experts in zoonotic surveillance and AVR. Once validated, the mutations identified will be seamlessly integrated into global avian influenza surveillance programs, particularly in Southeast Asia, to help combat the spread of resistant infections and reduce infection rates in healthcare settings and broader community. Study results will be useful for development of future antiviral therapeutics with molecules that circumvent resistance development. This project benefits from a collaborative partnership between the UK and Malaysia, promoting knowledge sharing, resource exchange, and adoption of best practices.
Point-of-Care Innovative Sequencing Technologies and AI-Based Methods for Effective Diagnosis and Management of Antimicrobial Resistance in Leprosy
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Antimicrobial resistance (AMR) in infectious diseases is increasingly recognized as a severe threat to global public health. AMR occurs when bacteria, viruses, fungi, and parasites evolve to resist the effects of medications, rendering standard treatments ineffective and leading to persistent infections. This resistance is fuelled by the overuse and misuse of antibiotics, poor infection control practices, inadequate sanitary conditions, and the global movement of people and goods. Leprosy, a chronic infectious disease characterized by granulomatous lesions affecting the skin and peripheral nerves, is caused by the bacterium Mycobacterium leprae (M. leprae). In 2022, approximately175,000 new cases were reported globally, predominantly in tropical regions. Standard treatment involves a multidrug regimen consisting of Dapsone, Rifampicin, and Clofazimine, administered over a duration of six months to one year. Since the 1960s, resistance to individual drugs has been observed, and recent findings indicate the emergence of multidrug-resistant M. leprae strains. As an obligate intracellular pathogen, M. leprae cannot be cultured in axenic media, necessitating the use of molecular diagnostics for detecting AMR. These diagnostics typically involve extracting M. leprae DNA, amplifying drug target genes via polymerase chain reaction (PCR),sequencing the amplicons to identify mutations, and performing bioinformatics analysis to determine the impact of the mutations on drug interactions and activity. While effective, this procedure requires advanced molecular/genomics laboratories, which are often unavailable in resource-limited settings, such as those in Southeast Asia. Additionally, the complexity and duration of in-vivo testing, which spans 6-8 months, make it impractical for routine diagnostic applications.Therefore, rapid, and accessible molecular diagnostic tools are crucial for effective disease management in endemic regions. The Philippines reports nearly 2,000 new leprosy cases annually. The absence of a decentralized diagnostic system for AMR in leprosy necessitates the development of innovative tools to ensure timely diagnosis and management. Understanding the mechanisms underlying AMR in leprosy is crucial for clinicians to identify alternative treatment regimens for drug-resistant cases. Leveraging our expertise in point-of-care compatible DNA amplification and sequencing technologies (Biomeme qPCR and Oxford Nanopore MinION based amplicon sequencing), along with our expertise in developing and maintaining sophisticated bioinformatics workflows and tools (such as HARP and HANSEN web databases), we propose the following objectives: WP1: Comparative evaluation of Biomeme qPCR and MinION-based DNAsequencing with conventional qPCR and DNA sequencing for detecting mutations in drug target-coding genes (rpoB, folP, gyrA, rpoC, fadD9, ribD, and nth) conferring AMR in leprosy. WP2: Development of a bioinformatics pipeline/workflow for the analysis of DNA sequencing data, determining mutations, and predicting the impacts of mutations on drug target protein structure, drug binding, and interatomic interactions. WP3: Decentralizing diagnosis of AMR in leprosy using point-of-care Biomeme qPCR and MinION-based DNA sequencing technologies at regional hospitals in the Philippines. WP4: Knowledge transfer, training, and capacity building of laboratory staff at the Department of Dermatology, Philippine General Hospital, and the College of Medicine, University of the Philippines, Manila. By advancing these innovative diagnostic tools and empowering local health systems, we aim to improve the management of leprosy and mitigate the impact of antimicrobial resistance in endemic regions.
Characterizing Molecular Adaptations and Drug Resistance in Leishmania spp. in Thailand: An Integrative Omics Approach to Combat Leishmaniasis
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Leishmaniasis, a neglected tropical disease caused by protozoan parasites of the genus Leishmania, presents a growing global health concern. In Thailand, the emergence of leishmaniasis, potentially transmitted by atypical vectors, poses a significant threat to immunocompromised individuals, particularly those co-infected with HIV. In addition, climate change is a potential increase in disease prevalence by altering insect vector distribution and population dynamics. Amphotericin B remains the primary treatment for leishmaniasis in Thailand, and Leishmania species of the subgenus Mundinia (L. orientalis and L. martiniquensis) exhibit relative insensitivity to this drug. Preliminary experiments displayed initial genomic and transcriptomic alteration after short-term treatments of L. orientalis with amphotericin B. This resistance is concerning as it may be associated with increased parasite fitness and potentially higher virulence. Addressing these critical issues necessitates a deep understanding of drug resistance and parasite adaptation mechanisms for the development of effective strategies for treatments. This research project leverages a pre-existing collaboration between researchers from the University of Glasgow (UK) and Kasetsart University (Thailand), which previously explored genomic structures of L. orientalis and L. martiniquensis strains in Thailand. The project aims to characterize molecular changes occurring during Amphotericin B selection in L. orientalis and L. martiniquensis using integrative omics technologies, parasite phenotyping and advanced computational analysis. We will investigate both innate and in vitro-acquired resistance using polyomic approaches, including bulk and single-cell sequencing and transcriptomics, proteomics, metabolomics and lipidomics, in parallel with assessing important phenotypes such as drug sensitivity and infectivity to macrophages. We will elucidate mechanisms of resistance and to identify markers that can predict Amphotericin-treatment failure. The collaborative research between the UK and Thailand teams will accelerate understanding these newly reported Leishmania parasites and benefit the control of leishmaniasis in Thailand and beyond. Bilateral knowledge exchange between Thailand and UK will be a key outcome of our project, leading to capacity building in Thailand and the establishment of critical collaboration between parasitologists working in the UK and scientists in Thailand, a country with an developing science base and an emerging problem with leishmaniasis.
Integrated Surveillance and Vaccine Development to Combat Community-Acquired Klebsiella Pneumoniae Infections
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Klebsiella pneumoniae (Kp) is a commensal bacterium commonly found in the human gut, nasopharynx and skins. However, it can also cause severe infections, particularly among those with comorbidities and immunocompromised conditions. The global health threat posed by Kp is recognized by the World Health Organization and international health agencies due to its escalating and challenging-to-control nature. In Vietnam and Southeast Asia, there has been a concerning rise in severe Kp infections, especially among the elderly. Two major pathotypes of Kp exist: classical Kp (cKp) and hypervirulent Kp (hvKp). cKp is known for its high antimicrobial resistance (AMR) and is a frequent cause of hospital-acquired infections among immunocompromised individuals. In contrast, hvKp is characterized by numerous virulence factors and its ability to cause severe invasive community-acquired infections, even in healthy individuals. Both pathotypes have been identified in Vietnam, posing a significant threat for the emergence of strains exhibiting both AMR and hypervirulence. While hospital-acquired Kp infections have received significant attention, leading to ongoing improvements in infection control and antimicrobial stewardship programs in Vietnam, the emergence of Kp, especially hvKp, in communities is less understood. Research into community-acquired Kp infections faces two main interlinked challenges. Firstly, the current hospital surveillance system is isolate-based and cannot effectively distinguish community-acquired infections, resulting in a poor understanding of at-risk populations, disease sources, and drivers of transmission within communities. Secondly, research capacity to develop effective preventive measures such as vaccines is limited, partly due to gaps in understanding disease and pathogen characteristics. In this proposal, we aim to integrate patient-oriented surveillance and vaccine development to combat community-acquired Kp infections in Vietnam. We will define the epidemiological and clinical features of community-acquired Kp infections, and quantify the transmission rates of Kp in the community. To achieve this, we will conduct a one-year patient-focused hospital study in three national and provincial hospitals in Ho Chi Minh City (HCMC) and Ha Noi. This study will identify all cases of community-acquired Kp infections and characterize their incidence, AMR and genotypic profiles, clinical features and outcomes. Furthermore, we will collaborate with HCM Center for Disease Control to enroll households of the hospitalized cases and independent community households in HCMC to quantify transmission rates of Kp (both cKp and hvKp) in the community. Additionally, metadata and gut microbiota characterization from patients and household members will help identify potential risk factors for Kp colonization and infection. These findings will be shared with local stakeholders and policy makers, facilitating the development of local treatment guidelines and targeted public health interventions. We will also assess the human immune responses to Kp antigens among patients with bloodstream infections and their correlation with treatment outcomes. By collaborating with University of Science in HCMC, we will measure antibody and T cell responses to candidate proteins among patients with bloodstream infections from the hospital study and healthy individuals, and correlate these data with disease outcomes (survival, severity score, length of hospital stays). This investigation will identify robust candidates associated with enhanced survival for further development of vaccines and monoclonal antibodies. Through this collaborative and strategic project, we will enhance research capacity in Vietnam to address public health challenges posed by Kp and other emerging pathogens. The project findings will contribute to global efforts in understanding community transmission dynamics of Kp and advance the development of targeted therapeutics and vaccines.
Accurate, Rapid, Robust and Economical diagnostic Solutions for UTI and drug resistance
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
There is an urgent need for the development and implementation of new tools for the rapid diagnosis of urinary tract infections (UTI) and its drug resistance profiling. In this co-developed project, we will, in concert, develop, evaluate and refine three approaches for the rapid and accurate diagnosis of UTI and their resistance profiles, and establish their clinical utility with our partners in Malaysia, Thailand and Vietnam, with the vision of promoting improved healthcare and wellbeing. Prompt and precise diagnosis including drug resistance profiling is critical for timely and accurate treatment of UTI, and reducing its progression to urosepsis. Sepsis kills 11 million people every year (2.9 million deaths under the age of five) and over 25% of sepsis cases start as UTIs. However, due to the lack of reliable and rapid diagnostics, patients are often empirically prescribed antibiotics. The rationale being that ‘gold standard’ culture-based techniques needed for bacterial identification and antibiotic susceptibility testing are time-consuming (typically up to 48 hours). This is a major cause of concern from many angles, as antibiotics can have serious adverse side-effects, and their overuse drives resistance. This happens as clinicians (and patients) are all busy, neither wants a repeat appointment, and the guess might work. What is needed is a work-flow where a patent’s urine sample is analysed (ideally within 30-60 mins), to allow the right antibiotic to be prescribed at the right time for the specific patient – in essence personalised medicine. The aims and objectives of this project are to support: (i) sustainable health via resource efficient early diagnosis of diseases through the innovative use of chemistry and electrochemistry and thus promoting well-being; (ii) inclusive and equitable training and technology validation with our partners and (iii) help develop sustainable livelihoods supported by strong foundations for sustainable, inclusive economic growth and innovation To achieve this, the objectives set encompass a series of parallel strands, as shown below: The application of a suite of technologies for the rapid and early assessment of UTI (and drug resistance profiles) in parallel with standard culture methods. A better understanding of and tackling key healthcare technology challenges specific to resource-poor settings Building focused, proactive and long-term interdisciplinary partnerships through dynamic collaborative relationships: establishing these as exemplars of best practice. Promoting across the international team both highly collaborative and multi-cross-disciplinary ways of working to enhance the provision and availability of better healthcare Leveraging the breadth of our international leading science excellence to: Provide training, skills development and knowledge transfer with our partners Embed within our partners an enhanced capability whilst promoting a strong culture of independence, innovation and entrepreneurship in the healthcare sector Enabling the very best, world-class collaborative research that builds stronger and lasting relationships and thus excellent research in the partner countries in the development of innovative research capability focused on affordable healthcare. The potential applications and benefits are myriad - The area of UTI and the antibiotic resistance profiling are the initial targets. Once validated, infections from multiple other areas will become accessible to the technology, showing its broad importance, and broader impacts. In addition, the project also has the potential to kick start a change in MedTech, in which electrochemical sensing, that offers low-cost solutions with robustness and quantification within a clinical diagnostic setting, becomes main-stream.
Development and assessment of novel, high-throughput immunological assays to improve surveillance of spillover of viral families of pandemic potential
DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY
Context Emerging infections pose a significant burden on healthcare systems and result in economic loss for societies worldwide as exemplified by the COVID-19 pandemic. Another new viral pathogen, causing ‘disease X’, will likely emerge in the future and pandemic preparedness is thus one of the top priorities of global agencies (UN, WHO, G20) and national governments. Vulnerable health systems, dense populations with close human-animal interactions, rapid urbanization and economic development, and stark health inequalities render Southeast Asia a hotspot for outbreaks of new and existing infectious pathogens, in particular zoonotic viruses. Yet, the region represents a weakness in pandemic preparedness and response. The challenge the project addresses Early detection of spillover events is critical to informing coordinated global responses, including the rapid development and deployment of effective and safe countermeasures, (especially diagnostics, therapeutics and vaccines) to prevent future pandemics or mitigate their health and societal impact. Existing surveillance platforms are primarily based on clinical diagnosis in healthcare settings supplemented, in some areas, by genomic surveillance. They often therefore fail to capture early cases and those with asymptomatic or mild infection. Despite their potential utility, owing to the current low throughput and technical challenges, antibody and T-cell assays are rarely used for zoonotic spillover detection. Here, we will first develop high-throughput, high-resolution antibody and T-cell assays to enable early detection of spillover events. We will then apply the developed assays to comprehensively map out the immune landscape against zoonotic viruses of the families Coronaviridae, Orthomyxoviridae and Paramyxoviridae in high-risk populations in Cambodia and Vietnam. The data will be used to evaluate how immunological data could be utilised as part of broader surveillance strategies and estimate their potential to improve earlier detection of spillover events. Finally, potent, broadly neutralizing antibodies against zoonotic viruses will be discovered using samples collected from study participants with a confirmed infection. Aims and objectives Our aims are To develop novel, high-throughput immunological tools for viral families of epidemic/pandemic potential To apply the assays developed under Aim 1 to map out the immune landscape against zoonotic viruses with pandemic potential in high-risk populations in Cambodia and Vietnam To utilize the data from Aims 1 and 2 to evaluate the utility of the novel immunological tools as part of broader surveillance strategies and estimate their potential to improve earlier detection of spillover events To discover potent and broadly neutralising antibodies against zoonotic viruses causing spillover documented under Aim 2 Potential applications and benefits Our project will ultimately build regional research capacity in immunology, metagenomics, modeling and monoclonal antibody discovery in Cambodia and Vietnam. Importantly, a strong collaborative network across the region, linked with international experts in the UK and Singapore will be established. Therefore, our collective outputs would lay the foundation for locally-led responses to future emerging infections.
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