NIHRDataInsights/HRCSData huggingface dataset:
Title: Establishing a Dengue Controlled Human Infection Model in Viet Nam
Funder: Wellcome Trust

Abstract: Dengue is a mosquito-borne viral infection of major global significance. Millions of infections occur annually encompassing a wide clinical spectrum from inapparent infection to severe and fatal disease. Infection can be caused by any of four related serotypes but second infections with a different serotype are more likely to be associated with severity than primary infections. Although the first dengue vaccine was recently licensed, efficacy was only moderate despite demonstration of neutralising antibody responses to all serotypes, and there are now major safety concerns regarding priming of naïve vaccinees for severe disease later. To evaluate alternative vaccine candidates, NIAID has identified two attenuated challenge viruses with excellent safety profiles in dengue controlled human infection models (Dengue-CHIM) in US adults. We plan to collaborate with this experienced group to establish a similar Dengue-CHIM in Vietnam. However, since this is the first application in an endemic setting and no legal/regulatory framework exists, we propose an initial phase focused on bioethics/stakeholder engagement to develop a suitable regulatory framework, before moving forward to explore crucial research questions. An endemic setting Dengue-CHIM has great potential to advance dengue vaccine development and address the role of dengue immunity in the protection and pathogenesis of natural infection.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Immunity dynamics and epidemiology of cross-reactive pathogens
Funder: Wellcome Trust

Abstract: Infections such dengue fever, Zika and influenza generate a substantial public heath burden. It is therefore crucial to understand the biological mechanisms driving individual-level infection and immunity, and how these shape population-level epidemiological dynamics. However, such viruses can cross-react with antigenically similar pathogens, which makes it challenging to analyse immune responses and the implications for future outbreaks. This project aims to address this knowledge gap using a combination of novel mathematical methodology and empirical data. First, I plan to quantify the contribution of different biological mechanisms to observed antibody responses against arboviruses and influenza. In particular, I will combine a unique longitudinal study of dengue and Zika in Fiji with novel mathematical models to reconstruct individual infection histories, and examine potential interactions in immune responses to these viruses. The work will also generate statistical tools for next generation seroepidemiological study design. This will make it possible to perform power calculations when pathogen cross-react and/or assays lack sensitivity/specificity. Finally, I will investigate how herd immunity generated by prior infection history shapes the antigenic evolution of influenza and re-emergence of arbovirus strains. This will improve our understanding of pathogen invasion and potential for future outbreaks.

Lay abstract: Infections such dengue fever, Zika and influenza generate a substantial public heath burden. It is therefore crucial to understand the biological mechanisms driving individual-level infection and immunity, and how these shape population-level epidemic dynamics. However, individuals can experience multiple infections over the course of their lifetime, which makes it challenging to analyse immune responses and the implications for future outbreaks. This project aims to address this knowledge gap using a combination of new mathematical methods and field studies. First, I will examine the human immune response to dengue, Zika and influenza viruses. Using new mathematical and statistical methods, I plan to untangle the different factors that influence observed patterns of immunity. As well as improving our knowledge of individuals' life history of infection and immunity, the work will also guide the design of future field studies, enabling researchers to address a wider range of hypotheses about viruses like influenza and dengue. With a better understanding of individual-level immune responses, it will also be possible to investigate the impact of immunity at the population level. In particular, I will investigate how immunity shapes influenza evolution, and the emergence (and re-emergence) of new infections in different areas.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Identification of niche-specific virulence factors via experimental evolution of Streptococcus pneumoniae
Funder: Wellcome Trust

Abstract: Streptococcus pneumoniae is a major human pathogen and the leading cause of death due to infectious disease in children under 5. S.pneumoniae colonises diverse host-tissue niches, each with unique immunological, nutritional and environmental challenges. Certain S.pneumoniae clonal lineages are associated with particular disease phenotypes but the bacterial factors governing tissue-tropism are unknown. This project will identify S.pneumoniae adaptive mutations associated with specific infection phenotypes. By serial passage of pneumococci through mouse models of (a) nasopharyngeal carriage, (b) pneumonia and (c) meningitis, I will select for mutations associated with survival in nasopharynx, lungs and brain, respectively. The significance of genetic differences identified in passaged isolates will be confirmed by genome-wide-association-studies performed with >6000 clinical isolates and by reproducing mutations singly in a laboratory S.pneumoniae strain. Transcriptomic analysis of nasopharynx, lungs or brain from infected mice will determine the impact of adaptive mutations on bacterial gene expression. Host responses to passaged and mutated strains will be characterized in mouse infection models. I aim to identify mutations, gene expression patterns and virulence factors associated with disease but not with stable nasopharyngeal carriage, to identify candidate antigens for inclusion in a future vaccine that is permissive for nasopharyngeal carriage whilst providing protection against disease.

Lay abstract: The pneumococcus is a bacterium that causes severe diseases throughout the world, but particularly in poorer countries. It is the most common cause of death from infectious disease in children under 5. We don't have a vaccine that protects against every type of pneumococcus. What makes pneumococcus so deadly is the ability to adapt to different challenges in different sites within the human body. For example, many people have pneumococcus living harmlessly in their noses and mouths, but the bacteria is also able to survive in the lungs (where it can cause pneumonia) and the lining of the brain (meningitis). This 5 year project aims to explain how pneumococcus thrives in different places. By comparing the genes of bacteria that cause different types of disease I will be able to find out which genes are required for infecting certain organs. I will then construct bacteria that lack these genes and find out if they are still able to cause disease. This will help us understand what changes in the 'safe' bacteria in our noses allow them to cause disease. I aim to find important bacterial proteins that could be targeted in new vaccines or drugs aimed at controlling pneumococcal disease.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Transmission facility for human malaria parasites
Funder: Wellcome Trust

Abstract: We will establish a facility for the transmission of human malaria parasites to the mosquito vector and onwards to humanized mice that is open to all members of the research community. Owing to the difficulty in transmission of human malaria parasites in laboratory settings, only few facilities exist where this can be achieved consistently. The three UK facilities capable of this are not open facilities, and none have established the humanized mouse model for investigating the liver stage of the parasite. notably, this facility will enable the investigation of transmission-blocking compounds, malaria vaccine development, basic research into the interaction of the parasite with the mosquito host and the mammalian liver using a humanized mouse model, the effect of insecticides on the transmission of parasites by insecticide-resistant mosquitoes, the trial of specific genetic modifications of mosquitoes, genetic crosses of malaria parasites and many other investigations. This will make available avenues of research that are currently out of reach for most members of the research community and support the acceleration of new and innovative interventions to halt the spread of malaria.

Lay abstract: Although the incidence of malaria has decreased greatly over the past twenty years, malaria remains one of the deadliest infectious diseases worldwide. Recently this decrease in incidence has stalled, owing to insecticide resistance in mosquitoes and the development of resistance to nearly all antimalarials by the parasite, to the point where the number of annual infections has changed very little in recent years. To further reduce malaria incidence, new approaches and new interventions are required. Blocking transmission of the parasite from man to mosquito has become an important focus of new interventions. We will establish a facility where human malaria parasites can be transmitted to mosquitoes and onwards to mice that is open to all members of the research community to facilitate research into compounds and vaccines that can block transmission. This will open up new avenues of research and innovation to accelerate our fight against malaria.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Hybridisation in urogenital schistosomiasis (HUGS): A multidisciplinary longitudinal population study revealing the transmission biology, epidemiological impact and clinical importance of Schistosoma haematobium-hybrids in Malawi
Funder: Wellcome Trust

Abstract: Our discovery of Schistosoma haematobium hybrids co-infecting Malawian children exposes critical knowledge gaps in WHO’s preventive chemotherapy (PC) strategy for schistosomiasis. Our HUGS (hybridisation in urogenital schistosomiasis) study will generate robust evidence that best informs medical, veterinary and environmental sectors in schistosomiasis control and interruption of schistosome transmission. This 4-year multidisciplinary investigation will develop new molecular assays that quantify multihost transmission dynamics and zoonotic spill-overs. We will reveal which pre- or post-zygotic drivers facilitate saltatory hybrid evolution. HUGS is set out in four objectives [% allocation] that: Obj-1 [25%]: Test if the proportion of hybrid co-infection is (non)uniform across two representative communities where S. haematobium-mattheei or S. haematobium-bovis occur, inclusive of household GPS mapping and identification of associated risk factors by questionnaire; Obj-2 [45%]: Verify, in a 2-year longitudinal population follow-up study with annual PC, if the above proportions and spatial patterns of hybrid co-infection hold or alter in the two communities; Obj-3 [15%]: Ascertain if there is any increased host morbidity (e.g. anaemia or urogenital disease) in hybrid co-infection(s) as measured by point-of-contact assays and portable ultrasonography; Obj-4 [15%]: Reveal hybrid environmental transmission by malacological inspections, livestock tracking and abattoir surveillance, with advanced molecular typing of collected schistosome material.

Lay abstract: Despite ongoing control, rural African communities typically suffer from schistosomiasis, a snail-borne parasitic worm disease. New unknowns are now emerging about the worms that cause urogenital schistosomiasis, a specific disease form afflicting millions and linked with predisposition towards HIV infection. In Malawi, abrupt changes in the genetic makeup of worms demonstrate, contrary to common assumptions, abilities to mate successfully with related worms in livestock. Hybrid worms are important, perhaps causing heightened disease and being more resilient to current control. Using state-of-the-art molecular and spatial surveillance methods, our 4-year study will specifically address these issues; as set against ongoing control, we will examine disease-dynamics in humans, snails and livestock. We seek to determine hybrid transmission pathways, clinical importance and wider health impacts in two exemplar Malawian communities, where two known hybrids are endemic. We will therefore judge if international red-flagging is needed with urgent revision of current control policies and practices.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: A comprehensive study of immunopathogenesis of SARS-CoV-2 infection
Funder: Wellcome Trust

Abstract: Since December 2019 the emergence of severe acute respiratory infections (COVID-19) in China, caused by the new coronavirus SARS-CoV-2, has posed a huge threat to global health with fatality rates up to 10% in elderly patients. Almost 100% of patients showed bilateral patchy shadows or ground glass opacity in their lungs by chest CT scans indicating acute lung injury (ALI). Therefore, understanding the underlying mechanism(s) of ALI induced by SARS-CoV-2 is very important to inform vaccine safety and immunotherapeutic strategies. In this proposal, we will investigate the host immune responses and their association with severity of ALI in patient samples and animal models. We will bring together a team of experts with complementary expertise including immunopathology in coronavirus infections, up-to-date lab technologies, and know-how to ensure the feasibility of this study with the following goals: 1) defining SARS-CoV-2 specific serum profiles (epitopes) using yeast display antigen library 2) determining antibody functions including antibody-dependent enhancement (ADE) vs neutralizing activities in vitro assays 3) studying T cell (CD4 and CD8) responses to whole SARS-CoV-2 genome 4) evaluating ALI in response to live SARS-CoV-2 infection with or without passive immunity (antibody or T cells) generated from vaccine candidates in a humanized mice model.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Sulfoglycolysis: a Potential Target for Attack on Bacterial Persistence
Funder: Wellcome Trust

Abstract: The persistence phenotype is an epigenetic trait exhibited by a subpopulation of bacteria, characterised by metabolic dormancy. It is a model of bacterial survival in the host to enable it to spread pathogenically in niche environments. Persistent bacteria are the major cause of chronic and recurrent infections difficult to treat with antibiotics, thus has affected the world economy by billions of dollars. Yet, the molecular mechanisms of persistence are still unclear. My research has shown that sulfoglycolysis - a novel regulated primary catabolic pathway for an abundant type of sulfo-containing monosaccharide, sulfoquinovose, increases the persistence level of pathogenic E. coli and Salmonella. In this Fellowship Programme, I seek to demonstrate crosstalk between the sulfoglycolytic pathway and other persistence-conferring pathways using a multidisciplinary approach. I will investigate whether the structural and electrostatic similarities of sulfoquinovose and its catabolic intermediates to other anionic sugars lead to pathway activation, extracellular polysaccharide incorporation, and inhibition of glycolytic enzymes. To identify new drug targets against persistence, key enzymes in the pathway will also be investigated. My findings will establish the regulatory and structural roles of the sulfoglycolytic pathway in bacterial persistence and will lead to a novel approach to tackling antibiotic ineffectiveness.

Lay abstract: Bad bacteria, like E. coli and Salmonella, contaminating water or food, can breach the human defense system and cause acute disease. A subpopulation of bacteria are able to “hibernate” in niche areas such as urinary tract, intestine, and gallbladder and develop persistence. This is a major problem, causing chronic and recurrent infections, with most current antibiotics ineffective against persistent bacteria. Recently, some of these bacteria were discovered to use an abundant sulfur-containing sugar as their source of energy. My research has found this process, called sulfoglycolysis, also gives persistent bacteria the advantage to survive antibiotic treatment. Understanding this will enable us to control persistent bacteria. My research programme will explore how these sugars are selected by persistent bacteria, discover how they are used, and study the proteins involved, for both safe and disease-causing bacteria. Our long-term goal is to discover a new approach for urgently-needed antibiotics to tackle bacterial persistence.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Emergence and global epidemiology of non-polio enteroviruses
Funder: Wellcome Trust

Abstract: I aim to identify the mechanisms driving the emergence of enterovirus serotypes as a new cause of disease and their spatio-temporal patterns of spread using multiple data streams and mathematical and statistical models. First, I will study the extent to which serotype-specific immunity explains the cyclical incidence of enteroviruses causing hand-foot-and-mouth disease, both by fitting transmission models to incidence data and exploring correlations with estimates of population immunity from serosurveys. Second, using cross-sectional seroprevalence and virus sequence data I will explore how gaps in population immunity and virus genotypic and phenotypic changes have led to the recent emergence of two new serotypes causing diseases (EV-D68 and CV-A6) following periods of low incidence of cases. Third, using phylogenetic and phylogeographic methods, I will characterise the geographical range of spread and global and regional patterns of viral movement of the three currently most important serotypes (EV-A71, EV-D68 and CV-A6), and I will explore how human mobility and other predictors drive these spatial patterns. Understanding the mechanisms underlying the epidemiological dynamics of enteroviruses will help prioritise strategies to mitigate the morbidity associated to these infections by informing the serotypes that should be targeted by future vaccines, and optimise outbreak control and vaccination strategies.

Lay abstract: Enteroviruses are a major cause of neurological and other illnesses. Recent outbreaks, such as hand-foot-and-mouth disease in Southeast Asia and severe respiratory illness and paralysis associated with enterovirus D68 worldwide, have raised basic and applied questions about the mechanisms determining their emergence and transmission dynamics. First, I will study how population immunity and viral genomic changes contribute to the emergence of new pathogenic enterovirus serotypes and determine their temporal incidence patterns. Second, I will study the geographical range of spread and regional and global patterns of enterovirus movement. I will do this using mathematical models and statistical analysis of case reports, serosurveys and viral sequence data from various settings, including collaborations with China, Malaysia, the UK and the Netherlands. This project offers an opportunity to understand the global epidemiology of enteroviruses and improve their control by ultimately contributing to outbreak preparedness and informing vaccine content and design of vaccination strategies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Optimising seasonal malaria chemoprevention and seasonal vaccination in childhood to address the resurgent malaria burden in Africa
Funder: Wellcome Trust

Abstract: Almost half of the 435,000 malaria deaths each year occur in countries of the Sahel region of Africa, and the majority of these deaths occur during the three-four month rainy season. Monthly seasonal malaria chemoprevention (SMC) is highly effective in these areas, reducing malaria cases by 75-80% in trials, and malaria-specific mortality by 40-50% under programmatic conditions. However, malaria remains a leading cause of disease and death in several countries deploying SMC. The key goals are therefore to understand how to 1) maximise the impact of SMC as currently designed (e.g. by timing it more accurately in different areas), 2) modify the SMC strategy to make it more effective (e.g. by identifying the causes of severe malaria in the context of SMC), 3) use other control tools, including seasonally-targeted vaccination, alongside SMC and 4) understand how improving malaria prevention in childhood would affect naturally-acquired immunity. Analysis of data from a comprehensive evaluation of SMC in 7 countries, an SMC trial in 20,000 children, and the first-ever trial of seasonally-targeted vaccination alongside SMC provides a unique opportunity to answer these questions. Mathematical models incorporating these results will enable malaria prevention packages to be optimised according to the local epidemiology.

Lay abstract: Around 400,000 malaria deaths occur worldwide each year. About half of these occur in the Sahel region of Africa, mostly during a short, intense rainy season. Monthly courses of antimalarial drugs (seasonal malaria chemoprevention, SMC) is highly effective in these areas. However, malaria remains a leading cause of child deaths in several countries with SMC programmes. I will analyse data from a large SMC programme across seven countries and two large clinical trials of SMC to understand 1) exactly when SMC should be delivered in different areas to maximise its impact, 2) which children get malaria despite SMC (which will indicate how SMC could be improved), 3) how best to use seasonally-targeted malaria vaccination alongside SMC and 4) how improved malaria prevention might affect naturally-acquired immunity. Development of computer-based simulations incorporating these results will enable malaria prevention packages to be targeted to local transmission patterns, maximising their impact on malaria.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION