NIHRDataInsights/HRCSData huggingface dataset:
Title: GMP manufacture and Phase I clinical trial of a thermostable single-dose rabies vaccine for pre-exposure prophylaxis for children in endemic areas
Funder: Medical Research Council

Abstract: The belief that rabies is a bygone disease for which an adequate vaccine exists is incorrect. Global rabies mortality is c. 59,000/year. Existing control measures are inadequate: current human vaccines are too expensive for mass use, and canine vaccination is challenging in many settings. We have developed a replication-deficient simian adenovirus vaccine encoding rabies glycoprotein. In a non-human primate trial, this outperformed the current human rabies vaccine: a single dose protected 100% of animals challenged 22 months after vaccination. The immunogenicity of the vaccine is such that the dose required to protect primates is 50-fold less than typically used for other adenovirus-based vaccines in humans. Moreover, we have developed an inexpensive thermostabilisation process to facilitate vaccine distribution. The vaccine will thus be sufficiently cheap to permit mass pre-exposure vaccination in rabies endemic low/middle-income countries, dramatically reducing mortality. Importantly, the project will provide clinical proof of concept for the thermostabilisation technology. The approach is applicable to other vaccines, out-performing lyophilisation and potentially enhancing reach and cost-efficacy by removing the need for expensive cold-chain distribution. We propose a milestone-based approach comprising 1. Process development 2. GMP manufacture of adenovirus; pre-GMP thermostabilisation tech transfer 3. GMP manufacture of thermostable formulation; pre-trial preparation (QC, toxicology, regulatory & ethics) 4. Phase I trial comparing standard v. stabilised adenovirus v. existing rabies vaccine. Post-DPFS development would piggyback upon trials of adenovirus-based malaria vaccines in children in Africa. Rabies vaccine licensure is based upon a surrogate of protection (in vitro virus neutralisation) and thus achievable without a large trial to directly demonstrate efficacy. The application is accompanied by a letter of support from the WHO.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: UK-Indonesian Consortium to Identify Biomarkers Predictive of Dengue Disease Severity.
Funder: Medical Research Council

Abstract: We will adopt an integrated 'omics approach, to correlate dengue disease severity with viral sequence variation and changes in the host transcriptome and proteome, using whole blood and serum samples from dengue patients with well defined clinical outcomes. The 'omics analysis will be supported by biochemical and immunological analysis of platelets in clinical samples and an analysis of the effects of serum on endothelial permeability using an in vitro model. Existing serum samples (from the UI and UP biobanks) from patients sampled at different times after hospital admission (during the febrile, critical and recovery phases) with different clinical outcomes (febrile illness non-dengue, dengue +/- warning signs and severe dengue disease) will be selected for viral metagenomic and proteomic analysis. Metagenomics will generate viral sequence data for analysis by the UoG's bespoke bioinformatics pipeline and identify other non-dengue viruses causing febrile illness. Serum proteins will be identified and quantified by tandem mass tagging of the peptides prepared from serum proteins by tryptic digest followed by high-throughput LC-MS/MS analysis at the UoB. A second phase of 'omics analysis will utilise prospectively collected samples (UI, UP, UJS). The samples will correspond to the above disease conditions. Along with sample storage, clinical variables for patients and data concerning the viral infection will be collected. These blood and serum samples will be analysed by metagenomics, RNAseq transcriptomic, proteomic studies and biochemical and immunological assays. The clinical and 'omics datasets will be integrated using a bespoke bioinformatics pipeline and analysed using statistical methods. This will identify candidate mRNA and protein biomarkers which will be further verified by qRT-PCR and targeted proteomics, using a larger prospective sample collection. Verified biomarkers will form the basis for novel diagnostic tests to predict severe dengue disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Transmission dynamics and molecular epidemiology of arboviruses in Indonesia
Funder: Medical Research Council

Abstract: Arthropod-borne viruses, or arboviruses, are becoming an increasing public health problem, especially in the tropics and sub-tropics. While Indonesia suffers a high burden of dengue and Chikungunya, relatively little is known about the epidemiology of these infections. As dengue virus (DENV) and Chikungunya virus (CHIKV) are rapidly-evolving RNA viruses, viral sequence data can offer insights into transmission, even with relatively limited samples. However, to date arboviral sequence data is limited; the number of sequences is relatively low, and sequences are often short, spanning only part of the viral genome. As such, the existing body of sequence data provides relatively little information on the transmission dynamics of arboviruses. The aim of this project is to use sequence data of DENV and CHIKV in order to better understand the dynamics of these co-circulating pathogens, over both space and time. We will compare and contrast the use of two next-generation sequencing platforms, the Ion Torrent Personal Genome Machine and the MinION nanopore sequencer, to generate near-full length genomes of DENV and CHIKV, as well as ZIKV, if positive samples are detected. Archived samples are available to allow a comparison of these platforms with conventional Sanger sequencing. We will pilot the use of these platforms in a prospective, hospital-based study in three areas of Indonesia. Individuals presenting at these hospitals with symptoms of dengue fever will be tested for DENV, CHIKV, and ZIKV, and viral sequences generated from positive samples. In order to link the viral sequence data with classical epidemiological data, we will build 'phylodynamic' models, which consider the relationship between transmission events and the viral phylogeny. This proposal will not only provide information on the molecular epidemiology of DENV and CHIKV, but also increase the capacity in bioinformatics and mathematical modeling in Indonesia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The Role of Complement Component C1Q in Tuberculosis and Diabetes Co-morbidity
Funder: Medical Research Council

Abstract: The C1q Complement component has been separately implicated in (TB), where it is upregulated in blood, and in T2DM where the proportion of free C1q is elevated due to a reduction in circulating adiponectin which usually complexes with C1q. This project will investigate C1q as a potential biological mechanism linking TB susceptibility and T2DM. C1Q gene expression (Cliff et al, JID 2013) and protein expression is elevated in TB patients' blood but its effects on macrophages are unclear. In healthy donors in the UK, we propose to 1) determine the human cellular source of C1q and whether expression is up-regulated by M. tuberculosis, and 2) determine whether C1q regulates macrophage function, including differentiation and polarisation to an alternatively activated M2 phenotype, M. tuberculosis phagocytosis and growth restriction, and cytokine production. We will exploit RNASeq technology to investigate the intracellular impact of exogenous C1q. T2DM patients reportedly have elevated circulating free C1q, which might interfere with macrophage control of M. tuberculosis. In Bandung we propose to 1) compare C1q, C1q-adiponectin and related factors in plasma from a cohort of TB, T2DM, TB-T2DM patients and HC, to determine whether a synergistic elevation in exists in comorbidity, and 2) investigate C1q involvement in macrophage control of M. tuberculosis in T2DM patients and HC, to determine whether the results obtained in healthy donors are clinically relevant. There is a strong capacity development component to the project, as a research assistant from Indonesia will spend 6 months receiving training in immunological laboratory skills in London. Assays will be transferred to Universitas Padjadjaran, so that immunology research can be further strengthened there to complement existing strengths in clinical and epidemiological research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Development of serology diagnosis of chronic aspergillosis and histoplasmosis in Indonesia
Funder: Medical Research Council

Abstract: Timelines Year 1 Aim 1 - development of lateral flow device (LFD) to prototype stage and initiation of Manchester extended validation Aim 2 - development of histoplama antibody assay: western blotting with small number of sera complete. Partial identification of key antigenic bands. Large scale batch cultures for supernatant completed and different purification, concentration and periodate oxidation methods compared for optimisation. Aim 3 - Ethical approval for histoplasmin skin testing gained. Shipping of histoplasmin from Mexico. 30% of skin testing completed. Year 2 Aim 1 - LFD validation on prospective samples in Indonesia complete (1000+ samples). Manufacture methodology defined precisely. Commercialisation discussions ongoing. Paper submitted for publication. Aim 2 - Development of ELISA assay complete. Partial validation done, with test and control sera. Second generation recombinant assay antigens decided. Aim 3 - Histoplasmin skin testing completed and paper written up. Possible chronic cases of histoplasmosis identified and sera collected for 100 cases. Skin testing Skin tests are performed by intradermally injecting 0.1mL of histoplasmin antigen in a 0.1ug protein/0.1mL into the inside of the left forearm of each volunteer using disposable tuberculin-type syringes . The same investigator will perform the intradermal tests and readings. Tests are read at 24 and 48h after injection. Induration over 8 mm in transverse diameter after 48 or 72 hours are considered to be histoplasmin positive


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 prevalence and phenotype of hepatitis B virus vaccine escape variants propagated by mother to child transmission in Indonesia.
Funder: Medical Research Council

Abstract: In order to assess the prevalence of HBsAg positive and HBsAg negative infections, we will screen 4000 maternal serum samples by direct PCR and HBsAg assay. Genotype will be established using routine sequencing methodology and HBV DNA titre estimated using quantitative PCR. Samples which are HBsAg negative and PCR positive will identify occult HBV infection, including candidate vaccine escape mutants. For those women and children in whom it is not possible to store serum, we will use dried blood spots (DBS) as a stable source of DNA. In order to estimate rates of incident infection and MTCT in the study cohort children we will analyse two sets of samples from children. i) Cord blood samples of mothers found to be HBV positive ii) serum samples taken from all children born to mothers in the study group at between 9 and 12 months of age, analysed by both PCR and HBsAg assays. The purpose of this collection is to identify all children with incident HBV infection. HBV positive samples will stored for further analysis using NGS. In order to detect, analyse and compare viral diversity in samples from HBV positive mother and child pairs using NGS we will i) conduct in depth sequence analysis of the viral population in mother and child by NGS ii) identify sequence diversity in coding and non-coding regions in HBsAg, including analysis of potential vaccine escape mutants iv) compare viral variants detected by NGS in mother and child to interrogate selection events operating on MTCT To assess the phenotype of candidate vaccine escape mutants we will clone the majority HBsAg sequence from patient sera and use the results of deep sequencing to inform a strategy of site-directed mutagenesis. The impact of genetic variation on viral phenotype will be assessed in established receptor binding and neutralisation assays. We also plan the use of lentiviral pseudoviruses expressing patient derived HBVsAgs to quantify infectivity in cell lines and primary human hepatocytes


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: A.Tiono, Centre National de Recherche et de Formation sur le Paludisme - Investigating the Human Malaria Reservoir of Transmission during Pregnancy
Funder: Medical Research Council

Abstract: Malaria is a major cause of morbidity and mortality worldwide, disproportionately affecting children and pregnant women. However, recent reductions in both deaths and infections have led to optimism and the implementation malaria elimination programmes. It is acknowledged that, to achieve elimination, malaria control programmes need also to focus on those who transmit infections to mosquitoes. Despite the recent advances, our knowledge of the human infectious reservoir of malaria, the proportion of the population that can transmit parasites to mosquitoes, remains limited. Understanding how different individuals in endemic populations contribute to disease transmission will enable specific targeting the most infectious individuals rather than blanket population coverage, reducing cost and logistical complexity. One group that has been largely overlooked as a potential reservoir of transmissible parasites are pregnant women. This is despite the 125 million pregnancies occurring in malaria-endemic countries every year, the increased susceptibility of pregnant women to malaria and prolonged infections with the parasite due to placental sequestration. The research project is designed to describe gametocyte carriage in pregnant women and the infectiousness of these gametocytes to mosquitoes. We will characterise gametocyte populations in pregnant women in an attempt to elucidate specific physiological reasons for any increased infectiousness. We will compare estimates of infection and infectiousness with key comparator groups in the population. These parameters will also be assessed in different seasons and in areas of moderate and low transmission to provide estimates of the effect of season and endemicity on reservoir contributions from different groups. Finally, we will assimilate and incorporate these data in mathematical models to allow simulations of the effect of interventions with and without targeting of pregnant women.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: F Ndungu, Pwani University, Determining Cellular Correlates of Immunity to Malaria in an Experimental Human Challenge Model of Exposed Adults
Funder: Medical Research Council

Abstract: Our preliminary data demonstrated variable parasite growth rates of blood stage Plasmodium falciparum following controlled human malaria infections (CHMI) in Kenyan adults. These growth rates were inversely correlated with levels of natural immunity, indicating that parasite growth rates can be accurate measures of naturally acquired immunity, which remains poorly understood. We are conducting a prospective screen for antibody correlates of immunity, using a high throughput protein micro-array system following CHMI. Cellular immune responses also play critical roles in the control of inflammation, antibody responses, and parasite growth rates. However, it has been difficult to determine cellular correlates of immunity in field studies owing to a lack of information on when natural infections happen and environmental confounding. In contrast, CHMI provide the opportunity to sample before, during and after genetically controlled infections. I will take advantage of this CHMI antibody study and test whether cellular immune responses before and immediately after exposure to blood stage parasites during CHMI of Kenyan adults with different levels of exposure correlate with levels of the host inflammatory response, levels of P. falciparum specific antibody responses after re-exposure, and blood stage parasite growth rates. I will, 1) characterize in detail the cellular immunity prior to malaria challenge, and immediately after first exposure to malaria parasites (days 7, 9 and 14 of CHMI), 2) measure markers of the subsequent inflammatory response during parasite growth, 3) measure the antibody response after CHMI, and 4) correlate the cellular immunity observed in 1) with 2), 3) and with parasite growth rates. My study will identify patterns of cellular responses that predict an individual's ability to a) control inflammation (disease severity), b) produce protective levels of high quality antibodies, and c) control parasite growth.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: H Mwandumba, CoM, Characterisation of the breakdown in immune competence of the lung that favours development of tuberculosis in HIV-infected adults
Funder: Medical Research Council

Abstract: Co-infection with Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) constitutes a huge burden on national healthcare services in sub-Saharan Africa where up to 70% of tuberculosis (TB) patients are HIV-infected. TB is now the leading cause of death of adults living with HIV in this region. This underscores the need for a better understanding of the mechanisms underlying host resistance and susceptibility to TB, which is central to the development of new approaches to prevent and/or treat HIV-associated TB. The risk of developing TB starts to increase early following HIV infection, even before significant depletion of CD4 T lymphocytes occurs in peripheral blood and persists during effective antiretroviral therapy (ART), indicating that the CD4 T lymphocyte count is not the only determinant of increased TB risk, and ART-mediated quantitative reconstitution of this cell subset alone is not sufficient to recover full protection against active TB. We propose conducting ex vivo infections of human alveolar macrophages (AMs) with fluorescent reporter Mtb strains to probe the mechanistic basis underlying the successful control of Mtb infection in the lung. The use of reporter bacterial strains is significant because they are immunologically unbiased readouts of host cell function. We will explore the impact of HIV co-infection and ART on the AM anti-mycobacterial response. By exploiting the HIV-mediated breakdown in immune control of Mtb infection in the lung, the project is bold and highly innovative in its approach to gain a comprehensive understanding of the optimal pulmonary immune environment for successful control of Mtb infection. It has tremendous potential to generate new insights that will impact the design and implementation of public health interventions in the control of TB in both HIV-uninfected and HIV-infected individuals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: A. Olotu, Ifakara Health Institute - Immune responses in malaria-exposed children immunised with a new generation blood-stage malaria vaccine.
Funder: Medical Research Council

Abstract: Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is a new generation and highly promising blood-stage malaria vaccine antigen. Preclinical and early clinical data show the antigen elicits functional antibodies against merozoites in non-human primates and malaria-naïve UK adults in contrast to those elicited by natural malaria exposure. The safety and capability of PfRH5 immunisation to induce functional immune responses in adults, young children and infants residing in malaria endemic countries is unknown. Using an age de-escalation dose-escalation randomised double-blind controlled trial, and established immunological techniques, the ARL candidate will establish the safe and well-tolerated dose of PfRH5 in adults, young children and infants and characterise the magnitude, quality and longevity of immune responses following immunization by a heterologous prime-boost approach with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) expressing PfRH5. The study will recruit volunteers from low malaria transmission areas in Bagamoyo, Tanzania. The study will provide new knowledge with regard to the potential for PfRH5 as a malaria vaccine and inform decisions to conduct larger field trials to evaluate efficacy. The immunological outcomes will provide data on the human antibody response, to determine if there is scope to further improve the PfRH5 immunogen in future iterations of the vaccine.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: The use of human monoclonal antibodies to inform and enhance influenza vaccine virus selection.
Funder: Medical Research Council

Abstract: The World Health Organisation coordinates a massive effort to monitor the evolution of influenza around the world to try and identify the viruses that are most likely to cause infections in the coming years, and select the best candidates for manufacture into a vaccine. The methods used to do this predominantly involve sequencing virus genes to monitor genetic drift, and testing primary ferret sera to monitor antigenic drift. Overall the effectiveness of the vaccines selected by these methods is quite poor at ~54%, so there is room for improvement. Recently it has become possible to isolate human monoclonal antibodies in large numbers from infected or vaccinated individuals. It is human antibodies that are thought to be driving the evolution of influenza in nature. We have found that some individuals focus their antibody response onto limited regions of the haemagglutinin surface to such an extent that a single amino acid substitution can greatly reduce the neutralizing power of a serum. Focusing of the antibody to influenza in humans is a logical outcome of the selection of memory B cells by repeated exposures to evolving viruses that share less and less surface identity as time passes. Multiple monoclonal antibodies isolated from such individuals select for substitutions at few sites and these correlate with the changes that have become dominant recently in circulating viruses. In effect viral evolution can be recapitulated in vitro by these methods. An example is the K163Q substitution in clade 6B pdmH1N1 viruses. We have also shown that in this example ferret antisera failed to detect the change. We plan to develop panels of human monoclonal antibodies that can help predict the future evolution of the virus, which will be distributed to the WHO Collaborating Centres around the world, for comparison to the standard ferret antisera to see if this new technology can improve vaccine selection.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION