NIHRDataInsights/HRCSData huggingface dataset:
Title: Parental incentives and quasi-mandatory schemes for increasing uptake of immunisations in pre-school children
Funder: Department of Health (England)

Abstract: Childhood immunisation programmes form a core component of public health strategies worldwide. Nationally and globally childhood immunisations have been highly effective in reducing the incidence of and associated morbidity and mortality from a range of infectious diseases. The World Health Organization (WHO) has set a goal of 90% coverage for all immunisations with 95% coverage for measles and diphtheria. In the UK coverage for pre-school vaccinations ranges from 85-95%. Incentives and quasi-mandatory interventions to increase uptake of pre-school vaccinations have been suggested by the National Institute of Health & Clinical Excellence as interventions worthy of further consideration. These can be thought of as both financial and non-financial gains or losses provided contingent on receipt or non-receipt of vaccinations. Examples include higher welfare benefits for families with children who have received all recommended vaccinations; and restricting school entry to children who are vaccinated.In order to explore the effectiveness and acceptability of such interventions we will conduct a series of three linked studies: a systematic review of existing research; focus group interviews with parents and individual interview with relevant professionals (e.g. health visitors practice nurses GPs head teachers); and an internet survey exploring parental preferences for a range of different interventions for increasing vaccination uptake.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.4 VACCINES
Health categories: INFECTION
Title: Establishment of a Resource for Long-Term Study of Hepatitis C Virus Infection in the UK - HCV Research UK
Funder: Medical Research Council

Abstract: The healthcare burden associated with chronic hepatitis C virus (HCV) infection will continue to increase in the UK for the foreseeable future. While there has been considerable progress with understanding the biology of the virus and improvements in healthcare provision, many issues relevant to the characteristics of HCV infection in the UK remain unresolved, such as the host, viral, and environmental factors that contribute to development of serious liver disease and failure to respond to treatment. To address these issues, this proposal aims to: a) Establish a national cohort of 10,000 HCV-infected patients, supported by an integrated, standardised clinical database with demographic, clinical and laboratory parameters, b) Create a biobank of biological samples from the cohort for studies of host and viral factors associated with disease outcome and treatment response, c) Execute a limited set of research studies to generate viral and host sequence data to demonstrate the value and potential of the cohort and biobank, and d) Generate a bioinformatics database from the viral and host sequence data [acquired in c)], which can be linked to the clinical database [in a)]. Assembling a cohort of this size is necessary to generate a representative but sufficiently diverse collection of patient characteristics and clinical samples to explore in detail the determinants that may contribute to HCV pathogenesis and response to treatment. The infrastructure will be supported by and build upon existing knowledge and expertise at national agencies (Health Protection Agency and Health Protection Scotland), the Gastroenterology and Liver Disease Biomedical Research Unit at Nottingham and the MRC Virology Unit in Glasgow. Patients will be recruited from clinical centres across most of the UK who provide care for HCV-infected patients. To provide proof of principle for the utility of clinical research and sequence databases combined with the availability of a biobank of clinical samples, a limited series of research projects will be performed. The projects will focus on examining whether there is a correlation between single polynucleotide polymorphisms in host genomic sequences and treatment outcome. In addition, the viral sequences of a large number of isolates for HCV genotypes 1 and 3 in different ethnic groups will be determined. These studies will provide the foundation for the information that will be deposited in the sequence and bioinformatics database. The availability of such a well-structured resource is highly likely to stimulate greater clinical and fundamental research into HCV infection in the UK and will also form the basis for longitudinal studies into the natural history of chronic infection in a large cohort of patients.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Molecular approaches to distinguish between latent and active tuberculosis and identify factors involved in protection.
Funder: Medical Research Council

Abstract: Mycobacterium tuberculosis (Mtb) is estimated to infect a third of the world's population, yet only 10% develop active tuberculosis (TB),causing 1.8 million deaths annually. The immune factors protecting the remaining 90% of latent individuals who do not develop disease are as yet unclear. It has already been shown that there is a specific transcriptional signature from mycobacterial antigen-stimulated blood that is present in healthy vaccinated, latent and active TB individuals, but absent in unvaccinated healthy individuals. Aim: To determine whether there is a specific transcriptional signature in Mtb and Mtb-specific antigen-stimulated blood cells of latent TB and BCG vaccinated individuals but absent in active TB patients, before and after treatment. Objectives: Define and compare the transcriptional signature by microarray analysis, and cytokine and chemokine profiles by immunoassay, after different stimulation times with Mtb and mycobacterial antigens of whole blood or peripheral blood mononuclear cells (PBMC) from: healthy non-BCG vaccinated, healthy BCG vaccinated, individuals with latent TB and those with active TB (pre and post-treatment). Design and Methods: 4 cohorts of individuals as described above will be enrolled. Samples of their whole blood/PMBCs will be stimulated in vitro with Mtb, Mtb antigens (ESAT6, Ag85, PPD), SEB (positive control) and TLR-2 ligand PAM3Cys. Blood and PBMC stimulated for different time points will be frozen, RNA will be isolated and microarray analysis undertaken to identify signatures of protection or pathogenesis. Supernatants will be collected at the same time points for immunoassay. Scientific and medical opportunities: The identification of a specific transcriptional signature which differentiates between latent and active TB will help identify factors involved in protective innate and adaptive immunity to help design future vaccines as well as identifying biomarkers for use in monitoring response to vaccines.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: The Evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB
Funder: Medical Research Council

Abstract: The study is a non-inferiority randomised controlled trial designed to assess a regimen for MDR-TB based on the treatment given in Bangladesh described by Van Deun, 2010. The experimental regimen consists of moxifloxacin, clofazimine, ethambutol and pyrazinamide given for 9 months supplemented by kanamycin, isoniazid and prothionamide in the four months of the intensive phase; the continuation phase lasts 5 months. Standard doses are given for all drugs except for isoniazid and moxifloxacin which are given in higher doses. All drugs are given daily (seven days a week) except for kanamycin which is given daily for 3 months and then thrice-weekly subsequently. The intensive phase and total duration may be extended by up to two months if sputum smears are slow to convert. Patients on the control regimen will receive the locally-used WHO-approved MDR-TB regimen, given for a minimum of 18 months after culture conversion; this commonly takes 4-6 months and so most standard regimens last approximately two years. Patients will be randomised to either the experimental regimen or the locally-used WHO-approved MDR-TB regimen in the ratio 2:1 and be followed up to 27 months post-randomisation. The primary efficacy outcome is status at the end of follow-up i.e. the proportion of patients with a favourable bacteriological outcome 27 months after randomisation, provided they have not already been classified as unfavourable. Change of more than one drug for adverse reactions or any other reason is considered an unfavourable outcome. The primary safety outcome is the proportion of patients experiencing a grade 3 or greater adverse event during treatment and follow-up. Reference: Armand Van Deun et al. Short, Highly Effective and Inexpensive Standardized Treatment of Multidrug-resistant Tuberculosis. American Journal of Respiratory and Critical Care Medicine 2010; 182 684-92


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Safety of discontinuing Cotrimoxazole Prophylaxis among African adults on ART. A randomised controlled trial
Funder: Medical Research Council

Abstract: Cotrimoxazole (CTX) is a broad spectrum antimicrobial medication that is widely used as primary and secondary prophylaxis against opportunistic infections among HIV infected individuals. On the other hand, treatment of HIV infection with antiretroviral drugs permits restoration of the immune system with a resultant reduction in susceptibility to many of the opportunistic infections to which people with HIV are prone. Research done in industrialised countries has shown that it is not necessary to continue prophylactic treatment with CTX prophylaxis in patients on antiretroviral therapy (ART); and it is standard practice in industrialised countries to discontinue prophylactic treatment with CTX once immune restoration to a CD4 count of 200 cells/mm3 has been documented. In Africa, where there is a different spectrum of opportunistic infections among HIV infected patients, but where there is also increasing access to ART for HIV infected patients, there have been no controlled studies done on whether or not this additional prophylactic treatment with CTX can safely be discontinued once patients are stable on ART. Clinicians in Africa are uncertain about the safety of discontinuing CTX, yet continued indefinite administration of CTX for has the potential disadvantages of a high pill burden, possibility of side effects and increased costs. It is therefore important to establish in a controlled trial, whether CTX prophylaxis can be safely discontinued once patients on ART have regained their immune competence. The proposed non-inferiority trial will investigate the safety of stopping CTX medication among HIV infected patients who are also on ART, once they have achieved a CD4 count level of 250 cells/mm3 and above. HIV infected adults receiving both ART and CTX will be randomised to either continue with their combined medication (control group), or to receive their current ART plus CTX placebo (experimental group). About 2000 patients will be recruited in total at two study clinics of the MRC Uganda Research Unit on AIDS. They will be followed 3-monthly intervals for a median of 2 years and whenever ill. The primary outcome measure will be the incidence of serious CTX preventable clinical events and side effects of CTX. Secondary outcome measures will include the incidence of all clinical events including malaria episodes, mean change in CD4 count and other haematological parameters after 12 months on the trial, time to failure of ART, serious adverse events and compliance with ART regimens, trial drug regimens and use of insecticide- treated mosquito nets.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: HPV – HIV association
Funder: Medical Research Council

Abstract: Observational studies suggest an association between human papillomavirus (HPV) infection and acquisition of HIV. However, there are limited data on the role of specific HPV genotypes in terms of increased HIV risk, and it is not clear whether different stages of HPV infection (e.g. persistent infection or clearance of HPV) are all associated with increased risk of acquiring HIV. Our study hypothesis is that HPV infection and persistence and clearance of HPV genotypes increase the risk of acquiring HIV in young women in sub-Saharan Africa, and that the population attributable fraction (PAF) of HIV infection associated with HPV infection is high because of the high prevalence of HPV. HPV vaccines are now being introduced in many countries. The goal of this proposal is to determine the association of HPV with HIV acquisition in order to inform the design and conduct of a phase IV cluster randomized trial of the effectiveness of HPV vaccination against HIV incidence among young women in Tanzania and South Africa. We will test for HPV infection in stored cervical samples taken from Tanzanian and Ugandan study cohorts that measured HIV incidence. Samples from 151 HIV-seroconverters (cases) and a random selection of 453 HIV negative controls will be tested by the Roche Linear Array® HPV Genotyping Test to examine the association between HIV acquisition and prevalent or persistent HPV infection, or clearance of prior HPV infection, in order to determine the potential effect size for HPV vaccine against HIV acquisition. We will compile up-to-date HIV incidence estimates from the proposed trial sites in Mwanza and Durban required for our trial sample size calculations. We will collect information on potential trial communities in both sites, including the number of eligible girls, in order to inform the trial design. Finally we will draft the main Phase IV trial protocol


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Biomedical Catalyst – Staphylococcus aureus Vaccine
Funder: Medical Research Council

Abstract: S. aureus is a bacterium that colonises the nasal lining and skin of >30% of people. Accidents, surgery or device implantation that breach natural barriers, allow invasion, which may result in life-threatening infections such as pneumonia and blood-borne infections particularly by the antibiotic resistant form (MRSA). Despite several attempts S. aureus no vaccine is yet available. All vaccine clinical trials have failed despite promising pre-clinical animal model data. The partners and subcontractors in this project led by Absynth Biologics Limited and the University of Sheffield are bringing together capabilities to address this problem namely: novel vaccine targets and technologies to more effectively stimulate the human immune system. This coupled with a greater understanding of the development of infection (physiological and immunological) will be used innovatively to select the best candidate vaccine for clinical development. The University of Sheffield research team will be core to the overall programme, participating throughout its tenure. Specifically we will be responsible for determining the correlates of disease such that successful vaccination regimes can be evaluated. In part this will involve analysis of infection dynamics by monitoring how bacterial populations change during disease progression. Our preliminary work has already revealed a bottleneck, such that single bacteria go on to found abscesses. Being able to target these founders will prevent the population expansion that can lead to serious later consequences for the host. The use of animal models of infection and vaccination are at the heart of the programme as without these one cannot determine vaccine efficacy. In Sheffield two complementary pathogenesis models will be used (sepsis and peritonitis) within which the correlates of disease will be determined (such as weight loss and specific immune response) in order to elucidate those parameters that are markers of infection. Onto these findings the vaccine candidates produced by other members of the programme will be evaluated. The Sheffield work will be set within the context of the ongoing studies of all partners and contractors. An integrated programme will ensure that the fundamental results from Sheffield will immediately be translated into vaccine development. The anticipated outcome of the programme is proof of concept to support the advance of the vaccine to clinical trials by Absynth and/or a corporate partner. A vaccine to prevent S. aureus infections and the scourge of drug resistant MRSA will have a great impact with associated healthcare, societal and financial implications.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Adult HIV Clinical Trials
Funder: Medical Research Council

Abstract: This programme aims to address important questions about the best time to start HIV treatment, whether there are alternative aprpoaches using anti-inflammatory drugs, and whether there are alternative strategies to reduce costs and improve long term outcomes.||There are several trials in the programme that address the optimal timing of therapy. The SPARTAC trial has randomised 366 patients with acute HIV infection to ART (12 or 48 weeks) or no ART to determine the time taken for the CD4 count to fall below 350 cells. The trial will report in 2011. The START trial will randomise 4000 patients with CD4 cell counts above 500 cells/mm3 to receive immediate ART or to have treatment deferred until the CD4 count falls below 350 cells. The trial aims to determine what benefits (if any) result from earlier treatment and to assess the health-economic issues around early ART. ||HIV leads to immune activation and increased inflammation, both of which may play a critical role in HIV pathogenesis. The HCQ-01 trial examines whether hydroxychloroquine, a cheap and well tolerated immunomodulatory drug, can decrease immune activation in ART-naive patients with CD4 cell counts above 400 cells. A decrease in immune activation may lead to slowing of disease progression, thereby delaying the timing of starting conventional ART. ||The advent of more potent individual drugs, particularly the protease inhibitors (PIs) means that combination triple therapy may no longer be needed to control HIV viral replication. The PIVOT trial will determine whether PI monotherapy is non-inferior to triple therapy over long-term follow-up, an approach that may reduce long term toxicity as well as result in substantial health economic benefits. The trial has recruited 560 patients at 50 sites across the UK, and will run until 2013. ||There is virtually no evidence from randomised controlled trials to determine the best option for second line therapy in patients who fail treatment with a standard first-line NNRTI-based combination. The Europe-Africa Research Network for Evaluation of Second-line therapy (EARNEST) Trial, will randomise 1200 patients to one of three options: lopinavir/ritonavir with 2 NRTIs (the standard of care) or lopinavir/ritonavir plus raltegravir (a new integrase inhibitor) or lopinavir/ritonavir monotherapy (after a period of induction with raltegravir). The trial will run until 2013.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Molecular and cellular mechanisms of synapse-mediated spread of Epstein Barr virus: overcoming the CD21-restricted cellular tropism.
Funder: Medical Research Council

Abstract: The aim of this research is to understand one of the fundamental aspects of viral pathogenesis: How does Epstein Barr virus (EBV) gain entry to epithelial cells, T and NK cells which do not express CD21, the virus receptor? (1) Efficient infection of epithelial cells requires EBV-loaded B cells to act as virus donors; physiologically this is likely to be lytic plasma cells. Using lytic B cell lines at different stages of plasma cell differentiation, or non-transformed B cells induced into plasma cell differentiation by CpG DNA and interferon alpha treatment, we will examine the formation of a virological synapse between plasma cells and uninfected epithelial cells. Viral synapse formation is triggered by viral and cellular molecules which polarise with adhesion molecules to the point of cell-cell contact. Using fluorescently-labelled recombinant viruses and cellular components, we will monitor relocalisation of virus capsid, adhesion molecules and intracellular transport machinery by live cell confocal microscopy and determine their individual roles in synapse formation. (2) T and NK cells are refractory to EBV infection in vitro so may require a donor B cell for infection. Lytic plasma cells will be cultured with a panel of well characterised, HLA-matched CD4 and CD8 T cells and interferon alpha-induced NK cells to examine transmission of EBV via the virological synapse. Using a panel of recombinant viruses, we will determine the viral and cellular factors required. Finally, CD21 is temporally expressed on immature T and NK cells during differentiation from lineage negative haematopoietic stem cells into T or NK cells. Using the OP9-DL1 system to in vitro differentiate T and NK cells and using we'll take advantage of this temporal CD21 expression and infect the immature cells prior to lineage commitment. We will then be in a position to determine if EBV infection per se is sufficient to drive the T and NK associated pathologies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Shiga toxin translocation across human intestinal epithelium in a microaerobic infection model
Funder: Medical Research Council

Abstract: Shiga toxin-producing E. coli (STEC) are foodborne pathogens that cause bloody diarrhoea and severe systemic complications such as haemolytic uraemic syndrome (HUS). HUS is the leading cause of acute renal failure in children and associated with production of bacterial Shiga toxins (Stx), which are highly cytotoxic to renal microvascular endothelium. After ingestion via contaminated food or water, STEC colonise the intestinal epithelium but do not invade. Therefore, Stx has to cross the intestinal epithelial barrier to get access into the bloodstream. The mode of Stx translocation across human intestinal epithelium, which lacks the Stx receptor (Gb3) and is resistant to Stx cytotoxicity, is unknown. Progress has been hampered by the absence of a suitable model for experimental study. We have recently established an experimental system based on polarised monolayers of Gb3-negative human colon carcinoma cells in a vertical diffusion chamber (VDC) which allows to perform infections under microaerobic (MA) conditions. Most cell culture infection models use atmospheric oxygen levels to maintain cell viabilty, but this is unlike the intestinal milieu where oxygen is restricted. Using the VDC system, we have shown that microaerobiosis enhances STEC type III secretion and colonisation and also promotes Stx2 translocation during STEC infection. As this latter effect was only observed in the context of infection and not with purified Stx2 alone, these results lead to the hypothesis that MA conditions induce STEC factors which promote Stx2 translocation across human intestinal epithelium. In this application, we propose to continue the MA VDC studies to (1) characterise the Stx transport pathway during MA infection, (2) to identify STEC factors which are induced during MA infection and test their involvement in Stx2 translocation, and (3) to examine whether Stx2 production and translocation during infection are linked to human virulence.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION