ORCID Profile
0000-0002-6902-9886
Current Organisation
University of Oxford
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Publisher: Elsevier BV
Date: 03-2021
Publisher: Cold Spring Harbor Laboratory
Date: 11-05-2021
DOI: 10.1101/2021.05.11.21256877
Abstract: Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1 38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Cold Spring Harbor Laboratory
Date: 15-02-2023
DOI: 10.1101/2023.02.12.23285726
Abstract: Respiratory syncytial virus (RSV) is the leading cause of hospitalisation associated with acute respiratory infection in infants and young children, with substantial disease burden globally. The impact of additional respiratory pathogens on RSV disease severity is not completely understood. The objective of this study was to explore the associations between RSV disease severity and the presence of other respiratory pathogens. Nasopharyngeal swabs were prospectively collected from two infant cohorts: a prospective longitudinal birth cohort study and an infant cross-sectional study recruiting infants year of age with RSV infection in Spain, the UK, and the Netherlands during 2017–20 [part of the REspiratory Syncytial virus Consortium in EUrope (RESCEU) project]. The s les were sequenced using targeted metagenomic sequencing with a probe set optimised for high-resolution capture of sequences of over 100 pathogens, including all common respiratory viruses and bacteria. Viral genomes and bacterial genetic sequences were reconstructed. Associations between clinical severity and presence of other pathogens were evaluated after adjusting for potential confounders, including age, gestational age, RSV viral load, and presence of comorbidities. RSV was detected in 433 infants. Nearly one in four of the infants (24%) harboured at least one additional non-RSV respiratory virus, with human rhinovirus being the most frequently detected (15% of the infants), followed by seasonal coronaviruses (4%). In this cohort, RSV-infected infants harbouring any other virus tended to be older (median age: 4.3 vs. 3.7 months) and were more likely to require intensive care and mechanical ventilation than those who did not. Moraxella, Streptococcus , and Haemophilus species were the most frequently identified target bacteria, together found in 392 (91%) of the 433 infants ( S. pneumoniae in 51% of the infants and H. influenzae in 38%). The strongest contributors to severity of presentation were younger age and the co-detection of Haemophilus species alongside RSV. Across all age groups in both cohorts, detection of Haemophilus species was associated with higher overall severity, as captured by ReSVinet scores, and specifically with increased rates of hospitalisation and respiratory distress. In contrast, presence of Moraxella species was associated with lower ReSVinet scores and reduced need for intensive care and mechanical ventilation. Infants with and without Streptococcus species (or S. pneumoniae in particular) had similar clinical outcomes. No specific RSV strain was associated with co-detection of other pathogens. Our findings provide strong evidence for associations between RSV disease severity and the presence of additional respiratory viruses and bacteria. The associations, while not indicating causation, are of potential clinical relevance. Awareness of coexisting microorganisms could inform therapeutic and preventive measures to improve the management and outcome of RSV-infected infants.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2021
DOI: 10.1038/S41467-021-25265-4
Abstract: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV ersity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus ersity than RSV-A at the population level, while exhibiting greater within-host ersity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
Publisher: Springer Science and Business Media LLC
Date: 10-03-2022
DOI: 10.1038/S41467-022-28898-1
Abstract: The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2021
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Society for Microbiology
Date: 28-12-2011
DOI: 10.1128/CVI.05379-11
Abstract: The rate of decay of antibody concentration following serogroup C meningococcal (MenC) polysaccharide-protein conjugate vaccination varies between in iduals. This depends partly on vaccination age but may be influenced by human genetics. We studied 721 single nucleotide polymorphisms (SNPs) across 131 candidate genes in a first cohort of 905 Caucasians (11 to 21 years old mean time after vaccination, 4.9 years) and 30 SNPs across 17 genes in a replication study using 155 children, aged 6 to 12 years (mean time after vaccination, 6.7 years), and 196 infants (1 year old mean time after vaccination, 8 months). In iduals were classified as responders or nonresponders for total MenC IgG concentration and MenC serum bactericidal antibody (SBA) measurements. Associated genes were examined further for quantitative outcome measures. Fifty-nine SNPs in 37 genes were associated with IgG persistence (adjusted for age at measurement), and 56 SNPs in 36 genes were associated with SBA persistence (adjusted for age at measurement and vaccine used). Three SNPs each within the Toll-like receptor 3 (TLR3) (rs3775291, rs3775292, and rs5743312) and CD44 (rs11033013, rs353644, and rs996076) genes were associated with IgG (adjusted for age at measurement) or SBA (adjusted for age at measurement and vaccine used) persistence in the initial genetic study ( P , 0.02 to 0.04). Single SNPs within the TLR3 (rs7657186) ( P = 0.004 [unadjusted]) and CD44 (rs12419062) ( P = 0.01 [unadjusted]) genes were associated with IgG persistence in the replication study. These results suggest that genetic polymorphisms in the TLR3 and CD44 genes are associated with the persistence of the immune response to MenC vaccines 1 to 6 years after vaccination.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Oxford University Press (OUP)
Date: 28-07-2022
Abstract: Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants and young children worldwide. Here we evaluated host demographic and viral factors associated with RSV disease severity in 325 RSV-infected infants under 1 year of age from 3 European countries during 2017–2020. Younger infants had a higher clinical severity (ReSViNET) score and were more likely to require hospitalization, intensive care, respiratory support, and/or mechanical ventilation than older infants (& months vs 3 to & months and 3 to & months vs ≥6 months). Older age (≥6 months vs & months), higher viral load, and RSV-A were associated with a greater probability of fever. RSV-A and RSV-B caused similar disease severity and had similar viral dynamics. Infants with a more severe RSV infection, demonstrated by having a higher ReSViNET score, fever, and requiring hospitalization and intensive care, were more likely to have developed subsequent wheezing at 1 year of age. NCT03756766.
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
Publisher: Elsevier BV
Date: 2021
Publisher: Oxford University Press (OUP)
Date: 23-07-2020
Abstract: Targeted metagenomics using strand-specific libraries with target enrichment is a sensitive, generalized approach to pathogen sequencing and transcriptome profiling. Using this method, we recovered 13 (76%) complete human respiratory syncytial virus (RSV) genomes from 17 clinical respiratory s les, reconstructed the phylogeny of the infecting viruses, and detected differential gene expression between 2 RSV subgroups, specifically, a lower expression of the P gene and a higher expression of the M2 gene in RSV-A than in RSV-B. This methodology can help to relate viral genetics to clinical phenotype and facilitate ongoing population-level RSV surveillance and vaccine development. Clinical Trials Registration. NCT03627572 and NCT03756766.
Publisher: Elsevier BV
Date: 03-2022
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Daniel O'Connor.