NIHRDataInsights/HRCSData huggingface dataset:
Title: Using pneumococcal carriage and invasiveness to inform vaccine policy in tropical Africa
Funder: Wellcome Trust

Abstract: Despite strong evidence of efficacy, Pneumococcal Conjugate Vaccines have unpredictable impacts at population level and are expensive. Continuous monitoring of invasive pneumococcal disease is required to optimise programme implementation but few African countries have such surveillance. I propose to investigate nasopharyngeal carriage as a proxy surveillance tool and estimate disease burden from the ‘invasiveness’ of carried pneumococci; serotype-specific invasiveness is likely to be relatively stable and geographic variation may be explicable through observable epidemiological factors. I will estimate invasiveness for each serotype by analysing all available linked data on carriage/invasive disease. Next, I will work with epidemiologists in DRC, Ethiopia and Nigeria to undertake sequential carriage studies and convert carriage data into population estimates of disease burden. With mathematical modellers at LSHTM, I will fit transmission models to these data to predict the outcome of potential policy options and share these predictions with in-country policy collaborators. This approach assumes that estimates of invasiveness are not confounded by temporal fluctuations in carriage data; that invasion is determined only by the ‘dominant’ strain in multiple-serotype carriage; and that serotype is the principal phenotype driving invasion. I will test these assumptions with colleagues at the Sanger Institute using bio-banked specimens from Kilifi.

Lay abstract: Pneumococcal Conjugate Vaccines have had a tremendous impact on pneumonia, meningitis and sepsis among children in the UK/USA and early studies suggest they also work in Africa. However, they are expensive, and their effects are not always the same in each place. Pneumococcal disease surveillance is therefore essential after vaccine introduction but, unlike the UK/USA, African countries cannot afford surveillance. Here I propose an affordable alternative to monitor vaccine impact. By sampling the nasal mucous of healthy people we can observe whether the vaccine is interrupting transmission of pneumococci and, using mathematical models, we can predict how much disease is being averted and how the programme could be optimised. I will undertake nasal surveys in DRC, Ethiopia and Nigeria and share the results with government decision-makers. Predicting disease levels entirely from nasal surveys is novel so I propose validation studies in epidemiology and genomics to test the idea's validity.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Molecular and Cellular Interactions in Helminth Infections
Funder: Wellcome Trust

Abstract: The proposed research aims to (i) build fundamental understanding of mechanisms of immune evasion by helminth parasites, (ii) explore helminth modulation of the intestinal tissue niche; and (iii) to develop a new strategy towards vaccination to prevent infection. Helminths exploit a key immunological pathway within the immune system to induce suppressive regulatory T cells, and dampen innate effector cells. We have discovered a key player to be a novel parasite mimic of TGF-beta (TGM), which we will analyze structurally and funtionally on (i) immune cells and (ii) intestinal epithelium. The intestinal environment will be modelled through organoids (enteroids) in which parasites can modify stem cell differentation and therefore epithelial composition; we will investigate whether this is caused by TGM or an unrelated mediator. To promote immunity to infection, we focus on extracellular vesicles (EVs) released by parasites, which we have shown inhibit innate cell activation but can be neutralised by specific antibodies. In this model, antibodies to EVs direct them to uptake by phagocytes and lysosomal degradation, abolishing the inhibitory effect on immune cells. Taken together, the research will define how helminths may modify host signals and pathways, and how we may best interrupt this process to achieve protective immunity.

Lay abstract: Helminth (worm) parasites are highly prevalent in human populations (~ 2 billion people in tropical countries) and livestock (including in the UK), but existing drugs only temporarily suppress infection and effective vaccines are unavailable. Helminths are also particularly successful at evading and manipulating the host immune system, and frequently occupy niches such as the intestinal tract. My laboratory established that parasites exploit a natural "brake" on immunity, named TGF-beta. We discovered a new parasite protein that mimics this pathway; the proposed project seeks to understand this new protein and test it as a novel anti-inflammatory agent. We are also interested in how parasites accommodate themselves in the intestinal tract which undergoes major changes during infection, and which changes permit parasite survival. Finally, we propose a new strategy for vaccination, targetting immunomodulatory extracellular vesicles released by helminths which, if bound by antibodies, are inactivated thereby protecting the host from parasite immunosuppression.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Fungal peptide toxins in pathogenicity and immunity
Funder: Wellcome Trust

Abstract: Fungal infections kill ~1.5 million individuals each year. Despite this, the pathogenic processes promoting fungal infections and the host immune responses preventing infections are largely unknown. Our discovery of the pore-forming peptide toxin “candidalysin”, secreted by Candida albicans, represents a seminal advance in understanding fungal pathogenesis, as human pathogenic fungi were not known to possess such toxins. Candidalysin is critical for C.albicans virulence and induction of innate immunity, and belongs to a small family of toxins produced by hypha-producing Candida spp. We have now discovered a multitude of new peptide toxins in other pathogenic fungi. This proposal will employ a multi-disciplinary approach, blending structural biology, biophysical, biochemical, molecular, genetic, cellular and immunological methodologies to: 1. Determine the molecular structure of candidalysin pores. 2. Delineate the epithelial cellular mechanisms activated by candidalysin. 3. Determine the epithelial-related proteins that drive protection against candidalysin. 4. Determine the importance of other peptide toxins in fungal disease and innate immunity. This work will determine the mechanisms by which candidalysin and peptide toxins promote fungal disease and innate immunity. It will develop a new field of science, improve understanding of innate immunity, and identify novel fungal and host targets for developing new immunotherapies and vaccines.

Lay abstract: Fungal infections affect a quarter of the world’s population and kill ~1.5 million people each year, surpassing the numbers killed by either malaria, breast or prostate cancer. Despite these alarmingly high figures, it is still largely unknown how fungi cause these infections or how they lead to mortality. One of the most medically important fungi is Candida albicans, which causes millions of skin, mucosal (mouth, vagina, gut) and life-threatening infections each year. We recently discovered that C. albicans produces a small toxin that accounts for how this fungus causes damage to the host and induces immune responses. Our discovery of this toxin represents a major breakthrough in understanding fungal disease, as human disease-causing fungi were not known to possess such toxins. We have now identified a multitude of new toxins produced by other disease-causing fungi. This proposal will determine how these toxins contribute to fungal disease and induce immune responses.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Gonococcal vaccine initiative
Funder: Wellcome Trust

Abstract: Neisseria gonorrhoeae (Ng), a leading cause of STI and co-factor for HIV transmission, has developed extensive antimicrobial resistance. Therefore innovative measures to combat Ng are urgently required. While vaccines have been remarkably effective for preventing bacterial infection, there has been scant progress towards Ng vaccines. However, recent advances provide the first prospects for success in decades. We will exploit these advances and our expertise to validate effective antigens for inclusion in a gonococcal vaccine through five related aims. We will :- 1) identify Ng antigens through a clinical trial of an outer membrane vesicle (OMV)-containing vaccine from Neisseria meningitidis as an immunological probe in an Ng-exposed population, 2) define the conservation and distribution of Ng antigens by interrogating our genomic database of Ng, 3) generate lead candidates (exploiting their atomic structures and variation) and produce engineered OMVs which will be characterised by state-of-the-art proteomics, 4) evaluate the immunogenicity and protective efficacy of our candidates in the murine model of Ng infection, and examine cellular and serological responses, and 5) refine and combine antigens to deliver pre-clinical validation for effective Ng vaccines, and derive correlates of protection for this important pathogen.

Lay abstract: Sexually transmitted infections caused by Neisseria gonorrhoeae (Ng) are becoming more common and increasingly resistant to antibiotics. This bacterium causes long term health problems such as chronic pelvic infections, infertility and can even cause in blindness in new born children. Ng infection increases the spread of HIV, and cases in the UK have increased three fold over the past decade. We aim to combat this problem by developing vaccines to protect individuals from Ng infection. We will use knowledge of the genetic blueprint (DNA) of the microbe from nearly 5,000 cases across the globe, together with results from a study in at-risk individuals to identify vaccine candidates. We will make designer vaccines taking into account how our immune system recognises and is deceived by the bacterium, and variation in resistant strains and those from across the world. Our goal is to generate novel effective vaccine candidates against the gonococcus.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Erythrocyte invasion in malaria: molecular mechanism to precision therapeutics
Funder: Wellcome Trust

Abstract: Invasion of erythrocytes is one of the most critical steps in the life cycle of the malaria parasite. Prevent erythrocyte invasion, and we can prevent parasite growth, disease symptoms and transmission. Essential for erythrocyte invasion is the PfRCR complex of Plasmodium falciparum, consisting of PfRH5, PfCyRPA and PfRIPR. This proposal will use structural insights to guide experiments to understand the function of PfRCR in erythrocyte invasion, and to guide development of future vaccines and therapeutic antibodies. Over the next five years, I will: (i) Determine structures of PfRCR and PfRIPR and understand whether complex formation is necessary for invasion. (ii) Understand molecular mechanisms of the most invasion-neutralising human antibodies targeting PfRH5, PfCyRPA and PfRIPR. (iii) Determine how PfRH5 induces calcium flux in erythrocytes. (iv) Use structural insights to design improved therapeutic monoclonal antibodies and vaccine immunogens targeting PfRCR. These studies will deepen our understanding of this critical event in erythrocyte invasion. They will reveal the human antibody response to PfRCR vaccination and use this insight to guide design of the malaria therapeutics of the future.

Lay abstract: Malaria remains the mostly deadly parasitic infection to affect humans, causing around half a million deaths and hundreds of millions of cases each year. Most deaths are of children under the age of five. Sadly, recent reductions in malaria cases have stalled and we urgently need additional interventions, such as a highly protective vaccine or therapeutic antibodies. In order for the malaria parasite to divide and to cause disease symptoms, it must get inside human blood cells. In particular, a piece of parasite machinery called PfRCR is required for blood cell invasion and could act as an Achilles heel for the parasite. In this proposal, we aim to understand what PfRCR looks like and how it works. We will also study the antibody molecules that are produced when human volunteers are vaccinated with components of PfRCR. This insight will guide us to generate improved vaccine immunogens and therapeutic antibody cocktails.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The local immune response in the airways and blood of contacts early after TB exposure determines outcome
Funder: Wellcome Trust

Abstract: Most individuals infected with Mycobacterium tuberculosis remain healthy, while a subset only progress to active tuberculosis (TB) disease. Early local immune events following infection in humans, determining the pattern of ensuing host immunity and risk of disease progression, are unknown. We defined a blood transcriptional signature of active TB, absent in the majority of latently exposed asymptomatic individuals and healthy controls, that reflected the extent of radiographic lung disease. I recently demonstrated immunological heterogeneity in the blood transcriptome of a cohort of recent TB contacts. A small proportion expressed a persistent TB signature and subsequently progressed to active TB disease, whereas 50% of contacts who were sensitized to M. tuberculosis infection but did not progress to disease, exhibited a similar, but not identical, transient blood signature, suggesting early local immune responses are critical determinants of outcome from infection. I will now lead a study of TB contacts, to detect changes in immune events in the airways early after TB exposure, comparing with TB patients, in a low TB burden setting.The findings I will generate on the local early response to M. tuberculosis infection are critical for developing novel approaches for effective TB control and prevention and the improvement of vaccines.

Lay abstract: Tuberculosis (TB) is an infectious disease caused by the bacterium M.tuberculosisthat affects 10-million people worldwide each year. The infection is acquired by aerosol from an infectious TB patient, but is usually controlled by immune processes in the lung. In 5-10% of infections, active TB develops within up to 2 years, indicating failed immune protection, mechanisms of which are poorly understood. My proposal aims to characterise the cellular and molecular immune responses in the airways as compared to blood of TB-exposed contacts and compare to well-defined populations with TB. We will apply state-of the-art genomic and molecular methods to investigate the immune response and compare this between contacts that remain healthy with those developing TB. Our approach will transform knowledge of immune processes that are either protective, or confer susceptibility to TB, and provide new strategies for treatment and vaccine development.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: RECOVERY International
Funder: Wellcome Trust

Abstract: The Phase 3 RECOVERY platform has been a success, recruiting over 13,500 patients and producing 3 clear, world practice-changing results in the first 100 days of recruitment. The RECOVERY team has been approached by clinical investigators from various LMICs who wish to participate in RECOVERY. As it becomes clear that this pandemic will continue at various locations and paces over the next 24 months, there is an opportunity to increase the impact of the RECOVERY trial by expanding internationally. Expansion has the potential to speed up the assessment of novel treatments, increase the global relevance of the trial results, build capacity, and reduce wasted efforts on small uninformative studies. The key goal is to establish RECOVERY internationally, initially in Indonesia, Nepal and Vietnam, with a view to opening sites also in Africa.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: TyVOID
Funder: Wellcome Trust

Abstract: This study will: assess the change of medium-term efficacy of the new Typhoid Conju-gate Vaccine (TCV) in children, by comparing the relative risk of typhoid in those initially vaccinated in 2017/2018 with later cohorts vaccinated in 2020 and 2021; assess the de-cline in individual-level immunity 3-5 years after vaccination; measure ongoing popula-tion-level impact against typhoid fever in the community. The data collected will help identify correlates of medium-term protection; inform the need for, timing of and potential cost-effectiveness of adding booster doses to vaccine schedules; permit the develop-ment of a mathematical model to predict future impact of typhoid vaccination in two en-demic settings.

Lay abstract: Enteric fever is a major public health problem, affecting 11-26 million people every year and disproportionately impacting low- and middle-income countries.The disease especially affects children and young adults. The World Health Organisation’s (WHOs) Strategic Advisory Group of Experts (SAGE) recommended use of the new typhoid conjugate vaccine (TCV) in October 2017 in regions with a high burden of typhoid. We established two large-scale randomised controlled trials of TCV effectiveness in children aged 9 months to < 16 years in Nepal and Bangladesh, implemented through the Typhoid Vaccine Acceleration Consortium in 100,000 children to provide the first field efficacy data for the vaccine. Our interim analysis of the efficacy of TCV in Nepal provided the first field efficacy data for the WHO pre-qualified TCV, with an 81.6% efficacy at 1 year. At the end of the current trial the control group of 10,000 children will be vaccinated with TCV.Major questions remain, however, which are important for countries planning implementation and were highlighted by WHO. The key question is about duration of protection and thus the number of doses required to control disease. In this proposal, with co-funding from the Bill&Melinda Gates Foundation, we aim to provide the key data to determine the duration of immune response by measuring antibody decay, and vaccine effectiveness by enhanced passive surveillance of children in the two countries for 2 years from the end of the current trial. At the end of this study we will provide data which are critical for WHO policy decisions.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Understanding and mitigating the impact of emerging antifungal resistance
Funder: Wellcome Trust

Abstract: While emerging antimicrobial resistance is widely recognised in bacteria, the emergence of fungi that are resistant to antifungal drugs is underappreciated yet is compromising our ability to treat these serious diseases worldwide. The most widely used class of chemicals, the azoles, are driving the evolution of fungal multidrug resistance through their dual-use in both agricultural and clinical settings. However, we lack critical insights into how these antifungal chemicals are leading to changing patterns of disease in humans. We focus on Aspergillus fumigatus, an environmental fungus to which all humans are exposed causing disease in millions, and which is rapidly evolving resistance to azole antifungal drugs worldwide. Our project aims to understand the risk that azole-resistant aspergillosis presents to public health by identifying the extent to which patients are acquiring resistant infections from environmental sources. We will explore whether the emerging spectrum of mutations that confer drug resistance come with a fitness cost, how these mutations impact upon the global population of A. fumigatus with respect to undesirable phenotypes such as virulence and infectivity. The science that our study produces will be focused on tackling this pandemic in order to retain the efficacy of essential current, and incoming, clinical antifungal drugs.

Lay abstract: We are all exposed daily to spores from the fungus Aspergillus fumigatus in our air, a fungus that can cause fatal disease in susceptible patients. Our main treatment is a class of antifungal chemicals known as ‘azoles’. However, azoles are also used by the agricultural industry in huge quantities and our evidence suggests that ‘dual-use’ is leading to this fungus becoming resistant to our frontline drugs, leading to increased disease. Our approach is to use DNA sequencing to explore the extent that natural populations of Aspergillus are being changed by azoles, which we believe is amplifying undesirable features such as increased virulence. We will measure the extent that patients are being infected by azole-resistant Aspergillus from their environment and will investigate whether they transmit their infections. Our research will not only measure the extent of this emerging problem, but also its impact on the next generation of antifungal drugs.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Entry, innate sensing and replication of enteropathogenic caliciviruses.
Funder: Wellcome Trust

Abstract: Our overarching aim is to gain insights into the biology of enteropathogenic caliciviruses, focusing on the fundamental aspects that have remained elusive to date: viral entry into target cells, the interplay with the host innate response and the recruitment of host-cell co-factors that support replication. Having significantly improved the culture systems for human noroviruses and developed reverse genetics, we now have the first opportunity to study human norovirus replication in a physiologically relevant system. We will focus on three areas: 1. C-type lectin receptors (CLRs): We have found that CLRs may work in concert with blood group antigens to allow norovirus infection. We will further dissect the role of CLRs in the norovirus life cycle. 2. Innate responses to infection: We have found that type I/III interferons restrict norovirus replication but that infection induces the COX-2/PGE pathway to promote replication. We will dissect the response to infection in the organoid system and characterise a novel virus-encoded regulator of the NF-kB system. 3. Trans-acting factors: We will examine their role of a number of host factors (VapA/B, Squle and PI4Kalpha) in norovirus replication and expand this study to an undertake an unbiased analysis of the human norovirus replication complex.

Lay abstract: The long-term focus of our work is to develop ways of preventing and controlling gastroenteritis caused by noroviruses and sapoviruses. They have a societal impact of >$60 billion pa. yet we have no drugs or vaccines to prevent or treat infections. Noroviruses were first identified in 1972 but we have only been able to grow them in the lab since late 2016. We are now able to address some fundamental questions on how they infect cells and cause disease. We have discovered that a set of molecules on the surface of cells known as lectins, in combination with blood group antigens, potentially play a role in determining host susceptibility to infection. We will further characterise this interaction and identify the role these molecules play in the viral life cycle. We also wish to understand how cells respond to infection as we have previously shown that by regulating this response using clinically approved drugs, we can inhibit viral replication. Finally we aim to identify cellular proteins required for viral replication as new potential targets. This work will also give us new information relating to biological processes within host cells and how cells respond to infection.

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