NIHRDataInsights/HRCSData huggingface dataset:
Title: COV-AD: COVID infection in patients with antibody deficiency
Funder: Medical Research Council

Abstract: Our national case series has found that individuals with primary and secondary immunodeficiencies are more likely to develop severe COVID-19. Individuals with immune deficiency respond poorly to some vaccinations and concern has been raised suboptimal immune responses may allow viral persistence, accelerated viral evolution and the emergence of viral escape variants that may potentially pose a public health risk. Understanding the immune response to the SARS-CoV-2 virus following natural infection or following vaccination is, therefore, of the upmost importance in individuals with immune deficiency. This multicentre study, involving a network of Clinical Immunology centres across the United Kingdom, will recruit 1050 individuals with antibody deficiency to study the magnitude and quality of their immunological responses following natural infection with SARS-CoV-2 and/or their response to vaccination. In partnership with the SavingLIVES charity, individuals will be invited to submit swabs and dried blood spots which will be tested for the presence of the virus and the presence of antibodies against the SARS-CoV-2 spike glycoprotein respectively. Serial swabs will be used to understand the prevalence of persistent viral infection in individuals with antibody deficiency and this information will be correlated with symptom diaries the spectrum of disease in patients with antibody deficiency. PCR positive samples will be submitted to the UK COG consortium for sequencing and phylogenetic analysis. Separate study arms will examine whether patients with immune deficiency make antigen specific antibody and cellular responses to the virus following natural infection or vaccination. This study will provide valuable insight into how SARS-CoV-2 infection manifests in immunologically vulnerable individuals and inform on whether public health countermeasures including vaccination are likely to be successful in preventing infection and disease in this population.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Immune responses to SARS-CoV2 cause activation of platelets, resulting in thrombosis, which can be ameliorated by re-purposed drugs
Funder: Medical Research Council

Abstract: Severe COVID-19 infection is associated with thrombosis in the lung, heart, kidneys and other organs, and is likely to contribute substantially to the high levels of mortality and morbidity in these patients. Whether abnormal platelet function accompanies disease progression is unknown. We will use deep-phenotyping approaches combined with established multi-parameter analysis to determine whether platelet function is altered in patients upon hospital admission, if this changes through disease progression, and whether levels of change correlate with disease severity. This will be incorporated an interventional study (MATIS) designed to test the benefits of repurposing drugs that target signalling proteins expected to diminish the inflammatory response to virus, which is proposed to lie behind severe disease pathology. These targets, the kinases Syk and Jak, also regulate platelet function. We will therefore also assess the impact of drug administration on platelet function, in comparison with standard of care, and establish whether potential benefits are associated with diminished platelet function. Preliminary data indicate that abnormally glycosylated antibodies produced early in COVID-19 infection enhance platelet function through stimulation of the platelet IgG receptor. We will therefore also determine whether immune-driven activation of platelets (thrombo-inflammation) is inhibited by the licenced Syk and Jak inhibitors. The outcomes from this study will establish whether abnormal platelet function lies behind life-threatening COVID pathology, and whether use of drugs that target both the platelet and immune responses to the virus offer promising therapeutic options. If successful, drug repurposing would offer the potential for rapid impact on patient outcomes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Determining the immunological basis for weakened SARS-CoV-2 vaccination outcomes
Funder: Medical Research Council

Abstract: COVID-19 vaccine efficacy in people living with HIV (PLWH) and other immunosuppressive conditions such as B cell malignancies remains poorly evaluated. The objective of this study is to establish the quality and durability of responses to inform future recommendations/policy. Optimisation of vaccine responses will maximise protection against disease and new emerging variants in this vulnerable population. In this study we will use our combined expertise and well curated longitudinal cohorts of clinical samples to: 1. Perform an integrated analysis of innate and adaptive components of the immune responses and dynamic changes post vaccination to allow stratification of functional anti-SARS-CoV-2 responses regardless of clinical drivers. 2. Determine mechanistically why these inferior responses occur by testing the hypothesis that breadth is limited by inefficient B cell recall (assessed by BCR sequencing of spike-reactive B cells) due to sub-optimal T cell help and/or excessive NK cell regulation. To achieve these aims we have available samples pre and post vaccination from a well-characterised longitudinal cohort of HIV negative (n>100), PLWH) (n>100), and patients with B cell malignancies (n>70). In addition, we are uniquely placed to sample additional PLWH with suboptimal responses to vaccination through the current SARS-CoV-2 seroprevalance study (>1500 participants). Our approach is to investigate extreme ends of the immunosuppression spectrum by investigating mild to severe T cell impairment (PLWH) and major B cell dysfunction during malignancy. This will yield data to allow informed vaccination choices/boosters based on immunological phenotype rather than clinical presentation, facilitating translation of these results beyond the study populations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Optimising Vaccine Efficacy in Multi-Disease Patient Cohorts with SARS-CoV-2 vaccine failure (OCTAVE-DUO)
Funder: Medical Research Council

Abstract: The multi-centre OCTAVE study is a flagship UK CTIMP evaluating the immune response following COVID-19 vaccination in people with immune mediated inflammatory diseases, hepatic/gastrointestinal disease, renal failure, solid or blood cancers, solid organ transplant, and patients who have received haematopoietic stem cell transplant (HSCT) or chimeric antigen receptor T cells (CAR-T). Uniquely, OCTAVE seeks to comprehensively assess SARS-COV-2 vaccine responses within and between disease cohorts using common platforms in patients recruited across the UK. Early data show that approximately 30% of patients mount a low, or undetectable immune response after two homologous SARS-CoV-2 vaccines evaluated by serology based assays. It is not known whether re-vaccination booster strategies will initiate, or further enhance the immune response to thereby provide appropriate protection from COVID-19 in these prevalent and clinically vulnerable disease cohorts. Leveraging our existing and successful OCTAVE consortium, and its related infrastructure, the OCTAVE-DUO study will investigate the effectiveness of homologous and heterologous re-vaccination strategies using licensed vaccines to generate a protective immune response in patients within our disease cohorts who have sub-optimal primary vaccine responses. Patient will be stratified based on low/no serological vaccine response and state-of-the-art optimised immune assays will characterise the magnitude, functionality, and durability of T cell and humoral immune responses following re-vaccination. NHS data linkage and standard pharmacovigilance approaches will determine the level of protection afforded by revaccination and adverse events related to a third vaccine exposure. Identifying immune and clinical parameters that predict which patient populations will benefit from re-vaccination strategies will critically inform UK health and government policies during the ongoing pandemic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Lymph node remodelling for optimal vaccine responses
Funder: Medical Research Council

Abstract: Vaccines are one of the most important medical developments. Despite this there are many at-risk populations for whom vaccines are ineffective, in particular older individuals. Vaccine-induced protective immunity relies on the generation of long-lived plasma cells that secrete high affinity antibodies that prevent infection. Plasma cells are the ultimate output of the germinal centre (GC), a reaction that occurs in secondary lymphoid tissues such as lymph nodes. The spatial architecture of lymph nodes is dictated by the stromal cell network and remodelling of this network is required for optimal GC formation. This proposal aims to understand how vaccines stimulate the stromal cell network, how this is linked to the quality of adaptive immunity, and how this can be co-opted to improve vaccine efficacy in older individuals. Using state-of-the-art single cell RNA sequencing, I will determine how the diversity of lymph node stromal cells is altered by vaccine adjuvants, how this is causally linked to the distribution of immune cells, and how these novel stromal cells influence GC formation. I will use in vitro and in vivo models to understand the cellular and molecular pathways that lead to the activation and differentiation of stromal cells and how these novel cell types support diverse immune outcomes in different vaccine settings. Finally, I will determine how these pathways that are dysregulated with advancing age and how this may be overcome to improve vaccine efficacy in older individuals. The outcomes of this research will directly impact on the rational design of vaccines and improve vaccine efficacy in the ageing population, but may also benefit diseases where successful vaccination has thus far been elusive, for example malaria, tuberculosis and respiratory syncytial virus. Given the current global pandemic, understanding how vaccines generate protective immunity and how they can be improved is of particular importance.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: 'Mechanisms of impaired neutrophil phagosome maturation and its impact on invasive bacterial infections
Funder: Medical Research Council

Abstract: Critically ill patients suffer systemic inflammation and simultaneous failure of anti-microbial functions, which leads to secondary infections including pneumonia. I have demonstrated that complement component C5a, released in large quantities during critical illness, can impair neutrophil phagocytosis and is associated with an increased risk of secondary infections. During my early post-doctoral fellowship I developed a novel multi-parameter assay of neutrophil function and combined it with phosphoproteomic profiling tools. Using these I demonstrated impairment of phagosomal maturation in neutrophils from critically ill patients, and how this could be driven by C5a. I also demonstrated a role for the phosphoinositide 3-kinase VPS34 in phagosomal maturation. My findings imply that the defect in patients is in the recently characterised LC3-associated phagocytosis (LAP) process, of which VPS34 is a key signalling node. My objective is to understand mechanisms that drive neutrophil phagosomal maturation and LAP, how this is disrupted by C5a and the consequences of this disruption on bacterial killing. I will use primary human neutrophils and gene-edited stem cell-derived neutrophils to establish mechanisms by which the proteins I have identified affect phagocytosis and phagosomal maturation. I will use subcellular fractionation and hyper localization of organelle proteins by isotope tagging (hyperLOPIT) proteomics to map protein locations within neutrophils, using confocal microscopy validate these findings. Using a neutrophil-conditional VPS34 knockout mouse I have developed, I will investigate the relevance of these findings in models of bacterial pneumonia. My existing neutrophil phosphoproteomic profile is detailed, and I will use computational methods to identifying further pathways for investigation. Using these tools I aim to identify targets for future non-antibiotic therapy, enhancing neutrophil functions in bacterial infections.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Dynamics of human T cell memory in blood and secondary lymphoid tissue in shaping vaccine induced immunity in ageing
Funder: Medical Research Council

Abstract: Aims To compare T cell memory in secondary lymphoid tissue and blood in younger and older adults after intramuscular immunisation with a model (influenza) vaccine Objectives To determine a) peak reactivity in secondary lymphoid tissue b) frequency, phenotype, activation and cells in cycle amongst cTfh/Tfh c) the evolution of vaccine-specific T cell clones amongst cTfh/Tfh Methodology Participants aged 18-45 and 65+ years will receive adjuvanted influenza vaccine and donate samples at baseline and at Day 3-28. Lymph node cells will be processed alongside peripheral blood mononuclear cells and viably cryopreserved or used immediately. Aim 1: USS will establish the peak time point of reactivity in secondary lymphoid tissue proximal to the site of vaccination in 5 healthy volunteers per group. Aim 2: will measure the frequency, phenotype, activation status (CD38+) and proliferation status (Ki67+) of cTfh and Tfh amongst PBMCs and LNCs using multiparameter flow cytometry from 16 healthy volunteers per age group and cohort. Antigen specificity will be determined using an activation induced marker (AIM) assay or fluorochrome-conjugated tetramers. Specificity will be determined in PBMCs and the same TCR signature analysed amongst LNCs. Aim 3: will use simultaneous scRNA-seq, antibody-dependent tagging (CITE-seq) and scTCR/Ig seq to comprehensively profile T and B cell subtypes and activation states in lymph node and blood before and after vaccination from 16 healthy volunteers in each age group. The well-established 10x Chromium platform will be employed using isolated CD45+ cells, and the single-cell TCR/Ig repertoire analysis will provide T/B clonality characterisation. Internal controls will come from sampling ipsilateral and contralateral nodes. Scientific and medical opportunities: Discovery of how key vaccine T cell subsets respond in ageing will identify pathways for manipulation and an in vivo model in which to test them.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;3.4 VACCINES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: A novel innate signalling pathway and its viral antagonism
Funder: Medical Research Council

Abstract: Appropriate cell-intrinsic recognition of intracellular pathogens is essential for the generation of effective innate and adaptive antiviral immunity. Viral sensors and their signalling components thus provide a crucial first line of host defence. Using new proteomic approaches, we have identified two novel signalling components (proteins 1 and 2) pivotal in understanding innate immune recognition of diverse DNA and RNA viruses, in addition to how HCMV persists in vivo. Importantly, activation of protein 1 represents an entirely novel trigger for interferon-independent induction of antiviral gene products, whereas protein 2 promotes expression of proviral factors. We will now determine: 1. How do proteins 1 and 2 respond to viral infection? Using biochemical approaches, RNAseq and proteomics in human fibroblasts and primary dendritic cells infected with HCMV or Sendai virus, we will: a. identify upstream sensors and kinases; b. characterise cellular transcriptional effects and transcription complex components; c. characterise cell-type specific similarities and differences. Using cellular gene knockout and viral mutagenesis, we will then: d. determine which protein 1-dependent cellular proteins restrict HCMV, and characterise the proviral effect of protein 2 on viral and cellular transcription over time. 2. How do HCMV and other viruses subvert proteins 1 and 2? Using interaction studies, viral mutagenesis and biochemical/structural approaches, we will: a. characterise the viral antagonist targeting protein 1 b. determine the mechanism of HCMV-mediated subversion of protein 2 c. collaborate to define protein 1/2 subversion by EBV, HSV and SARS-CoV-2. Overall, these studies will provide detailed characterisation of crucial host antiviral defence pathways, revealing fundamental insights into innate immunity. Furthermore, the small-molecule therapeutic opportunities offered by identification of these key viral-host interactions may be unparalleled.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Dectin-1-mediated suppression of protective anti-mycobacterial immunity
Funder: Medical Research Council

Abstract: C-type lectin receptors (CLR) trigger intracellular signalling cascades that induce a wide range of cellular and immunological responses which play critical protective roles in antimicrobial immunity. We recently discovered that one such CLR promotes susceptibility to, rather than protection against, infection with Mycobacterium tuberculosis (MTB), one of the world's deadliest bacterial infections. Our unpublished data suggest that this occurs, at least in part, through alterations in the host's ability to restrict mycobacterial replication. We therefore will elucidate the immunological, cellular and molecular mechanisms by which this CLR mediates its negative effects on anti-mycobacterial immunity. We will use receptor-deficient mice to determine the role of this receptor during infection with MTB, by characterising bacterial burdens, inflammation and other key immune parameters, including T-cell responses, over the course of infection. Using in vitro approaches, we will determine the impact of the receptor on a variety of key cellular responses, including antimicrobial mechanisms. We will also establish which signalling pathways are involved and identify the mycobacterial ligand recognised by the receptor. Furthermore, we will translate our findings to the human system. To achieve this we will establish the function of this receptor in primary and transfected human cells, and the impact of receptor polymorphisms known to affect its function. With collaborators, we will explore the possibility of an association between these polymorphisms and alterations in disease susceptibility in human populations. In sum, we have discovered a CLR that promotes susceptibility to infection with MTB. The experiments described here will provide substantial and definitive insights into the roles and functions of this molecule in both mice and humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Is autophagy in macrophages important to the pathogenesis of Buruli ulcer?
Funder: Medical Research Council

Abstract: Buruli ulcer (BU) is a necrotizing skin infection caused by Mycobacterium ulcerans (Mu). Virulence depends on an exotoxin, mycolactone, which suppresses immune responses by inhibiting the Sec61 translocon, blocking production of most cytokines, chemokines and immune cell receptors. The bacteria are extracellular but can be found inside some macrophages within lesions and evidence is accumulating that macrophages may play an important role in controlling the infection. Macrophages have been shown to phagocytose Mu and also to produce IL-1 beta in response. We recently discovered that both mycolactone and Mu bacilli induce an increase in macroautophagy in macrophages. Interestingly, genetic studies have identified an SNP in a key autophagy gene associated with Crohn's disease, ATG16L1, that reduces BU severity. Macrophages expressing the SNP variant protein, ATG16L1-T300A are less able to clear intracellular bacteria by autophagy but, since ATG16L1 also regulates inflammasome activity, these cells show an enhanced IL-1 beta response during bacterial infection. We hypothesise that the interaction between Mu and macrophages is a deciding factor in the outcome of Mu infection and that the SNP in ATG16L1 could protect against ulceration in BU by enhancing IL-1 beta production. In our laboratory at the University of Surrey, in collaboration with scientists at Imperial College London, the Crick Institute and Harvard, we will define the autophagic response of macrophages to Mu and the impact of the ATG16L1-T300A polymorphism on survival of both macrophage and bacteria in vitro, disentangling the effects of the bacterium and mycolactone. We will investigate the effect of ATG16L1-T300A expression on global macrophage responses and cytokine production induced by Mu using RNAseq and cytokine array. Finally, we will determine the role of the polymorphism in Mu infection and establish the importance of IL-1 in an in vivo model.


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