NIHRDataInsights/HRCSData huggingface dataset:
Title: What is special about pandemic HIV-1? How capsid cofactor interactions regulate DNA synthesis, innate immune detection and pandemic potential
Funder: Wellcome Trust

Abstract: The HIV-1 pandemic originates from one of many zoonotic simian lentiviruses. A key unanswered question is: what is special about pandemic HIV-1? Our previous work suggests a pivotal role for lentiviral capsids as molecular machines that determine innate immune evasion capacity and pandemic potential. Lentiviral capsids simultaneously regulate viral DNA synthesis, viral genome uncoating, nuclear entry and integration targeting, through coordinated and dynamic recruitment of host cofactors. The goal of this application is to understand how capsids work by considering the structural changes that result from interactions with known and novel cellular cofactors and drugs, the biological consequences of these changes and how they drive infection, zoonosis and pandemicity. We propose three aims that integrate structural, single-molecule and chemical biology with comparative virology. In aim one we will use state of the art structural approaches to understand cofactor capsid interactions. In aim two we will determine how host cofactors manipulate capsid function to temporally and spatially orchestrate DNA synthesis and genome uncoating to facilitate evasion of innate immunity. In aim three we will use our novel CA inhibitor series as tools to probe capsid function and to develop a new paradigm for treatment of infection.

Lay abstract: There are twelve different types of HIV but just one has caused almost all 87 million infections. We aim to find out what is special about this common variant. We focus on the viral capsid, the core of the virus that cloaks HIV from immune detection by the infected cell. Cloaking requires recruitment of host proteins called cofactors that attach to the outside of the capsid. We will ask "What are cofactors doing to the virus and how does this differ between common and rare HIV? Our interdisciplinary approach uniquely combines structural biology, infection experiments and examination of single viruses using microscopes. Ideas developed in one system can be tested in another providing unprecedented potential for understanding how HIV works and how the common virus is different. We will use this knowledge to develop drugs that uncloak the virus and empower our natural immune response, a completely new therapeutic approach.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: Targeting a new kingdom: the nature and significance of Type VI secretion system-mediated anti-fungal activity
Funder: Wellcome Trust

Abstract: Microbial organisms, including bacteria and fungi, normally live in mixed communities whose members interact co-operatively or competitively by a variety of mechanisms. The Type VI secretion system (T6SS) is used by many Gram-negative bacteria to deliver toxic effector proteins into rival bacterial cells as a means of interbacterial competition. We recently discovered that the T6SS can also be used as a potent weapon against fungal competitors and identified the first fungal-specific T6SS effector proteins, which cause fungal cell death via distinct mechanisms. We propose that T6SS-mediated anti-fungal activity is widespread, mediated by a variety of effector proteins and able to shape diverse polymicrobial communities, including those important for human health and disease. In this project, we have assembled an expert, multi-disciplinary team to investigate the nature, role and molecular basis of T6SS-mediated anti-fungal activity. Our specific Aims are to: 1. Examine the distribution and significance of T6SS-mediated anti-fungal activity 2. Understand the interaction between the fungal cell and the bacterial T6SS 3. Define the mode of action of T6SS-delivered anti-fungal effectors Our findings will illuminate the fundamental mechanism and biological relevance of T6SS-mediated anti-fungal activity, whilst paving the way for potential future anti-fungal therapeutic developments.

Lay abstract: Infectious diseases caused by bacteria and fungi represent a major threat to health, particularly given ever-increasing antimicrobial resistance. Such microbial organisms normally live in mixed communities whose members interact in diverse ways. Studying inter-microbial interactions is important to understand how they shape microbial communities and the mechanisms by which one microbe can help, influence or kill another. We have discovered that a bacterial weapon, the Type VI secretion system (T6SS), can deliver ‘effector’ proteins into fungal cells to disable or kill them. We believe that anti-fungal T6SSs are important in many microbial communities, including health- and disease-associated, and deliver varied effectors. We will combine expertise in bacterial and fungal biology with cutting-edge molecular techniques, to investigate the nature and role of T6SS-dependent anti-fungal activity and understand, at a molecular level, how T6SSs intoxicate fungal cells. This will reveal new aspects of microbial biology and may contribute towards future anti-fungal therapies.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: ISARIC
Funder: Wellcome Trust

Abstract: The International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) is a federation of clinical research networks whose aim is to prevent illness and deaths from infectious diseases outbreaks. This aim is supported by two key objectives: (i) To generate and disseminate clinical research evidence for outbreak-prone infectious diseases, whenever and wherever they occur; (ii) A global federation of clinical research networks, providing a proficient, coordinated, and agile research response to outbreak-prone infectious diseases. The first objective will be achieved by implementing collaborative, multi-member, inter-epidemic research projects on severe acute respiratory infections, Lassa fever, and plague; and ‘pre-positioning’ clinical trial protocols for MERS-CoV and Nipah virus. In addition, the ISARIC Global Support Centre and the ISARIC membership will provide technical and operational support to other ISARIC members and stakeholders wishing to conduct research in preparation for or in response to outbreaks. The second objective will be achieved both through the process of developing and implementing collaborative clinical studies and through a programme of membership engagement and capacity development activities that includes scientific seminars, fellowships, and training in clinical research methods. To ensure ISARIC is a truly global asset, the programme will be implemented in close partnership with WHO and others.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Data-driven approaches for rabies elimination
Funder: Wellcome Trust

Abstract: To achieve the 2030 global target of eliminating human deaths from dog-mediated rabies necessitates overcoming enduring challenges of weak surveillance and inefficiencies in vaccine delivery. Fundamental understanding of rabies transmission dynamics gained through my long-term research can now be leveraged to target and coordinate control measures to eliminate rabies and sustain disease freedom. With my team I will develop and apply cutting-edge surveillance tools to transform the implementation of rabies control and prevention, iteratively combining methodological development with implementation science. Drawing from our extensive data I will develop new inference methods to exploit novel integrated genomic and epidemiological approaches that increase case detection, identify incursions, pinpoint their sources and track transmission to delineate foci of persistent circulation. Working collaboratively in settings representative of broader global challenges on the path to rabies elimination (East Africa, Philippines, Peru), I will use these new methods to implement enhanced surveillance to generate data for improved decision-making. Guided by this surveillance I will co-design and test synergistic interventions to increase dog vaccination effectiveness and cost-effective human post-exposure vaccine provisioning. This approach will empower scientists and practitioners whilst establishing trust and engaging communities, generating transferable lessons and best practice needed to achieve the 2030 goal.

Lay abstract: Rabies kills thousands of people every year despite vaccines that can prevent human infections and interrupt transmission in reservoir populations. Global efforts are at last mobilizing to eliminate human deaths from dog-mediated rabies by 2030, but weak surveillance is an enduring challenge leading to ineffective vaccine targeting that threatens progress towards this goal. I aim to accelerate rabies elimination by developing cutting-edge surveillance approaches to detect and track circulating infection and transform the implementation of rabies control and prevention. In settings representative of challenges on the path to elimination (East Africa, Philippines, Peru), we will adaptively co-design and test interventions to determine how best to improve human rabies vaccine provisioning, and target and coordinate dog vaccination, guided by enhanced surveillance. This embedded collaborative research will bring immediate public health benefits as well as transferable lessons and best practice, building political, programmatic and public support to achieve and sustain rabies freedom.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Trinity Challenge: Community Surveillance for better control of AMR
Funder: Wellcome Trust

Abstract: We propose a partnership between The Trinity Challenge (TTC) and The Wellcome Trust, using a proven Challenge Methodology as a way to assist Low- and Middle-income countries (LMICs) develop tools to capture and interpret data relating to bacterial disease and antimicrobial resistance (AMR) in their own Communities, in order to drive local and National action. Working together with an Expert Advisory Group (EAG) we would develop the challenge questions. This, and the application stage, would be supported by ‘sandbox / ideas collision’ workshops in LMICs for citizens, local community and experts, to engage local communities building engagement, knowledge, involvement, ideas, collaborations and action in bacterial diseases and AMR understanding including prevalence. They would be run by known Partners e.g. the UK Fleming Fund which works in the country. The Wellcome Trust would act as the ‘anchor funder’, funding the core secretariat and initial prize commitment, while helping to bring in other partner funders. The inaugural TTC, in 2021 addressing pandemics, demonstrated the value of our Challenge approach in pulling through innovative tools that work for the global south, being relevant, equitable, new, and scalable solutions. The Winners (8) are now being supported to develop and scale.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: INFECTION
Title: Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS)
Funder: Wellcome Trust

Abstract: Southeast Asia (SEA) represents a weakness in global COVID-19 pandemic response because many countries do not have the required capacity to conduct advanced analysis to determine the potential threat of SARS-CoV-2 variants. Our aim is to develop and apply a multidisciplinary research platform for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby supporting local policy makers with evidence-based decision. We will deliver our proposal through four Objectives: 1. Establish a new SEA research platform that supports locally-led investigations evaluating the biology of emerging SARS-CoV-2 variants. 2. Employ state-of-the art structural biology to provide rapid prediction of the ability of new variants to evade host immunity and drugs. 3. Evaluate the impact of circulating variants of concern on antibody and T-cell responses in SEA populations, and the clinical consequences of infection. 4. Create a framework for effective communication and engagement with policy makers and the public concerning new virus variants and their potential to threaten public health. Our proposal will be delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in SEA (Indonesia, Singapore, Thailand and Vietnam), the UK and the USA. It will strengthen regional scientific capacity that can be rapidly deployed for future outbreak responses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION
Title: A small RNA based innate immune system guards germ cell genomes.
Funder: Wellcome Trust

Abstract: For any species to survive, parents must faithfully pass their genomes to their progeny. This necessity is threatened by, among other things, the presence of parasitic genetic elements, called transposons, that have taken up residence within the genomes of all living things. Failure to control these elements leads not only to increases in their numbers but also to a breakdown in germ cell development that leads to sterility. Nearly a decade ago, my laboratory discovered a fundamental mechanis m, termed the piRNA pathway, which all animals use to control transposons, preventing them from increasing their numbers in the germ cells that give rise to the next generation. In this Wellcome Trust proposal, we detail our plans to study the mechanisms by which the piRNA pathway enables us to recognize self, namely our own genes, from non-self, in this case parasitic genetic elements and enables us to control them. Our studies will not only provide knowledge of a critical and fundamental ele ment of biology but also may reveal how parasitic genetic elements might impact fertility in humans and other animals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)
Funder: Wellcome Trust

Abstract: We propose to set up and validate a pharmacometric platform to provide quantitative assessment of antiviral effects in low risk adult patients with recent onset uncomplicated COVID-19 and high viral burdens. This assessment is based on measurement of oropharyngeal viral clearance rates. This will be a randomised, open label, group sequential adaptive platform trial to quantitate the antiviral activity of currently available potential (i.e. repurposed) treatments in low-risk adult patients with early COVID-19, through adjusted qPCR of serial oropharyngeal samples. It will be a mainly outpatient study conducted in three locations; one each in the Americas, Europe and Asia. The interventions to be evaluated in this first phase are hydroxychloroquine, lopinavir/ritonavir, ivermectin, miglustat, remdesivir, intranasal heparin, with the Regeneron monoclonal antibody cocktail or Peginterferon-lambda as a "positive control". This will identify drugs with a >90% probability of accelerating virus clearance compared to no treatment and will reject drugs with <10% corresponding probability. Drugs identified as accelerating viral clearance will undergo a further nested pharmacometric evaluation to characterise exposure–response relationships and inform dosing. This study will provide a platform for choosing antiviral drugs for phase 3 clinical trials. Once validated the platform can be used to evaluate new antivirals.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: ACORN 2.0 - A Clinically Oriented antimicrobial Resistance Network
Funder: Wellcome Trust

Abstract: The ACORN project will establish a network of hospitals and clinical laboratories in Asia and Africa to implement efficient patient-focused antimicrobial resistance (AMR) surveillance. Network data will be used to determine AMR disease burden, risk factors, and patient and economic impacts for key clinical syndromes and associated pathogens. ACORN will address the need for better systems for linked clinical and microbiology data analysis to enable clinicians and ministries of health to understand and respond to the locally and nationally relevant AMR challenges and to engage meaningfully with international surveillance efforts. ACORN will provide simple to use data collection, visualisation, and analysis tools along with a framework for sites to improve clinician utilisation of diagnostic microbiology resources. Targeted clinical and outcome data collection will enable local use of pathogen and antimicrobial susceptibility data, for example by identification of high-risk patients and for development of empiric treatment guidelines. Global AMR surveillance and mitigation endeavours are weakened as a result of limited active healthcare provider engagement via local data use. Project engagement efforts will focus on promotion of widespread adoption of ACORN, through collaborative links with key AMR stakeholders, to ensure that future global surveillance has meaning, from the ground up.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Differentiated prevention and care to support virtual elimination of infectious HIV among sex workers in southern Africa
Funder: Wellcome Trust

Abstract: Community empowerment to support harm reduction and engagement with HIV prevention and care services has been a successful HIV control strategy among female sex workers (FSW) in “concentrated” HIV epidemics, especially in Asia. In the “generalised” epidemics of sub-Saharan Africa, most focus has been on general population approaches, although mathematical modelling suggests that a high fraction of transmissions are directly or indirectly attributable to commercial sex. In Africa, sex work is heterogeneous, stigmatised, and largely illegal. Risk and health service engagement appears to vary as women transition in and out of sex work. HIV prevalence and incidence in FSW are extremely high, and many studies show gaps in the “continuum of care” of HIV diagnosis, treatment and viral suppression. Efficacious HIV treatment and prevention technologies are widely available, yet strategies to maximise their population impact by ensuring high uptake and optimal use are lacking. We hypothesise that an intensified, risk-differentiated sex work programme, tailored for the African context, can raise uptake and adherence to prevention and treatment among FSW to levels that could lead to the virtual elimination of HIV transmission attributable to sex work: if so, then this could be a cost-effective and translatable component of HIV epidemic control.

Lay abstract: Empowering female sex workers (FSW) to collectively reduce their vulnerability to HIV and increase engagement in HIV prevention and treatment is a successful HIV control strategy where the epidemic is concentrated among high-risk populations, particularly in Asia. In the "generalised" epidemics of sub-Saharan Africa HIV programmes have focused on the general population, even though mathematical modelling suggests a high fraction of new infections occur due to commercial sex. In Africa, little is understood about how risk and health-seeking behaviour varies as women transition in and out of sex work. HIV prevalence and incidence remains extremely high, suggesting inadequate uptake of effective HIV prevention and treatment. We aim to demonstrate that an intensified sex work programme tailored to the African context, improves FSWs’ engagement in care to levels likely to achieve virtual elimination of HIV transmission attributable to sex work and is cost effective and transferable throughout southern Africa.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Manufacture of a GMP SARS-CoV-2 challenge agent
Funder: Wellcome Trust

Abstract: In the current COVID-19 emergency, a controlled SARS-COV-2 human infection model (CHIM) has the potential to accelerate the understanding of pathogenesis, induction of immunity and immune mechanisms of resistance to disease, as well as a means to test novel diagnostics and treatments, especially between waves of the pandemic, when occurrence of natural disease is relatively uncommon. A large number of SARS-COV-2 vaccine candidates are at various stages of development internationally including those which have recently entered mid-late stage clinical testing in field studies. In order to make the greatest public health impact, there is an urgent need to select the most promising vaccines in the shortest possible timeframe. In addition, human infection challenge can contribute to the identification of correlates and mechanisms of protection against infection and shedding of virus in vaccinated volunteers. Finally, the model may be useful in the determination of the durability of protection in seropositive individuals with documented prior wild type infection. This proposal is a dose titration study to generate two GMP challenge agents and establish the safety of a wild-type SARS-COV-2 controlled infection in the upper respiratory tract of young healthy volunteers that will allow swift and robust assessment of vaccine efficacy.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Development of a High Efficacy Vaccine against P. falciparum Malaria
Funder: Wellcome Trust

Abstract: The Wellcome Trust has awarded a new £5.1 million Translation Award to the University of Oxford entitled "Development of a High Efficacy Vaccine against P.falciparum Malaria." The awardees are principal applicant, Professor Adrian Hill and co-applicants Professors Simon Draper and Sumi Biswas, all of the Jenner Institute, Oxford. The programme will develop vaccine candidates targeting multiple stages of the parasite's life cycle to phase liB trials in Africa as a potential high efficacy combination vaccine to help prevent disease and death caused by malaria in endemic regions.

Lay abstract: Malaria is one of the biggest killers of children in the developing world with almost half a million deaths annually. Current malaria control tools, such as bed nets and insecticides, have limited life-spans and there is a real danger that malaria will get worse in the 2020s as these tools wear out. New vaccines provide a realistic opportunity for saving many lives and helping to eventually eradicate malaria. We have developed the first malaria vaccine that targets all four stages of the parasite’s life cycle. This approach, utilising leading vaccine technologies and parasite antigens, has shown promise in animal studies and initial clinical trials. Although malaria vaccine development has been difficult, the chances of success appear good with this deployable multi-pronged vaccine approach designed to minimise the risk of parasites evolving to escape vaccine immunity. We will develop this multi-stage vaccine from initial trials in the UK, to testing in adults and then infants in West Africa, culminating in a large safety and efficacy trial in infants at leading malaria research units in three African countries. Success would support investment in a subsequent licensure trial to make this vaccine available to protect the populations most in need of a vaccine.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION