NIHRDataInsights/HRCSData huggingface dataset:
Title: Immunomodulation and Vaccine/Co-Infections Programme
Funder: Medical Research Council

Abstract: Our goal is to understand the impact of infection exposure on human immunological programming and health. Our overarching hypothesis is that chronic and cumulative infection exposure influences immunological mechanisms through active processes (during current infection), lasting epigenetic modifications, and genetic selection; that (therefore) some effects do not immediately respond to treatment; and that effects critically impact upon major health outcomes including vaccine responses and susceptibility to pathogens, allergy-related disease and metabolic conditions (Figure 8.8). The main focus of our work is on vaccine responses, addressing the role of infectious exposures in striking population differences in vaccine immunogenicity. We also support studies on the role of chronic infection in allergy-related and metabolic disease susceptibility. Building on recent findings, exploiting unique platforms that we have established, we aim to determine the effects of infectious exposures (prenatal, cumulative life-time and current, active exposures) on health outcomes comprising: 1. Vaccine immunogenicity 2. Infectious disease susceptibility – focussing on oncogenic viruses 3. Asthma phenotypes and allergy-related effector mechanisms 4. Infection, inflammation and cardio-metabolic risk To obtain deeper insights into mechanisms by which infections have their effects, we plan complementary studies (for which funding is available, or being sought elsewhere) on the mediating role of the microbiome and on the mediating role of epigenetic modifications In addition, the programme supports related studies on tuberculosis and schistosomiasis, and genetic studies.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: HIV EPIDEMIOLOGY AND PREVENTION / International AIDS Vaccine Initiative
Funder: Medical Research Council

Abstract: The overall aim is to conduct studies that inform the design for a protective HIV vaccine. Our work aims at conducting studies of significance to HIV vaccine development and builds on our experience in conducting clinical trials. This work is in collaboration with and support from International AIDS Vaccine Initiative (IAVI). Objectives: 1. To recruit, follow up, counsel, and test at-risk volunteers for HIV infection 2. Estimate incidence of HIV infection in at-risk volunteers 3. Establish reliable and efficient volunteer contact and tracking systems to maximize volunteer retention, and determine reason(s) for loss of volunteers to follow-up. 4. Evaluate risk factors for incident HIV infection 5. Recruit and follow up a cohort of recently HIV infected volunteers to inform HIV vaccine design 6. To design and conduct new studies that have significance to HIV vaccine development and trial design 7. To evaluate potential HIV vaccines in phase I/II clinical trials Objectives 1-4 are through a prospective, open cohort, observational study that recruits and follows up adult male and female adult volunteers, from 18-49 years of age at risk for HIV infection that meet the study inclusion criteria, and are willing to comply with protocol requirements. Objective 5 is a prospective, observational, multi-centre study that evaluates laboratory, clinical, immunologic and viral markers of disease progression in recently HIV-infected volunteers. To answer objective 6, studies that inform vaccine development and design are conducted such willingness to participate and be retained in HIV vaccine trials by enrolling volunteers in simulated vaccine efficacy trial. Objective 7: we aim to evaluate potential HIV vaccines as and when good candidates become available. Currently we are planning a phase I double blind placebo-controlled clinical trial to evaluate the safety and immunogenicity of the combination of DNA-HIV-PT123 and AIDSVAX® B/E in HIV-1-uninfected adult participants with or without underlying Schistosoma mansoni infection.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: HIV EPIDEMIOLOGY AND PREVENTION / A Randomized Phase III Trial of Adjunctive Dexamethasone in HIV infected Adults with Cryptococcal Meningitis
Funder: Medical Research Council

Abstract: The problem being addressed by this multicentre trial is the high mortality rate associated with Cryptococcal Meningitis (CM) among AIDS patients. Management of CM even in cases where recommended antifungal medications have been used has remained challenging. There has been little improvement in management of CM, and matters have not been helped by lack of any new antifungal medications since the 1970s, before advent of the AIDS epidemic. The few trials that analysed use of adjunctive dexamethasone for treatment of CM had many limitations. There is therefore still a need to investigate dexamethasone further in a Randomised Controlled Trial. This study therefore aims to determine whether adjuvant therapy with dexamethasone in addition to standard antifungal therapy will reduce mortality rate from CM in AIDS patients. Dexamethasone is a cheap, readily available, practicable intervention which will be easy to scale out if found to be beneficial and its side effect profile is also relatively well known. The study is currently being conducted in 2 African countries (Uganda and Malawi) and four South East Asian countries (Laos, Indonesia, Vietnam and Thailand). The study is a randomized, double blind, placebo-controlled phase III trial of adjunctive Dexamethasone in HIV infected adults with CM. This trial aims to determine whether adjuvant therapy with dexamethasone in addition to standard antifungal therapy will reduce mortality rate from CM in patients with HIV. In this double blind trial, patients are randomised to receive either dexamethasone or placebo for 6 weeks in addition to optimal antifungal therapy. The primary aim is to investigate the effect of dexamethasone adjunctive therapy on 10-week survival in adult HIV infected patients with cryptococcal meningitis. The secondary aims are; to determine the effect of adjuvant treatment with dexamethasone on survival at 6 months, disability at 10 weeks and 6 months, the rate of sterilisation of cerebrospinal fluid (CSF), the frequency of grades 3, 4 and serious adverse events, the incidence of Immune Reconstitution Inflammatory Syndrome (IRIS), the incidence of other opportunistic infections, re-treatment for cryptococcal meningitis, and the presence of visual deficit at 10 weeks. In addition, the effect of steroids on survival by continent will be assessed.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Studies to understand the response of the infant’s immune system to infectious diseases and vaccines
Funder: Medical Research Council

Abstract: Millennium Development Goal 4 sets out to reduce mortality in children under five-years of age. Despite progress with this overall, including in many countries across sub-Saharan Africa, mortality in infancy and in particular in newborns has so far been comparatively resistant to intervention. Although the reasons for this are multi-factorial, many deaths in this period occur as a result of infections. Consequently, understanding the distinct way in which infants respond to infections and vaccines, facilitating the rational development of novel interventions to protect newborns is a top global health priority. These areas are the focus of current research within infant immunology. Objectives: To characterise the key elements of the immune response to given pathogens (e.g. pneumococcus, staphylococcus) which may be associated with the development of natural immunity to these agents in order to facilitate the develop novel protective strategies To describe, at both a cellular and a humoral level, the immunity generated by currently licensed (e.g. rotavirus) as well as experimental (e.g. malaria, HIV, TB) vaccines in order to guide future rational vaccine development To establish the optimum regimens for the use of current vaccines (e.g. inactivated poliovirus vaccine, pneumococcal conjugate vaccines) which will maximise the protection of infants while also ensuring the logistical challenges of vaccine delivery on a large scale (e.g. through using fractional doses, novel delivery methods, maternal immunisation, multi-dose vials) are met Methodology: These critical objectives are being addressed across a series of maternal and infant cohorts. A combination of interventional studies, including GCP-clinical vaccine trials, as well as longitudinal observational studies, is used according to the questions being addressed. We have the established capacity to recruit mothers antenatally allowing newborns to be followed right from delivery. We also recruit infants over the first year of life as they are presented for their routine immunisations A range of laboratory approaches are used including large-scale serological studies monitoring correlates of vaccine induced protection, as well detailed immunological investigations. Such studies, which are often nested within larger scale trials, use techniques including multi-parameter flow-cytometry, ELISpot assays, evaluation of cytokines and antibodies using Luminex-based multi-analyte technology. Impact The findings of certain key studies (e.g. inactivated poliovirus vaccine trial) are expected to directly influence WHO policy over the coming year. Other work is focussed on studying pathogens (e.g. pneumococcus, malaria, rotavirus) which remain at the top of the research agenda internationally and address question recognised to be high priority.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: DISEASE CONTROL & ELIMINATION SEED FUNDING
Funder: Medical Research Council

Abstract: The Disease Control & Elimination theme aims to conduct cutting-edge, multidisciplinary research to develop approaches to curb the burden of diseases of public health importance. The inclusion of the word “elimination” in the theme definition encompasses the research portfolio that includes trachoma, a disease that has almost been eliminated in The Gambia, and malaria, for which pre-elimination level should be achieved by 2018. The research on hepatitis B within the theme provides a link between the control of communicable and non-communicable diseases, i.e. hepatitis B infection and hepatocellular carcinoma. The Disease Control & Elimination theme will exploit the availability of excellent laboratory facilities and the scope to carry out population studies to elucidate complex and heterogeneous host-pathogen/parasite-vector interactions. Understanding such interactions in areas under intensified disease control is critical for the development of scientifically-based control/elimination plans for the whole African continent. In-depth analysis of the human behavioural factors including migration that affect disease risk is an essential component of the theme’s methodological approach. Joint research projects with Institutions located in other West African countries allows a wider view of specific public health problems and provides the opportunity to compare the impact of new interventions in settings with different disease endemicities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Vaccines & Immunity Research MRC Unit, The Gambia
Funder: Medical Research Council

Abstract: Vaccines & Immunity represents one of the three identified key themes of research at the MRC Unit in The Gambia and is headed by Prof Kampmann. Our research portfolio within Vaccines & Immunity comprises the following three areas, which are headed up by 3 senior investigators: Infant Immunology (Dr E Clarke), Molecular Diagnostics (M. Antonio) and Tuberculosis research (J. Sutherland). Our research covers basic laboratory science, translational research and clinical trials from phase I to phase IV: 1. we aim to understand basic immunological mechanisms of protection and susceptibility in children of different ages to a wide range of infectious diseases causing major morbidity and mortality in our regional context, such as TB, pneumonia, diarrhoea, congenital infections 2. we investigate mechanisms of carriage and invasion of a variety of bacterial pathogens (strep pneumo, staph aureus, haemophilus and other causes of neonatal bacterial infections). These results guide the development of protective vaccines and other interventions. 3. We conduct clinical trials at all clinical stages of vaccine development, aimed at preventing serious infections in resource-poor settings in particular (pneumococcal vaccines, T vaccines, HIV, malaria, polio) Over the last 12 months, we have completed a large-scale phase 4 trial of intramuscular polio vaccination (Lancet Global health 2016) and started another pneumococcal vaccine trial. We have completed the evaluation of a novel preparation of a pneumococcal vaccine which has now progressed to licensure via the EMA. We have set up a platform for the conduct of maternal immunisation trials and led an international conference on the issue. Our basic research is describing the interactions between the neonatal microbiome and early immune responses and explores age-related development of innate immune mechanisms in vitro. The international collaborations have enabled us to establish a number of new immunological assays in the Unit. Please find detailed descriptions of projects in the Infant Immunology report and the TB-CC report.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Basic Science Programme /Dissecting the immunological interplay between poverty-related diseases and helminth infection (IDEA Project)
Funder: Medical Research Council

Abstract: Major aim: Although worm infections and HIV, TB and malaria have been extensively investigated, only recently there has been increasing attention to the potential impact of co-infections between worms and HIV, TB and malaria. Firstly, the interaction between these diseases may have major public health implications by increasing the diseases burden since effective vaccines are not yet available for worms, HIV, TB and malaria. Secondly, although the worm-, HIV-, TB- and malaria-specific immune responses have been the target of extensive investigation, the immune correlates of protection remain unknown for these diseases. Thirdly, there is no information on whether worms-induced immunity modulates HIV-, TB- and malaria-specific immune responses. Fourthly, there is limited knowledge of the influence of underlying worm infections on the clinical course of HIV, TB and malaria. Finally, the impact of worm infections on various vaccinations requires further investigation as limited data suggest reduced effectiveness of vaccination in subjects with worm infections. The project has the following major objectives: 1) to determine the modulation of polarized worm-specific immune responses on the functional and molecular profile of HIV-, TB- and malaria-specific immune responses; 2) to determine the impact of worm co-infections on the parameters of disease activity for HIV, TB and malaria; 3) to determine the effects of the complex interaction between worms and HIV on HIV-specific immune response and HIV replication; and 4) to determine the modulation of worm co-infections on vaccination and vaccine-induced immune responses. Methods: Flow cytometry will be used to study both adaptive and innate immune responses. Innate immune responses will be characterized by flow cytometry, Luminex technology and RT-MLPA or gene microarray. For adaptive immunity we will look at Th1, Th2 and Tregs, and will study the cytotoxic capacity of HIV speficific CD8 T cells, profiling the homing and migratory properties. At MRC/UVRI Entebbe we will study the effect of worm infection on the incidence of HIV infection in a fishing population cohort, using a case-control design to determine the odds of worm infections among people who become HIV infected compared to controls. These individuals will also be investigated for adaptive and innate immune responses. The effect of worms and worm treatment on HIV disease progression (CD4, viral load and HIV immune responses) will be studied in 400 HIV+/schistosome+ participants and a comparison group of 100 HIV+/schistosome –ve participants, by randomising HIV+/schistosome+ individuals participants to high intensity versus low intensity praziquantel treatment. Work conducted at MRC/UVRI Entebbe is funded by the EU with co-funding from MRC (UK).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Uganda Non-Communicable Diseases Programme
Funder: Medical Research Council

Abstract: Maintaining adherence to HIV treatment is critical to determining long-term health outcomes, yet presents specific challenges for young people which have yet to be qualitatively studied over time. This is a qualitative study investigating factors mediating adolescents’ adherence to Highly Active Anti-retroviral Therapy (HAART) in Uganda. This study is embedded within a funded, clinical trial to assess the acceptability of Short Cycle Therapy as an intervention to promote optimum adherence amongst young people. The study aims to explore social context, barriers and facilitators to adherence amongst HIV positive adolescents in Uganda, the acceptability of Short Cycle Therapy and their experience of participating in an international clinical trial. This project is funded by the Economic and Social Research Council.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFECTION
Title: Hepcidin and its Regulatory Pathways in Malaria and in Adaptive Immunity
Funder: Medical Research Council

Abstract: Hepcidin is the hormone that governs iron homeostasis – it is equivalent in importance top the role of insulin in glucose balance. Iron is the most important nutrient in host / pathogen interactions; iron affects the outcome of infection, and infections can also lead to the anaemia of chronic inflammation. We aim to understand the role of hepcidin in major infectious diseases including malaria, tuberculosis, HIV-1, and candidiasis. We wish to understand how hepcidin is influenced by, and influences different types of adaptive immune responses, cellular immune function and vaccine efficacy. We will also test how manipulating hepcidin expression and activity can be used as a way of modulating infection and inflammation. Iron deficiency and anaemia are major global health problem, but iron supplementation to anaemic individuals with high hepcidin is both useless and dangerous. Hepcidin is the major determinant of iron absorption in African children with varied types of anaemias. This means that hepcidin could be a useful diagnostic guide to improve safety and efficacy of iron supplementation, and we have studies planned to test this concept. Generally chronic infection / inflammation leads to persistently raised hepcidin levels and predisposes to anaemia, but the exception is chronic Hepatitis C virus (HCV), which causes low hepcidin and hepatic iron accumulation. We investigated the molecular basis of this phenomenon and found HCV interferes with the bone morphogenetic protein (BMP) signaling network that underpins homeostatic control of hepcidin transcription. Stimulating the BMP pathway restores hepcidin levels, but surprisingly also suppresses HCV replication and renders cells more sensitive to interferon. We now wish to understand how BMP signaling intersects with viral sensing and IFN function, and whether BMPs can be used to inhibit other viruses. Developing our studies on BMP signaling and its antiviral properties has potential benefit for understanding innate immune defences against viruses, and using this knowledge to predict how some patients will respond to infection and current treatment regimens. We are developing new small molecule BMP agonists with antiviral activity that could improve treatment efficacy. The advantage of this approach is that by boosting a hitherto unappreciated arm of innate immune defence we may generate broadly acting antivirals that synergise with current therapies against a variety of viruses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Membrane Traffic Pathways in Viral Replication and Pathogenesis
Funder: Medical Research Council

Abstract: The mechanisms used by viruses to invade and replicate in cells are of fundamental interest, both in terms of improved understanding of infection and pathogenesis, with implications for health and economic wellbeing, but also because viruses are extraordinary tools for revealing how cells work. Because they have membranes, we are focussed on understanding how enveloped viruses interact with cellular membrane systems, how these interactions facilitate or restrict the transmission of viruses from cell to cell and how they impact on pathogenesis. We are developing these themes through existing and new programs of work with the aim of exploiting our current know-how to develop knowledge-based interventions against viral infection and/or pathogenesis. In new programs of work, we are investigating (1) how interferon-induced transmembrane (IFITM) proteins inhibit the entry of a broad range of enveloped viruses, (2) the potential to develop broad-spectrum antivirals that inhibit the entry of viruses that exploit the same endocytic entry mechanisms, and (3) the cell biological processes underlying virus particle formation. The work focuses on three new projects developed during the previous QQ. The program synergises with the programs of other MRC LMCB groups, in particular those of Mercer, who is also interested in the cell biology of viral replication, Henriques, with whom we are developing new methods for investigating virus-cell interactions using advanced imaging methods, and Paluch, Cutler, Pichaud, Stefan and Baum, with whom we will collaborate to develop understanding of the mechanisms through which viruses that assemble at the cell surface deform the membrane and overcome the barrier imposed by the cortical cytoskeleton. Our main objectives are: 1.To determine the molecular mechanism(s) through which IFITM proteins inhibit enveloped virus entry. 2.To use and expand our understanding of arboviruses to develop novel broad-spectrum antivirals. 3.To use novel imaging techniques to further develop our understanding of how HIV and related viruses assemble at the plasma membrane, and to gain insight into how the physical properties of the plasma membrane and cortical cytoskeleton impact on these events.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION