NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the effect of climate extremes and global warming on HIV outcomes in sub-Saharan Africa
Funder: Wellcome Trust

Abstract: Sub-Saharan Africa (SSA) has the highest HIV burden in the world and will be the region most affected by climate change, with the largest projected decrease in rainfall and limited resources to deal with the consequences. Global warming will lead to more droughts and decreased food yields, resulting in increased food insecurity. Emerging evidence suggests food insecurity could lead to increased HIV transmission risk and sub-optimal HIV treatment outcomes, due to such factors as women resorting to selling sex for survival, access to HIV treatment being interrupted, and decreased HIV treatment absorption in the absence of food. This project will: - involve epidemiological analyses (regression, systematic reviews, meta-analyses) on large HIV datasets from SSA to improve the evidence base for the effect of drought and food insecurity on HIV treatment outcomes, HIV incidence and sexual risk behaviours in SSA. - use mathematical modelling to simulate the existing impact of drought and food insecurity on HIV transmission and morbidity in several countries in Eastern and Southern Africa. - model the potential effect of global warming in these countries on increasing the impact of drought and food insecurity on HIV transmission and morbidity, as well as the impact of potential interventions.

Lay abstract: Sub-Saharan Africa contains more than 70% of the world’s HIV burden and will be the region most affected by climate change. Global warming will lead to more droughts and increased food insecurity (less stable access to food) in Sub-Saharan Africa. Food insecurity could cause HIV transmission to increase due to women selling sex for survival and HIV treatment being interrupted or less effective on an empty stomach. I will combine data on droughts with datasets on HIV risk behaviour, transmission, and treatment to investigate how times of droughts and food insecurity are related to HIV transmission and illness in Sub-Saharan Africa. I will use mathematical models to estimate how much effect global warming is currently having, and could have in future, on HIV outcomes in Sub-Saharan Africa. I will also look at the effect of interventions (such as food parcels) to reduce the impact of food insecurity on HIV outcomes.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The eco-epidemiology of leptospirosis in South Africa and Madagascar
Funder: Wellcome Trust

Abstract: In a changing world, zoonotic pathogens are an increasing risk to human health. Leptospirosis is a widespread and common zoonotic disease with the greatest burden of disease falling on the poorest communities in the developing world. Leptospirosis is increasingly being recognised as a public health threat in South Africa and Madagascar and an urgent need has been identified to establish which Leptospira strains are responsible for human infections and what their key reservoir hosts are. Leptospira are notoriously challenging and time consuming organisms to culture. Therefore, using recent advances in DNA capture and enrichment technologies, I aim to identify evidence of transmission between reservoir hosts and humans by generating culture-independent high resolution molecular typing data directly from human and reservoir host samples. These data will be used to refine diagnostic antigen panels, identify the animal sources of human infection and inform control programs. Increasing the Leptospira genomic resources from sub-Saharan Africa will also allow me to explore fundamental questions related to the microevolutionary changes required for cross-species transmission of zoonotic pathogens and the role of horizontal genetic transfer in the evolution of bacteria in a real world system.

Lay abstract: Zoonotic diseases, diseases which are transmitted from animals to humans, include some of the most important diseases in humans. Many of the organisms which cause these diseases are difficult or dangerous to grow, leading to underdiagnosis and a poor understanding of how to control them. Leptospirosis, caused by the Leptospira bacterium, is one of the most common zoonotic diseases in the developing world with rodents or livestock usually acting as sources of infection. In South Africa and Madagascar, the disease is increasingly being recognised as a problem in some communities. Using a method for capturing DNA from clinical samples, I aim to identify the Leptospira strains responsible for human infections, the animals which act as sources of infection and the evolutionary changes which allow these strains to be transmitted between animals and humans. These results will be used to design better methods for diagnosing and controlling the disease in Africa.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Yellow fever vaccination- will a booster be needed?
Funder: Wellcome Trust

Abstract: A highly effective vaccine against yellow fever (YF) is available and part of the Expanded Program on Immunisation in YF endemic countries. Following a change in WHO guidance in 2014, YF vaccination is now restricted to a single dose given in infancy and expected to provide life-long protection. Recent data have highlighted that this schedule might be insufficient as low antibody titres have been documented in infants who received a primary dose at the age of 9 months. A booster dose of the vaccine might be required in order to ensure long-term protection. Data to support future decisions regarding the ideal timing of a potential booster dose and its subsequent immunogenicity are now urgently required. Our Aim is to assess if a YF booster dose is required for children who received a single dose of YF vaccination in infancy and if so, at what age this booster dose might be most effective to administer. We will enrol three well characterised cohorts of children aged between 15 months and 8 years of age with available data on primary immune response to YF vaccination to determine ideal timing for a booster and examine underlying innate and cellular immune responses related to sero-protection.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Creating demand for Fishermen’s Schistosomiasis and HIV services (FISH): piloting and delivery of a 3-arm cluster randomised control trial (cRCT) in Malawi
Funder: Wellcome Trust

Abstract: One million people died of HIV in 2017 and an estimated 160 million Africans had active schistosomiasis, a cause of male and female genital lesions likely to increase risk and transmission of HIV. Control of both HIV and schistosomiasis relies mainly on treatment of active disease, with prior diagnosis essential for HIV but not schistosomiasis. For HIV, ~25% remains undiagnosed, concentrated in hard-to-reach groups, including men. Here I propose to adapt my previously successful secondary-distribution model for oral HIV self-test kits to pilot and trial peer-based approaches to increasing HIV testing care and prevention by fishermen, while also promoting presumptive praziquantel treatment for schistosomiasis. Both schistosomiasis (S. haematobium) and HIV are highly prevalent and poorly-controlled in fishing communities throughout Africa. The need to include adults in mass drug administration campaigns is recognised, but not yet well implemented, and likely to need different approaches for men and women. I will also use this opportunity to investigate how effectively peer-delivered strategies penetrate social and sexual networks, and to develop my skills in quantitative social network analysis and health economics modelling. Formative work will include exploring social networks before the trial allowing me to spend part of my first year developing methodologies.

Lay abstract: HIV remains a public health problem despite large scale efforts aimed at diagnosing people living with HIV (PLWH) as well as getting PLWH onto life-saving treatment. While there have been reductions in new HIV infections worldwide, certain groups including men remain a challenge to reach with proven interventions. HIV self-testing (HIVST) is a novel method that allows people to conduct their own HIV test and can be utilized to target hard to reach groups, including high risk men living in fishing communities who are also under-served by deworming for an important parasite (schistosomiasis) acquired through water contact. My previous HIVST work showed that providing HIV tests through a female partner or a peer was highly acceptable to men and fishermen. Here I will use peers to educate and promote uptake of HIV testing and schistosomiasis, using a randomised trial comparing 3 approaches that includes HIV self-testing.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: CRUKD/20/002 SPIKE-1 trial: A randomised Phase II/III trial in a community setting, assessing the use of camostat in reducing the clinical progression of COVID-19 by blocking SARs-CoV-2 Spike protein-initiated membrane fusion
Funder: Cancer Research UK

Abstract: Coronavirus-induced disease 2019 (COVID-19) caused by SARS-CoV-2 infection is a highly contagious disease with a high and unpredictable morbidity and mortality, for which there is currently no specific treatment. Progression from a mild fatigue, fever and cough, to severe respiratory failure requiring mechanical ventilation may occur 1 to 2 weeks into the disease. This provides a window of opportunity in which patients in the early phase of the disease could be treated with a disease-modifying agent, to halt disease progression, prevent hospital admissions with respiratory failure and prevent death. Camostat is a serine protease inhibitor in clinical use in Japan since 1985 to treat patients with chronic pancreatitis (inflammation of the pancreas) and has an acceptable safety profile. Camostat has been shown to inhibit SARS-CoV-2 entry into epithelial cells in vitro. A trial of this repurposed drug for treatment of COVID-19 in humans is urgently required to assess its impact on disease progression to respiratory failure and whether it can reduce mortality. The trial has a pilot phase and then a continuation phase. Patients will be randomised into a treatment arm (camostat tablets) or control arm (best supportive care). Patients will be called daily at home for 14 days by the clinical trial team to collect symptoms and record the general well-being of the patient. The primary aim of this trial is to determine if camostat can reduce the clinical progression of COVID-19 and therefore the need for hospital admission and supplemental oxygen. Secondary aims include collection of patient reported health status, severity of symptoms and biological markers of the virus. As the understanding of COVID-19 develops and improves, the inclusion criteria may be adapted to support the trial outcomes. Patients will be recruited through various settings which may include primary care 'COVID-19 hub' clinics, COVID-19 community-based testing centres or other clinical environments.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Development of a Universal Group A Streptococcus Glycoconjugate Vaccine
Funder: Wellcome Trust

Abstract: The pathogenic bacterium Group A Streptococcus (GAS) causes a range of infections, ranging from mild tonsillitis to invasive necrotising fasciitis, sepsis and toxic shock syndrome. GAS also induces severe long-lasting autoimmune disease, including rheumatic heart disease. Annually, GAS infections kill >500,000 people worldwide. While antibiotics are considered a reliable first line of defence against GAS infections, globally emerging antimicrobial resistance is an enormous threat. The WHO has included GAS in its vaccine priority list to finally reduce the high mortality and morbidity. We will use our developed novel modular system to produce the first dual-acting and lowcost GAS vaccine candidates targeting all >150 GAS strains. Our approach provides the first robust and affordable solution to target and prevent GAS infections, urgently required for the global population and in particular the people in low-income countries.

Lay abstract: Group A Streptococcal (GAS) infections kill >500,000 people annually worldwide and currently no vaccine exists. Antimicrobial resistance is emerging globally, and a GAS vaccine is a current global imperative that the WHO has included in its vaccine priority list. An effective GAS vaccine needs to cover all >150 variant strains known and has to be low-cost to be deployed in low income countries where it is most needed. Recently the polyrhamnose sugar backbone that coats GAS cells was validated as vaccine candidate. Sugars are excellent vaccine candidates, particularly when conjugated to carrier proteins, but current methods to achieve this are complex and costly. Using our novel technology, we will conjugate the polyrhamnose sugar to conserved GAS proteins developing a vaccine against all GAS strains. We will use simple E. coli cells that act as mini factories to produce the low-cost vaccine providing the first robust global solution to GAS infection.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Leveraging COG-UK expertise to support the global dissemination of SARS-CoV-2 genome sequencing
Funder: Wellcome Trust

Abstract: Control of the COVID-19 pandemic depends on the development and equitable roll-out of vaccines that remain effective over time. But the evolution of SARS-CoV-2 variants that exhibit variable degrees of immune evasion, and other characteristics including greater transmissibility and/or lethality, threaten to undermine our ability to control COVID-19. It is widely accepted that vaccines will need to be altered over time as the virus mutates. Effective vaccine re-development is dependent upon the availability of global viral sequence data, but there is a lack of sequence data for much of the world, including low, middle and high-income countries. The COVID-19 Genomics UK Consortium (COG-UK) (including the Wellcome Sanger Institute) will leverage its expertise to develop a comprehensive global learning programme on SARS-CoV-2 genome sequencing (COG-GLOBAL). This will be achieved by working with experienced on-line educators. Specific aims include the development of an open access, online modular global learning programme on SARS-CoV-2 sequencing and analysis, allowing users to follow pathways of learning according to professional expertise (laboratory scientist, clinical practitioner, data scientist & epidemiologist, bioinformatician or policy maker); and the development of train-the-trainer courses in collaboration with the Wellcome Connecting Science Advanced Courses, Wellcome Africa and Asia Programmes, and other contributors.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Novel Wolbachia strains in malaria vectors and their role in malaria disease control
Funder: Wellcome Trust

Abstract: The proposed research would focus on two novel resident Wolbachia strains I have discovered and started to characterise in Anopheles moucheti and Anopheles species 'A'. The first aim would be to determine the prevalence rates in wild mosquito populations and assess the effect of resident Wolbachia strains on the prevalence of malaria parasites, arboviruses and the mosquito microbiome. Fieldwork would be undertaken to establish colonies of Wolbachia-infected Anopheles species with a focus on Cameroon for An. moucheti and a field site in DRC has been established for collection of Anopheles species 'A' larvae. We aim to determine the maternal transmission rates, tissue tropism and density of resident Wolbachia strains from wild caught females and analyse the phenotypic effects including cytoplasmic incompatibility & effects on mosquito host fitness from colonised lines. We would determine the effect of novel resident Wolbachia strains (which are higher density than in An. gambiae s.l. populations) on malaria transmission through artificial infection experiments. Finally, the recent sequencing of these two Wolbachia genomes will allow further genetic analysis underlying phenotypic effects and we have evidence of strain variants in Anopheles species A with variable allele profiles for coxA MLST gene locus despite identical hcpA and wsp sequences.

Lay abstract: Malaria is a parasitic disease transmitted by mosquitoes within the Anopheles (An.) genera. Resident bacterial species compromise a part of the mosquito microbiome and can influence the development of Plasmodium malaria parasites. Wolbachia is an endosymbiotic bacterium that resides in ~40% of insect species but historically was thought to be absent from Anopheles species. Recent studies have provided evidence for infections in wild An. gambiae (major malaria vectors in Sub-Saharan Africa) and I have discovered two novel resident strains in An. moucheti and another Anopheles species 'A'. Experiments will determine how prevalent strains are in wild mosquito populations and if they have inhibitory effects on the transmission of malaria parasites. Our preliminary studies have revealed these novel Wolbachia strains are phylogenetically diverse and are high density infections (dominating the microbiome) which suggests they are ideal candidate strains for biocontrol strategies using transinfection of uninfected or species containing low density strains.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Establishing Shigella Human Infection Studies in an endemic population in Kenya for evaluating Shigella vaccines
Funder: Wellcome Trust

Abstract: This is a joint application that will leverage expertise spanning regulatory, ethical, clinical, and laboratory to establish Shigella human infection studies (HIS) at two sites in Kenya, Kericho and Kilifi. Shigella causes a high burden of disease in low-and-middle income countries (LMICs), where 70% of all cases occur in children under 5 years who form the target population for disease prevention through vaccination. However, there are no licensed Shigella vaccines in routine use with several candidates still in various stages of clinical development. Shigella human infection studies have played a key role in the vaccine development pathway to assess vaccine efficacy. Thus, the goal is to successfully establish Shigella HISs in Kenya. This will be achieved by: (a) conducting dose-finding and dose verification Shigella studies that safely and reproducibly induce &ge;60% attack rates under the guidance of experienced clinicians and scientists; (b) assessing vaccine efficacy against a Shigella serotype that is impractical in more traditional field efficacy studies; and (c) explore the ethical and social implications of conducting these studies in a LMIC setting. Once established, the model will accelerate Shigella vaccine development by facilitating the early selection of the most promising vaccines for more extensive testing in LMICs.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Gene Transfer Agents: Prevalence, Biology and Impact on Bacterial Genetic Diversity
Funder: Wellcome Trust

Abstract: Bacteria are highly adaptable and can rapidly exchange genes in response to environmental pressures. Gene transfer agents (GTAs) are an understudied mechanism of genetic exchange that package the entire bacterial genome into bacteriophage-like particles. Indeed, phenomenally high frequencies of GTA gene transfer have been reported in the natural environment. Indiscriminate transfer of genes could clearly have a major impact on bacterial evolution, fitness and antimicrobial resistance. Over the past decade, several pleiotropic regulators have been shown to indirectly influence GTA production and I recently discovered the missing link, GafA, that couples GTA production to host regulatory pathways. GafA homologues were found in numerous species and those homologues I tested also enhanced GTA production in their respective hosts. In this proposal I aim to define the mechanism of action for GafA in the model GTA host, including its interaction with the enigmatic RNA polymerase Omega subunit, and to explore the impact of GafA/GTAs in wider range of bacterial species. I will also study the relationship between GTA production and adaptive immunity to bacteriophage infection. Understanding the role and prevalence of GTAs is essential to assess their impact on issues such as AMR and novel interventions to slow its spread.

Lay abstract: Horizontal Gene Transfer (HGT) is a fundamental and powerful process for the exchange of genes between bacteria. HGT drives bacterial evolution, adaptation and spread into new ecological niches and is the primary means for rapid distribution of characteristics such as antibiotic resistance and virulence. Gene Transfer Agents (GTAs) are small virus particles that can transfer almost any gene at extraordinary frequencies and yet little research has been done on the real world impact of GTAs. My research goals are to understand how bacteria control GTA production, to determine how widespread GTAs are in bacterial pathogens and to assess the ability of GTAs to spread genes for enhanced fitness or antibiotic resistance between bacteria. My work will provide insight into an important mechanism for bacterial evolution and could lead to the development of novel insights or interventions to slow the spread of antibiotic resistance.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION