NIHRDataInsights/HRCSData huggingface dataset:
Title: Structural studies of the clustering of PfEMP1 proteins on the surface of Plasmodium falciparum-infected erythrocytes
Funder: Medical Research Council

Abstract: Malaria is one of the most deadly diseases affecting humanity, causing around 2 million deaths, and 500 million serious cases each year. The symptoms of the disease occur during the erythrocytic phase of the Plasmodium life cycle, when the parasite divides within infected erythrocytes. During this phase, the parasite causes extensive remodelling of the erythrocyte. Structures called knobs form on the erythrocyte surface and adhesive PfEMP1 proteins are clustered at these knobs. This causes infected erythrocyte to adhere to human tissues or to the microvasculature, protecting the parasite from detection by the spleen and prolonging the infection. This adhesion also causes many of the most severe symptoms of malaria, with adhesive erythrocyte blocking tiny capillaries in the brain during cerebral malaria and binding to the placenta during pregnancy-associated malaria. The parasite protein KAHRP appears to act as the hub around which the knobs are formed. Important in the correct localisation of KAHRP, and the subsequent formation of knobs, is the interaction between KAHRP and the erythrocyte cytoskeletal protein, spectrin. We have determined the spectrin-binding region of KAHRP and have crystals of the KAHRP binding region of spectrin. We will use structural and biophysical methods to characterise this interaction in stereochemical detail. The intracellular domains of PfEMP1 proteins (the VARC domains) interact with KAHRP and this is thought to be important in clustering PfEMP1 proteins at knobs. We will use structural and biophysical methods, including protein crystallography and nuclear magnetic resonance (NMR) spectroscopy to investigate this interaction in stereochemical detail. We have shown that different peptides from KAHRP interact with VARC and that in the absence of binding partner, VARC is partially disordered. We will use NMR to study VARC-KAHRP complexes and will determine the structures of ordered complexes between KAHRP binding peptides and VARC subdomains. Finally we will initiate parasite mutagenesis studies in which we replace the KAHRP gene by genes containing mutant KAHRP lacking regions needed to bind to spectrin or VARC. We will study erythrocytes infected with these parasite strains and use confocal microscopy, electron microscopy and adhesion studies to determine the roles of different interactions in knob formation and function. These studies will provide detailed structural insight into the formation of knobs and will guide future attempts to develop inhibitors to block knob formation - molecules that will be useful as therapeutics for treatment of the symptoms of severe malaria.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Understanding how a complex intervention works: designing large-scale vaccination programs
Funder: Medical Research Council

Abstract: Despite possessing a sophisticated understanding of the theory underlying many aspects of the dynamics and control of infectious diseases, this knowledge is only rarely applied directly to the design and management of large-scale public health interventions. Substantial resources are routinely invested in disease control programs, but without accompanying studies that analyse how these complex interventions are really working, important opportunities are missed to learn why these programs succeed in some circumstances but not in others. As a consequence, the effectiveness and impact of these interventions can be diminished. Rabies is a horrific zoonosis responsible for an estimated 55,000 human deaths in Asia and Africa each year, mainly in children. The Bill and Melinda Gates Foundation (BMGF) have recently provided $10M to support extensive, long-term rabies vaccination programs of domestic dogs in Tanzania, the Philippines, and the Republic of South Africa, to demonstrate the feasibility and effectiveness of dog vaccination in preventing human rabies. This intervention provides a rare and important opportunity to learn about the large-scale control of rabies, the design of efficient and effective vaccination programs, and the adaptive management of the roll-out of a substantial public health intervention. The BMGF vaccination program will generate a wealth of spatial data on dog population size and distribution, vaccination coverage, and rabies incidence, but resources do not exist within this program to undertake sophisticated in-depth analyses of these data. Here, we have assembled an experienced, multi-disciplinary team of epidemiologists, modellers, veterinarians, virologists, and public-health workers to chaperone these field vaccination programs The team will conduct real-time modelling and analysis of the implementation and performance of this program to learn how the intervention works, and through a process of feedback, improve its efficiency, effectiveness, and likely sustainability. While most of the primary data will be generated through the BMGF program we are requesting limited resources for the acquisition of additional data where the resulting added-value is significant ? namely trace-back contact studies, and genome sequencing of selected rabies isolates to enhance our understanding of the origins and circulation of rabies virus in the study areas. Our proposed project will deliver enhanced understanding of the relationship between population size and required vaccination coverage, algorithms that prioritise the order and importance of vaccinating different parts of the study areas, the interval between pulse vaccination events, the cause of local control failures and the design of appropriate response actions.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Investigating the role of blood group antigens in campylobacter infections
Funder: Medical Research Council

Abstract: Campylobacter species are the commonest reported bacterial causes of gastroenteritis in the UK and industrialized world. C. jejuni is responsible for about 90% of cases, the majority of the remainder being caused by C. coli. Campylobacter species form part of the natural gastrointestinal flora of many birds and domestic animals, but chickens are thought to constitute the largest source of human infection. In humans, Campylobacter species cause diseases that vary in severity from mild watery diarrhoea to bloody dysentery. In a small subgroup of patients, the acute phase disease is followed by serious sequelae, including Guillain-Barre syndrome and reactive arthritis. Prevention and treatment of campylobacteriosis and its consequences are hampered by a poor understanding of the detailed molecular interaction between the host and the pathogen. Previous reports have indicated that adherence of C. jejuni to epithelial cells can be partially inhibited by fucosylated sugar components of human breast milk, which were later identified as the host blood group antigens (BgAgs) H1 and H2. Furthermore, the attachment of H2 antigen to C. jejuni could be inhibited by fucosyl-lactose contained in human milk. Our preliminary work leading up to this application confirmed that C. jejuni specifically binds all human BgAgs. The bacterial ligands responsible for binding are the flagellin protein FlaA and the major outer membrane protein (MOMP). Unusually, MOMP appears to be O-glycosylated, and may share a common BgAg binding site with FlaA, which has already been shown to be O-glycosylated. The data also suggest that the BgAgs can inhibit bacterial adhesion and biofilm formation. The overall aim of this proposal is to develop a better understanding of the host-pathogen interaction with the ultimate objective of developing preventative and/or modulatory agents that would block human and animal colonisation and disease. The immediate objectives of this study are to investigate the structure and function of the Campylobacter ligands that bind BgAgs and determine the role of BgAgs in Campylobacter auto-agglutination, biofilm formation, host-pathogen interaction and prevention and/or termination of C. jejuni colonisation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Developmental Clinical Studies-a novel vaccine candidate MVA-NS for use in a prime boost schedule in HCV infection.
Funder: Medical Research Council

Abstract: The global burden of hepatitis C virus (HCV) infection is immense with 180 million people infected world-wide leading to liver fibrosis, cirrhosis, liver failure and hepatocellular cancer. There is currently no vaccine for either the prevention or the treatment of HCV, and the best available current treatments are expensive, unpleasant and frequently ineffective. HCV infection is particularly susceptible to a T-cell vaccination strategy since it has been clearly shown by our group and others that spontaneous viral clearance occurs following primary infection in 20% of individuals and is crucially dependent on the induction of a robust and durable CD4 and CD8+ T-cell response. This forms the scientific rationale for our overarching aim-the development of a prophylactic and therapeutic T-cell vaccine for HCV. Since pre-existing anti-vector immunity may limit vaccine efficacy we have conducted a phase-I clinical trial in healthy human subjects using human (AdHu6) and simian (AdCh3) adenoviral vectors found at low sero-prevalence in human populations, in a heterologous prime/boost regimen. These encode the HCV non-structural proteins with a genetically inactivated polymerase gene (NS). We show that both vectors are safe and highly immunogenic following a single priming injection. In preclinical primate studies using identical vectors, heterologous boosting increased peak responses and long-term immunity. However, in humans it appears that although HCV specific T-cell responses increase following boosting, the magnitude of this response is significantly reduced compared to that observed during vaccine priming. This is due to the induction of cross-reactive immunity between the two vectors. In contrast, it has recently been shown that Modified Vaccinia Ankara (MVA) encoding the malaria antigen ME-TRAP very successfully boosts T-cell responses primed with a simian Adenovirus vector, inducing the highest level of CD4+ and CD8+ T-cell responses ever observed using a vectored vaccine and affording protection from malaria infection. For these reasons we now wish to develop an MVA construct encoding NS. This will be combined with AdCh3NS in a heterologous prime/boost vaccination regimen and used to assess the safety and immunogenicity of this strategy in healthy and HCV infected patients. We believe that the development of an MVA-NS vector and Phase I testing of the Adeno/MVA regimen will allow a comparison of the two most promising vectored vaccine approaches to date and so enable a comprehensive and rational approach toward development of an effective vaccine for HCV prevention and cure.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS;3.4 VACCINES
Health categories: INFECTION
Title: Cellular immunity to herpesvirus infections: studies with Epstein-Barr virus (EBV) and human cytomegalovirus (CMV)
Funder: Medical Research Council

Abstract: Our work focuses on two human herpesviruses, Epstein-Barr virus (EBV) and cytomegalovirus (CMV), which elicit strong T cell-mediated responses in the immunocompetent host but are life-threatening in immunocompromised settings. We propose three areas of work on:-. (i) Immunodominance and the evolution of viral immune responses : we shall study the different hierarchy of CD8 immunodominance among immediate early (IE), early (E) and late (L) antigens of the EBV lytic cycle (IE E L) with that found for CMV, where strong responses to IE, E and L antigens exist. Experiments, involving both infectious mononucleosis (IM) and X-linked lymphoproliferative disease (XLP) patients, will test the hypothesis that EBV-induced CD8 responses are directly primed by virus-infected B cells. We shall also compare the CD8 response to known immunodominant CMV epitopes with that to a range of new, subdominant epitopes, looking for inter-epitope differences in phenotype and age-dependent response inflation. Parallel work will study the size and kinetics of CD4 responses to newly-defined EBV and CMV epitopes in primary and persistent infection and ask whether, superimposed on the cross-primed response, there is enhanced reactivity to antigens which naturally access the MHC II pathway in lytically-infected cells. (ii) Immune evasion : here we extend the study of CD8 immune evasion by EBV, using gene-deleted viruses to ask what influence the three EBV lytic cycle proteins with known evasion function (BNLF2a, BGLF5 and BILF1) have upon antigen presentation in the natural context of the lytically-infected cell, in particular how their separate functions complement one another at different stages of lytic cycle. In parallel, we shall use the methods that have identified natural killer (NK) evasion functions in CMV to screen the whole EBV lytic gene set for evidence of similar NK evasion effects, and use newly-developed experimental approaches to examine the functional importance of four lytic cycle proteins (BZLF1, BGLF5, BCRF1 and gp42) which are candidate effectors of CD4 immune evasion. (iii) Virus-host balance in the immunocompetent and immunosuppressed : here we analyse virus-host interactions at the tissue level, looking at the homing and intra-tissue localisation of virus-specific T cells, and at the whole organism level through cross-sectional and prospective studies on newly-established cohorts of young immunocompetent, elderly and patient groups. There we focus on issues of response magnitude in relation to latent and lytic virus load, the antigen-dependence of response persistence, and the effect of virus carriage on overall composition of the T cell pool.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Methodological development in whole-economy modelling: P. falciparum malaria control in Africa
Funder: Medical Research Council

Abstract: The demand for economic evidence by policy makers is strong and increasing, used to indicate the relative burden of diseases, the distribution of that burden, and the desirability of specific interventions to affect disease. Such evidence is overwhelmingly generated by partial-equilibrium studies, based on analyses of economic effects upon individuals, households and the health sector. Such analysis is limited in exploring fully the economic impact of a disease with system-wide effects, such as malaria. Alternative, whole-economy analyses (considering impacts on national economic indicators and across non-health related sectors) have tended to be undertaken by development economists, typically using a health proxy as an explanatory variable in economic growth models, limiting opportunities to fully analyze the complex relationship between health, other aspects of the economy and broader economic indicators. Previous work has demonstrated the value of the Computable General Equilibrium (CGE) approach to whole-economy modeling, but highlighted the need for further development in its application to health issues; specifically, endogenization of the epidemiology and demography of disease. P. falciparum malaria control in Africa provides the ideal case-study for this methodological developmental work, as one of the most common global infectious diseases. Africa especially is heavily affected, and economic analyses of malaria and malaria control policies have demonstrated the limitations of both partial-equilibrium and cross-country econometric analyses. Indeed, Feachem and Sabot recently suggested that ?more robust analysis, taking into account factors such as effect on tourism and investment, should be a research priority? (Lancet, 2008; 371: 1634). The developmental work proposed here will take place in Ghana and Mozambique, as these reflect the East-West regional differences in malaria epidemiology. Overall, this project will produce a dynamic CGE model of malaria (control) applicable across a range of African counties. Together with existing work, this project will further contribute to a modeling capability applicable across a wide range of infectious diseases, causative agents and developed and developing countries, facilitating the wider application of this form of modeling within health economics, and increasing its relevance to health policy.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: The contribution of Chlamydia trachomatis to adverse reproductive health and the implications for control policy
Funder: Medical Research Council

Abstract: Chlamydia trachomatis (CT) is one of the commonest sexually transmitted bacterial infections in Europe. Untreated infection can lead to serious adverse reproductive outcomes but these can be prevented by diagnosing and treating infections. The control of CT is a public health priority and there is evidence to show that screening can reduce the incidence of complications. Investment in control programmes is mainly justified in order to reduce long term complications, including pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility. However, at present there are no consensus estimates of the risk of these complications following an infection. The aim of this research is to improve knowledge about the natural history of CT infection and use this to estimate the population attributable risk of CT for adverse reproductive health in order to improve estimates of the cost effectiveness of CT control activities. The gaps in the current evidence base around the natural history of CT and the cost effectiveness of control strategies will be addressed using a range of research methods. Firstly, a systematic review of the literature will be completed to update current estimates of the association between CT and adverse reproductive outcomes. Secondly, quantitative analysis of a large historical population cohort will be performed to measure the association between a diagnosis of CT and the chronic consequences. This work will then be used to inform the assumptions in a mathematical model of the transmission dynamics of CT that will be developed and used to inform cost effectiveness analysis of CT control strategies. Finally, qualitative techniques will be used to develop an understanding of the CT control policy context. The findings of the proposed research will be used to formulate policy recommendations. The proposed research will provide a comprehensive multidisciplinary training in research and it will advance current knowledge on the natural history of CT and the cost effectiveness of control strategies to inform policy at a regional, national and international level.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.4 POPULATION SCREENING
Health categories: INFECTION
Title: London Sch of Hygiene and Trop Medicine
Funder: Medical Research Council

Abstract: Aim: The overall aim is to explore the dynamics of access to HIV services including antiretroviral therapy among HIV-infected participants of a Tanzanian community HIV cohort study during the period 2005-2014 in order to inform policies to improve early and sustained access to HIV treatment. Objectives: 1. To examine trends in rates of access to HIV services (HIV testing, referral, ART, home-based care) among HIV-infected persons following seroconversion and to identify socio-demographic inequities in HIV service use and unmet need for ART. 2. To describe default and mortality rates over time among patients enrolled in the HIV treatment programme, taking into account the influence of time-dependent covariables (e.g CD4 progression) on multi-state outcomes (e.g. ‘pre-treatment monitoring‘ versus ‘on ART‘). 3. To evaluate the role of programme factors (e.g type and place of HIV testing service, place of referral, location of ART clinic) on early and sustained access to HIV treatment. 4. To explore the relationship between social support, family circumstances and partnership factors and timely, sustained access to HIV services. Design: Secondary analyses of quantitative data and nested qualitative studies in a community-level HIV cohort study Methodology: Data will be used from the Kisesa cohort study which includes 6 rounds of HIV serological surveillance between 1994 and 2009 with detailed surveys on health and sexual behaviour and 23 rounds of demographic surveillance, collecting information on spousal relationships, births, deaths and migration. These data have been anonymously linked to HIV testing, referral and ART data from the start of the national ART programme in early 2005. Survival analysis will be used to calculate rates of HIV service uptake, mortality and default from each stage of the process of accessing ART following seroconversion, with multi-level modeling used to identify individual-, partnership-, community- and programme-level factors associated with each outcome. ART needs, based on survival time post-HIV infection among seroconverters and age-specific mortality rates among prevalent cases will be compared with ART uptake to assess for trends in socio-demographic inequities in treatment coverage. Qualitative methods will be used to explore the influence of social and programme factors on access and retention in HIV treatment clinics. Scientific and medical opportunities: The findings will result in practical policy recommendations regarding the effectiveness of different HIV testing and ART delivery policies, and the potential need for more family-focused interventions to promote timely uptake, equitable access and sustained attendance in HIV programmes in Tanzania and beyond.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFECTION