NIHRDataInsights/HRCSData huggingface dataset:
Title: Import of adenovirus cores to the nucleus.
Funder: Wellcome Trust

Abstract: When a virus enters a human cell it must deliver its genetic information to the ideal location for that virus to replicate and make copies of itself. In the case of many viruses the normal place for replication is the centre of the human cell in an area called the nucleus. The nucleus is surrounded by a membrane with many holes in it called nuclear pore complexes. Many viruses use these holes in order to inject their genetic information into the nucleus of the cell which is also where the DNA of the human cell is kept. We are seeking to understand how this process works both in order to understand the life cycle of viruses better and to understand how we might be able in the future to efficiently deliver genetic information into a human cell artificially in order to cure certain types of genetically inherited diseases for example.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Conditional Translational Repression: a core regulatory mechanism of gene expression during development of the malaria parasite - study and applications.
Funder: Wellcome Trust

Abstract: More than 1 million lives in sub-Saharan Africa are lost annually to the pathological consequences of malaria infection caused by Plasmodium falciparum. A case for strategic prevention of transmission of the parasite between human and mosquito is supported by mathematics and practical experience. Transmission, sex and subsequent development of the Plasmodium zygote in the mosquito midgut are essential and linked phases of the parasite s life cycle. Use of antibodies to interrupt these early ev ents may critically reduce transmission below levels that will sustain spread of the disease. Consequently, an understanding of the molecular events underpinning this parasite development could have medical relevance. We have discovered a core mechanism, Conditional Translational Repression (CTR), that regulates expression of parasite genes essential for these stages in the parasite life cycle, and I propose to generate a highly detailed understanding of CTR. Furthermore, as this regulatory m echanism is used in humans, our relatively simple malaria model offers a unique experimental system of very broad potential in biology. We shall therefore also perform comparative analyses of the molecular mechanisms underpinning CTR, with the aim of exploiting parasite-specific details as potential as targets for prevention of disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: UK HIV Vaccine Consortium.
Funder: Wellcome Trust

Abstract: The HIV/AIDS epidemic is possibly the greatest current challenge to international public health, and HIV will only be contained through the development of a prophylactic vaccine. Despite 20 years intense research, there is still no credible HIV vaccine on the horizon. However, a number of groups have recently developed novel approaches to immunization which induce high level cellular immune responses in man, which are the first steps to a future HIV vaccine. The funding process has generally led to these products being developed in isolation, and there has been little direct comparison of different immunization strategies globally. We now propose to use a WT Strategic award to foster integrated research between funded UK research groups studying diverse vaccine constructs. A series of candidate vaccines containing identical HIV antigens will be generated, such that direct comparison can be achieved to understand most rapidly the most immunogenic strategy for immunization in man. These results will lead to a UK contribution in HIV vaccine research which is greater than the sum of its parts, and will contribute to the Global initiative for an AIDS vaccine (GHAVE), in the fastest and most effective manner.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Schistosomiasis, hookworm and atopy in Uganda: IgE function, regulation and immunity.
Funder: Wellcome Trust

Abstract: Key goals: Two schistosomiasis/hookworm treatment-reinfection studies in cohorts exposed to both infections, with detailed GIS and exposure analysis to give precise immunity estimates, and associations between infections controlled for overlapping transmission clustering. Study 1: compare first and second treatments for post-treatment immunological changes, and responses to in vivo Ag released from killed worms, for evidence of specific and non-specific cross regulation, affecting reinfection immunity. Specifically, measure: Schistosome, hookworm and aeroallergen IgE responses; Specific IgE function in passive histamine-release with Ag stimulation; Number/phenotype of circulating basophils and eosinophils, and tissue mast cell activity. Study 2: repeat most informative Study 1 assays, in relation to cellular responses: Whole-blood cytokine responses to schistosome and hookworm Ags; Active histamine-release from whole-blood samples stimulated native & recombinant schistosome, hookworm, aeroallergens; IL-10 and TGF-beta effects on in vitro cytokines induced by schistosome and hookworm; Skin-prick reactivity to aeroallergens; Identify cellular sources of IgE/IgE-effector modulatory molecules. Test hypothesis that: (a).Eosinophils have a regulatory role; in turn affected by immune modulators; non-responsive eosinophils are associated with reinfection susceptibility, (b).Susceptibility to schistosomiasis and hookworm is linked, via mechanisms that also affectallergy. (c).Life-stage expression and molecular structure of schistosome allergen-like Ags influence IgE and IgE-effector function triggering.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Investigation into Plasmodium falciparum rosetting mechanisms and development of rosette-disrupting interventions to treat or prevent severe malaria.
Funder: Wellcome Trust

Abstract: There is an urgent need for new drugs and vaccines to reduce global mortality from malaria. The development of new interventions is constrained by our incomplete understanding of parasite virulence factors and mechanisms of natural immunity. The only parasite virulence phenotype to date that has been consistently associated with severe malaria in African children is P. falciparum rosetting. My previous work identified members of the variant antigen family PfEMP1 (P. falciparum erythrocyte mem brane protein one) as the parasite ligands for rosetting, opening up the possibility of developing an anti-rosetting vaccine based on PfEMP1. However, there is currently little information on the diversity in rosetting mechanisms between strains, and whether rosette-disrupting antibodies raised to one PfEMP1 variant cross-react with other strains. The work in this proposal specifically targets the need to acquire further detailed information on rosetting mechanisms and cross-reactivity amongst strains that will be essential to inform future vaccine development. I also aim to pursue a therapeutic approach by developing a rosette-disrupting drug with broad-spectrum activity and no anticoagulant side effects. The key goals of this research are to provide a mechanistic understanding of rosetting and to identify rosetting-disrupting vaccine and drug candidates.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The virus-receptor interaction in lentiviral pathogenesis and immunity.
Funder: Wellcome Trust

Abstract: The disease a virus causes is determined in part by the cellular targets for infection. Just as influenza (flu) virus causes respiratory disease by binding to a molecule that is expressed on the cells lining the airways, the viruses that cause AIDS in humans (HIV) and in cats (FIV) destroy the body s ability to fight off infection by targeting helper T cells. Helper T cells are critical in controlling the immune response to infection and FIV targets these cells by binding to a molecule (CD134, t he receptor for the virus) that is expressed selectively on them. Armed with this knowledge, we are now able to understand better the way in which the virus causes AIDS. Some viruses appear to have a higher disease causing potential than others and we believe that this is determined by the way the virus binds to CD134. By studying the interaction between the virus and its receptor, we can improve the design of vaccines that will protect cats from infection with FIV and may lead to the developm ent of drugs to treat infected animals. These studies will also be of value to the development of vaccines that will protect against HIV infection in humans.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The Malaria Capacity Development Consortium Phase 2
Funder: Wellcome Trust

Abstract: The vision of MCDC phase 2 (MCDC-2) is to build on the experience and success of the MCDC to further strengthen malaria research groups at five African universities so that motivated and capable African scientists can lead vibrant, multidisciplinary MCDC Malaria Research Centres capable of conceiving, funding, implementing and reporting high quality research studies. The established critical mass and structure within these malaria research groups will support research beyond the immediate research group and provide an operational capacity building model. The research groups will operate both within the context of their own university and as part of established north-south and south-south institutional and project-based partnerships.We will transition the developed and tested PDP, mentorship and PhD supervisor training programmes within MCDC-1 to the five universities to ensure the availability of locally-run supervision, mentorship and career development training programmes for PhD and Postdoctoral fellows, their supervisors and mentors. Research and training systems and infrastructure will be strengthened by targeted investments identified through independent assessments of need.MCDC-1 has been described as a model for the strengthening of PhD programmes and postdoctoral training, our vision is to make MCDC-2 a model to support and strengthen successful research programmes and teams.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Capacity development in malaria research in Africa.
Funder: Wellcome Trust

Abstract: The international community is currently making greater efforts to control malaria than at any time since the attempt to eradicate malaria in the 1950s and 1960s. Large sums of money are being deployed for malaria control in Africa but little investment has been made in developing the careers of the staff who will be needed to ensure that this money is spent wisely. This proposal is directed at remedying this deficit. Support will be provided for about 30 African post doctoral scientists who ha ve obtained their PhD in the past two or three years with support from the Gates Malaria Partnership through small grants and mentoring programmes. In addition, a new cohort of approximately 20 African scientists will be selected in an open competition for doctoral training in some aspect of research related to the treatment or prevention of malaria. This training will be based at one of five universities in Ghana, Malawi, Senegal, Tanzania or Uganda and will be supported by staff from the Live rpool and London Schools of Tropical Medicine and the University of Copenhagen. The aim of this programme is to provide a model for PhD training in health sciences in African universities.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Studies of Dengue pathogenesis and vaccines in Vietnam for improved case management and primary prevention .
Funder: Wellcome Trust

Abstract: Dengue is an enormous public health problem in many parts of the world. There is no vaccine for dengue or drugs to treat it. There are many questions in dengue research that are unanswered. For example, we still don t know why some people don t get dengue despite clear exposure whilst others get sick, and for patients who are sick, we can t accurately predict who will get severe disease or die. This fellowship will address these issues and will be conducted in Vietnam as part of a well-establish ed collaborative research program between Oxford University and the Vietnamese Government and funded by the Wellcome Trust. The aims of the research are to a) to design a method to identify dengue patients who are at risk of developing a life-threatening complication of their disease, b) identify parts of the immune system that could explain why some people who get dengue get no symptoms whilst others get sick, and c) to test a promising new vaccine in Vietnamese volunteers with the hope that one day a vaccine to prevent dengue will be available in Vietnam. This research is important and could have long-lasting implications for how we treat patients and develop vaccines.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;3.4 VACCINES
Health categories: INFECTION
Title: Evaluating and enhancing the scale-up and population impact of concurrent HIV/AIDS prevention and treatment services in a well-characterised previously declining epidemic in sub-Saharan Africa.
Funder: Wellcome Trust

Abstract: In the proposed research, we aim to measure and evaluate the impact of scaled-up evidence-based HIV/AIDS prevention and treatment services on HIV infection and AIDS mortality at the population level in Zimbabwe. This will be done by: (i) continuing to monitor trends in HIV prevalence, HIV incidence and mortality and trends in utilization of prevention and treatment services in a large-scale (n=c12,000) general population cohort in eastern Zimbabwe; (ii) measuring associations between service uti lization and risks of infection and death at the individual level; and (iii) using mathematical models to isolate the likely contributions of increased availability and uptake of services to trends in the epidemic observed at the population level. Qualitative research and mathematical models will be used to identify ways in which the impact on the HIV epidemic could be enhanced by addressing factors affecting the demand for and supply of services.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Measuring the impact of naturally acquired immunity on the expression of Plasmodium falciparum variant surface antigens.
Funder: Wellcome Trust

Abstract: Plasmodium falciparum infected erythrocytes express on their surface, members of a diverse family of parasite molecules called PfEMP1 that are encoded by a family of 60 var genes. These molecules interact with the surface of host cells and mediate parasite sequestration in tissues including the brain, an important step in the pathogenesis of cerebral malaria. Although naturally acquired antibodies to PfEMP1 provide specific protection against the molecular variants that they recognise, PfEMP1 ar e often considered too diverse to be vaccine candidates. However, we and others have shown that parasites infecting children with severe malaria tend to express serotypes that are more broadly recognised suggesting they may be antigenically restricted. Studies of a laboratory isolate suggest that the most broadly recognised PfEMP1 types are encoded by a genetically distinct subset of groupA var genes. By sequencing short var sequence tags expressed in parasites from Kenya, we have shown that expression of sequences with groupA-like features are associated with younger children and that a smaller subset of these sequences are associated with severe malaria. We propose to identify new targets of malaria intervention by characterizing these specific subsets of PfEMP1 that are associated with infections of children with low natural immunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Development of a simple rapid test kit for the early diagnosis of enteropatogenic Escherichia coli (EPEC) in children with diarrhoea.
Funder: Wellcome Trust

Abstract: Tragically, 2 million children die of diarrhoea in developing countries every year, most before their second birthday. Diarrhoea is caused by various viruses, bacteria and parasites. Many cases subside after 2-3 days, especially if the child is treated to avoid dehydration. Cases caused by a type of bacterium called EPEC, however, are persistent, resulting in damage to the intestines that does not respond to such treatments. EPEC therefore accounts for the majority of deaths. The problem is that symptoms of various forms of diarrhoea are similar in the early stages, so by the time it becomes clear that a child has EPEC it may be too late to prevent potentially fatal damage. We propose to develop a rapid EPEC diagnostic kit for use in health centres in developing countries where resources and personnel are limited. By testing all children with diarrhoea, those with EPEC can be identified quickly and treated before the damage is done. The World Health Organisation aims to reduce childhood deaths worldwide from 6 million to 4 million by 2025. Our test will make a valuable contribution to this ambitious target. Diagnostic company SIFIN recognises this and is interested in commercialising the kit once it is validated.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: The potential impact of vaccination on RSV and other respiratory virus pneumonia in the developing country setting.
Funder: Wellcome Trust

Abstract: RSV is a major cause of childhood severe pneumonia in developing countries. Success in preventing this disease lies with the development of an effective vaccine. However, severe difficulties confront the design of suitable vaccines for delivery in early life where disease risk is highest. We propose to investigate the merits of targeting vaccine to other groups such as children in later infancy, elder siblings, and mothers, or school children. The effectiveness of such programmes will hinge upon the extent to which the incomplete immunity conferred by infection and by vaccination may indirectly protect others uninfected or unvaccinated, particularly infants. We will study who gets re-infected in the community and their role in infecting the vulnerable infant. We will study blood and nasal samples from children with known infection histories, and of varying severity, to identify what immune responses appear protective to disease, and how this relates to the infecting strain. We will ga ther together our knowledge on RSV to generate models of infection spread by which to improve understanding of the dynamic consequence of immunization, including the influence of co-circulating respiratory viruses. Our goals are to support vaccine development and define optimal strategies for vaccination.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: A proof of concept Phase IIb efficacy trial to evaluate the protective efficacy of a booster MVA85A vaccination administered to BCG primed infants in the Western Cape.
Funder: Wellcome Trust

Abstract: There is an urgent need for a better vaccine against TB. BCG fails to protect against pulmonary disease in the developing world. However, when administered at birth in the developing world, BCG does confer protection against disseminated disease in childhood. Therefore, a strategy designed to boost BCG rather than replace it will allow these beneficial effects to be retained. MVA85A is a leading candidate vaccine designed to boost BCG. A series of clinical trials with MVA85A in the UK, Gambia and South Africa have shown it to be safe and highly immunogenic in all populations tested to date. The next step on the development pathway is to test whether this promising vaccine actually works to stop people developing TB disease. The Western Cape in South Africa is one of the few places in the world where an efficacy trial of a new TB vaccine can be conducted within a realistic time frame because of the very high incidence of disease. This proposal will half fund a Phase IIb proof-of-concept trail of boosting BCG with MVA85A in infants in Cape Town. The trial will be funded with the Aeras Global TB Foundation.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Malaria in school-aged children: Epidemiological risk, disease burden and strategies for control.
Funder: Wellcome Trust

Abstract: Malaria is a major cause of illness and death in early childhood, and research and control efforts mainly focus on improving malaria in young children. As a result, few studies have examined malaria in older school-going children and we know surprisingly little about the impact of malaria on the health of schoolchildren. This lack of information means that older children often do not benefit from current control measures. This is further hampered by the fact that most schoolchildren show no sign of infection, the effects of which may be subtle and long-lasting, such as anaemia and loss of concentration in class. Some recent studies indicate that malaria may in fact have more profound consequences for the health and education of schoolchildren than was previously appreciated. This project aims to fill this information gap by examining and describing the impact of malaria on the health and learning of schoolchildren in West Africa. The project will also investigate the impact of two diff erent methods to control malaria in school-aged children. The information generated will provide decision-makers with a) more knowledge on how malaria affects school-aged children, and b) information with which to design better malaria control strategies to improve health and education.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Investigating the early post-entry steps of the retrovirus life cycle.
Funder: Wellcome Trust

Abstract: Retroviruses cause severe diseases. An estimated 39.5 million people are living with HIV/AIDS, and nearly 3 million died in 2006. Recently, a novel retrovirus called XMRV has been linked to prostate cancer, the most common cancer in men in the UK. Retroviruses need to use host cell proteins in order to replicate. Interactions between viral and host cell factors occur at every stage of the viral lifecycle, although most are poorly understood. Identifying and understanding these interactions are k ey to developing new treatments to combat disease. A greater understanding of retroviral replication might also be of use in research to advance gene therapy for other diseases, by improving the efficiency of retroviral-based vectors used for gene delivery. Furthermore, such knowledge could help to develop better animal models for HIV/AIDS. This proposal suggests experiments I would like to carry out to advance our understanding of the early stages of the retroviral lifecycle. I propose to s tudy mutant viruses that are unable to complete these steps to determine why they cannot replicate. I will also investigate cellular proteins called restriction factors that inhibit the early stages of retroviral infection and try to identify other cellular proteins that are involved in these processes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION