236 results on '"Openshaw, Peter J M"'
Search Results
202. Circulating histones play a central role in COVID-19-associated coagulopathy and mortality.
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Shaw RJ, Abrams ST, Austin J, Taylor JM, Lane S, Dutt T, Downey C, Du M, Turtle L, Baillie JK, Openshaw PJM, Wang G, Semple MG, and Toh CH
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- Blood Coagulation, Histones, Humans, SARS-CoV-2, Blood Coagulation Disorders etiology, COVID-19
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- 2021
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203. Durability of Immunity to SARS-CoV-2 and Other Respiratory Viruses: (Trends in Microbiology, 29, 648-662, 2021).
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Siggins MK, Thwaites RS, and Openshaw PJM
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- 2021
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204. Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study.
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Russell CD, Fairfield CJ, Drake TM, Turtle L, Seaton RA, Wootton DG, Sigfrid L, Harrison EM, Docherty AB, de Silva TI, Egan C, Pius R, Hardwick HE, Merson L, Girvan M, Dunning J, Nguyen-Van-Tam JS, Openshaw PJM, Baillie JK, Semple MG, and Ho A
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- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Pandemics, Prospective Studies, SARS-CoV-2, United Kingdom epidemiology, World Health Organization, Anti-Infective Agents, COVID-19 epidemiology, Coinfection drug therapy, Respiratory Tract Infections epidemiology
- Abstract
Background: Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19., Methods: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded., Findings: We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59-84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus . Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives., Interpretation: In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist., Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London., Competing Interests: All authors declare support from the NIHR, the Medical Research Council (MRC), the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, the NIHR HPRU in Respiratory Infections at Imperial College London, the NIHR Biomedical Research Centre (BRC) at Imperial College London, and the NIHR Clinical Research Network, for the submitted work. ABD reports grants from the UK Department of Health and Social Care (DHSC), during the conduct of the study, and grants from Wellcome Trust, outside the submitted work. PJMO reports personal fees from consultancies (GlaxoSmithKline, Janssen, Bavarian Nordic, Pfizer, and Cepheid) and from the European Respiratory Society, grants from MRC, MRC Global Challenge Research Fund, the EU, NIHR BRC, MRC–GlaxoSmithKline, Wellcome Trust, NIHR (HPRU in Respiratory Infection), and is an NIHR senior investigator outside the submitted work. PJMO's role as President of the British Society for Immunology was unpaid but travel and accommodation at some meetings was provided by the Society. JKB reports grants from MRC. MGS reports grants from DHSC, NIHR UK, MRC, HPRU in Emerging and Zoonotic Infections, and University of Liverpool, during the conduct of the study, and is chair of the scientific advisory board and a minority share holder at Integrum Scientific, outside the submitted work., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)
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- 2021
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205. Obesity, chronic disease, age, and in-hospital mortality in patients with covid-19: analysis of ISARIC clinical characterisation protocol UK cohort.
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Yates T, Zaccardi F, Islam N, Razieh C, Gillies CL, Lawson CA, Chudasama Y, Rowlands A, Davies MJ, Docherty AB, Openshaw PJM, Baillie JK, Semple MG, and Khunti K
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- Aged, Chronic Disease, Female, Hospital Mortality, Humans, Male, Middle Aged, Obesity complications, Obesity epidemiology, SARS-CoV-2, United Kingdom epidemiology, COVID-19
- Abstract
Background: Although age, obesity and pre-existing chronic diseases are established risk factors for COVID-19 outcomes, their interactions have not been well researched., Methods: We used data from the Clinical Characterisation Protocol UK (CCP-UK) for Severe Emerging Infection developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC). Patients admitted to hospital with COVID-19 from 6th February to 12th October 2020 were included where there was a coded outcome following hospital admission. Obesity was determined by an assessment from a clinician and chronic disease by medical records. Chronic diseases included: chronic cardiac disease, hypertension, chronic kidney disease, chronic pulmonary disease, diabetes and cancer. Mutually exclusive categories of obesity, with or without chronic disease, were created. Associations with in-hospital mortality were examined across sex and age categories., Results: The analysis included 27,624 women with 6407 (23.2%) in-hospital deaths and 35,065 men with 10,001 (28.5%) in-hospital deaths. The prevalence of chronic disease in women and men was 66.3 and 68.5%, respectively, while that of obesity was 12.9 and 11.1%, respectively. Association of obesity and chronic disease status varied by age (p < 0.001). Under 50 years of age, obesity and chronic disease were associated with in-hospital mortality within 28 days of admission in a dose-response manner, such that patients with both obesity and chronic disease had the highest risk with a hazard ratio (HR) of in-hospital mortality of 2.99 (95% CI: 2.12, 4.21) in men and 2.16 (1.42, 3.26) in women compared to patients without obesity or chronic disease. Between the ages of 50-69 years, obesity and chronic disease remained associated with in-hospital COVID-19 mortality, but survival in those with obesity was similar to those with and without prevalent chronic disease. Beyond the age of 70 years in men and 80 years in women there was no meaningful difference between those with and without obesity and/or chronic disease., Conclusion: Obesity and chronic disease are important risk factors for in-hospital mortality in younger age groups, with the combination of chronic disease and obesity being particularly important in those under 50 years of age. These findings have implications for targeted public health interventions, vaccination strategies and in-hospital clinical decision making., (© 2021. The Author(s).)
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- 2021
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206. Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study.
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Drake TM, Fairfield CJ, Pius R, Knight SR, Norman L, Girvan M, Hardwick HE, Docherty AB, Thwaites RS, Openshaw PJM, Baillie JK, Harrison EM, and Semple MG
- Abstract
Background: Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease., Methods: This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations., Results: Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84-1·07; p=0·35), critical care admission (1·01, 0·87-1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80-1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96-1·32; p=0·14), requirement for oxygen (1·00, 0·89-1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92-1·26; p=0·33)., Interpretation: NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity., Funding: National Institute for Health Research and Medical Research Council., Competing Interests: All authors declare support from the National Institute for Health Research (NIHR), the Medical Research Council (MRC), the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London, NIHR Biomedical Research Centre (BRC) at Imperial College London, and NIHR Clinical Research Network for the submitted work. ABD reports grants from the UK Department of Health and Social Care (DHSC), during the conduct of the study, and grants from Wellcome Trust, outside the submitted work. PJMO reports personal fees from consultancies and from the European Respiratory Society, grants from MRC, MRC Global Challenge Research Fund, EU, NIHR BRC, MRC, GSK, Wellcome Trust, NIHR (Health Protection Research Unit [HPRU] in Respiratory Infection), and is NIHR senior investigator outside the submitted work. PJMO's role as President of the British Society for Immunology was unpaid but travel and accommodation at some meetings was provided. JKB reports grants from MRC. MGS reports grants from DHSC NIHR, MRC, and HPRU in Emerging and Zoonotic Infections, University of Liverpool, during the conduct of the study, and honoraria from Integrum Scientific, outside the submitted work. All other authors declare no support from any organisation for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)
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- 2021
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207. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK.
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Bloom CI, Drake TM, Docherty AB, Lipworth BJ, Johnston SL, Nguyen-Van-Tam JS, Carson G, Dunning J, Harrison EM, Baillie JK, Semple MG, Cullinan P, and Openshaw PJM
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- Adolescent, Adult, Clinical Protocols, Cohort Studies, Female, Hospital Mortality, Hospitalization, Humans, Male, Middle Aged, Prospective Studies, Risk Assessment, United Kingdom, World Health Organization, Young Adult, Asthma complications, Asthma mortality, COVID-19 complications, COVID-19 mortality, Pulmonary Disease, Chronic Obstructive complications, Pulmonary Disease, Chronic Obstructive mortality
- Abstract
Background: Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use., Methods: We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16-49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists [SABAs], and long-acting β-agonists [LABAs]). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma., Findings: 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16-49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05-1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08-1·27]; p<0·0001), and patients aged 50 years and older with chronic pulmonary disease (with or without asthma) were significantly less likely than those without a respiratory condition to receive critical care (adjusted OR 0·66 [0·60-0·72] for those without asthma and 0·74 [0·62-0·87] for those with asthma; p<0·0001 for both). In patients aged 16-49 years, only those with severe asthma had a significant increase in mortality compared to those with no asthma (adjusted hazard ratio [HR] 1·17 [95% CI 0·73-1·86] for those on no asthma therapy, 0·99 [0·61-1·58] for those on SABAs only, 0·94 [0·62-1·43] for those on inhaled corticosteroids only, 1·02 [0·67-1·54] for those on inhaled corticosteroids plus LABAs, and 1·96 [1·25-3·08] for those with severe asthma). Among patients aged 50 years and older, those with chronic pulmonary disease had a significantly increased mortality risk, regardless of inhaled corticosteroid use, compared to patients without an underlying respiratory condition (adjusted HR 1·16 [95% CI 1·12-1·22] for those not on inhaled corticosteroids, and 1·10 [1·04-1·16] for those on inhaled corticosteroids; p<0·0001). Patients aged 50 years and older with severe asthma also had an increased mortality risk compared to those not on asthma therapy (adjusted HR 1·24 [95% CI 1·04-1·49]). In patients aged 50 years and older, inhaled corticosteroid use within 2 weeks of hospital admission was associated with decreased mortality in those with asthma, compared to those without an underlying respiratory condition (adjusted HR 0·86 [95% CI 0·80-0·92])., Interpretation: Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease., Funding: National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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208. A haemagglutination test for rapid detection of antibodies to SARS-CoV-2.
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Townsend A, Rijal P, Xiao J, Tan TK, Huang KA, Schimanski L, Huo J, Gupta N, Rahikainen R, Matthews PC, Crook D, Hoosdally S, Dunachie S, Barnes E, Street T, Conlon CP, Frater J, Arancibia-Cárcamo CV, Rudkin J, Stoesser N, Karpe F, Neville M, Ploeg R, Oliveira M, Roberts DJ, Lamikanra AA, Tsang HP, Bown A, Vipond R, Mentzer AJ, Knight JC, Kwok AJ, Screaton GR, Mongkolsapaya J, Dejnirattisai W, Supasa P, Klenerman P, Dold C, Baillie JK, Moore SC, Openshaw PJM, Semple MG, Turtle LCW, Ainsworth M, Allcock A, Beer S, Bibi S, Skelly D, Stafford L, Jeffrey K, O'Donnell D, Clutterbuck E, Espinosa A, Mendoza M, Georgiou D, Lockett T, Martinez J, Perez E, Gallardo Sanchez V, Scozzafava G, Sobrinodiaz A, Thraves H, and Joly E
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- Agglutination Tests methods, Antibodies, Monoclonal immunology, Antibodies, Viral blood, Antibodies, Viral immunology, COVID-19 blood, COVID-19 immunology, COVID-19 virology, Enzyme-Linked Immunosorbent Assay methods, Humans, Point-of-Care Systems, Polymerase Chain Reaction, SARS-CoV-2 immunology, Sensitivity and Specificity, Seroconversion, Antibodies, Viral analysis, COVID-19 diagnosis, COVID-19 Testing methods, Hemagglutination Tests methods, SARS-CoV-2 isolation & purification, Spike Glycoprotein, Coronavirus immunology
- Abstract
Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world.
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- 2021
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209. Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.
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Thomson EC, Rosen LE, Shepherd JG, Spreafico R, da Silva Filipe A, Wojcechowskyj JA, Davis C, Piccoli L, Pascall DJ, Dillen J, Lytras S, Czudnochowski N, Shah R, Meury M, Jesudason N, De Marco A, Li K, Bassi J, O'Toole A, Pinto D, Colquhoun RM, Culap K, Jackson B, Zatta F, Rambaut A, Jaconi S, Sreenu VB, Nix J, Zhang I, Jarrett RF, Glass WG, Beltramello M, Nomikou K, Pizzuto M, Tong L, Cameroni E, Croll TI, Johnson N, Di Iulio J, Wickenhagen A, Ceschi A, Harbison AM, Mair D, Ferrari P, Smollett K, Sallusto F, Carmichael S, Garzoni C, Nichols J, Galli M, Hughes J, Riva A, Ho A, Schiuma M, Semple MG, Openshaw PJM, Fadda E, Baillie JK, Chodera JD, Rihn SJ, Lycett SJ, Virgin HW, Telenti A, Corti D, Robertson DL, and Snell G
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- Angiotensin-Converting Enzyme 2 chemistry, Antibodies, Neutralizing genetics, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 virology, Humans, Mutation, Phylogeny, SARS-CoV-2 chemistry, SARS-CoV-2 pathogenicity, Spike Glycoprotein, Coronavirus chemistry, Virulence, COVID-19 immunology, Genetic Fitness, Immune Evasion, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus genetics
- Abstract
SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics., Competing Interests: Declaration of interests L.E.R., R. Spreafico, J.A.W., L.P., J.D., N.C., M.M., A.D.M., J.B., D.P., K.C., F.Z., S.J., M.B., M.P., E.C., J.D.I., H.W.V., A.T., D.C., and G.S. are or were employees of Vir Biotechnology and may hold shares in Vir Biotechnology. C.G. is an external scientific advisor for Humabs BioMed SA. J. Nix and T.I.C. are consultants with Vir Biotechnology. M.G.S. declares interest in Integrum Scientific, Greensboro, NC, outside the scope of this work. J.D.C. is a current member of the Scientific Advisory Board of OpenEye Scientific Software and is a scientific consultant to Foresite Labs. The Chodera laboratory (I.Z., W.G.G., and J.D.C.) receives or has received funding from multiple sources, including the NIH, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, XtalPi, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at https://www.choderalab.org/funding. The other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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210. Increased nasal mucosal interferon and CCL13 response to a TLR7/8 agonist in asthma and allergic rhinitis.
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Jha A, Thwaites RS, Tunstall T, Kon OM, Shattock RJ, Hansel TT, and Openshaw PJM
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- Adult, Female, Humans, Immunity, Innate drug effects, Interferons immunology, Male, Monocyte Chemoattractant Proteins immunology, Nasal Mucosa drug effects, Toll-Like Receptor 7 agonists, Toll-Like Receptor 8 agonists, Asthma immunology, Imidazoles pharmacology, Immunity, Innate immunology, Nasal Mucosa immunology, Rhinitis, Allergic immunology
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Background: Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with preexisting lung diseases such as asthma. Toll-like receptors are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured., Objective: We sought to assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy volunteers and volunteers with allergy., Methods: We administered the Toll-like receptor 7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA) or saline by nasal spray to healthy participants without allergy (n = 12), those with allergic rhinitis (n = 12), or those with allergic rhinitis with asthma (n = 11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time., Results: R848 was well tolerated and significantly induced IFN-α2a, IFN-γ, proinflammatory cytokines (TNF-α, IL-2, IL-12p70), and chemokines (CXCL10, C-C motif chemokine ligand [CCL]2, CCL3, CCL4, and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3, and CCL13 responses relative to healthy participants; those with asthma had increased induction of IFN-stimulated genes DExD/H-box helicase 58, MX dynamin-like GTPase 1, and IFN-induced protein with tetratricopeptide repeats 3., Conclusions: Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal IFN and chemokine response to the viral RNA analogue R848. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the outcome of viral exposure., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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- 2021
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211. Broad and strong memory CD4 + and CD8 + T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.
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Peng Y, Mentzer AJ, Liu G, Yao X, Yin Z, Dong D, Dejnirattisai W, Rostron T, Supasa P, Liu C, López-Camacho C, Slon-Campos J, Zhao Y, Stuart DI, Paesen GC, Grimes JM, Antson AA, Bayfield OW, Hawkins DEDP, Ker DS, Wang B, Turtle L, Subramaniam K, Thomson P, Zhang P, Dold C, Ratcliff J, Simmonds P, de Silva T, Sopp P, Wellington D, Rajapaksa U, Chen YL, Salio M, Napolitani G, Paes W, Borrow P, Kessler BM, Fry JW, Schwabe NF, Semple MG, Baillie JK, Moore SC, Openshaw PJM, Ansari MA, Dunachie S, Barnes E, Frater J, Kerr G, Goulder P, Lockett T, Levin R, Zhang Y, Jing R, Ho LP, Cornall RJ, Conlon CP, Klenerman P, Screaton GR, Mongkolsapaya J, McMichael A, Knight JC, Ogg G, and Dong T
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- COVID-19, COVID-19 Vaccines, Coronavirus Infections immunology, Coronavirus Infections pathology, Coronavirus Infections prevention & control, Epitopes, T-Lymphocyte immunology, Humans, Immunodominant Epitopes immunology, Pandemics, Pneumonia, Viral immunology, Pneumonia, Viral pathology, SARS-CoV-2, Spike Glycoprotein, Coronavirus immunology, United Kingdom, Viral Vaccines immunology, Antigens, Viral immunology, Betacoronavirus immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Immunologic Memory immunology
- Abstract
The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4
+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.- Published
- 2020
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212. Using imaging to combat a pandemic: rationale for developing the UK National COVID-19 Chest Imaging Database.
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Jacob J, Alexander D, Baillie JK, Berka R, Bertolli O, Blackwood J, Buchan I, Bloomfield C, Cushnan D, Docherty A, Edey A, Favaro A, Gleeson F, Halling-Brown M, Hare S, Jefferson E, Johnstone A, Kirby M, McStay R, Nair A, Openshaw PJM, Parker G, Reilly G, Robinson G, Roditi G, Rodrigues JCL, Sebire N, Semple MG, Sudlow C, Woznitza N, and Joshi I
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- COVID-19, Communicable Diseases, Emerging diagnostic imaging, Coronavirus Infections epidemiology, Databases, Factual statistics & numerical data, Diagnostic Imaging methods, Diagnostic Imaging statistics & numerical data, Female, Humans, Male, Pneumonia, Viral epidemiology, Program Development, Radiography, Thoracic methods, Radiography, Thoracic statistics & numerical data, Tomography, X-Ray Computed methods, United Kingdom, Artificial Intelligence statistics & numerical data, Communicable Diseases, Emerging epidemiology, Coronavirus Infections diagnostic imaging, Pandemics statistics & numerical data, Pneumonia, Viral diagnostic imaging, Tomography, X-Ray Computed statistics & numerical data
- Abstract
Competing Interests: Conflict of interest: J. Jacob reports fees from Boehringer Ingelheim and Roche unrelated to the current submission and is supported by a Clinical Research Career Development Fellowship 209553/Z/17/Z from the Wellcome Trust, and by the NIHR Biomedical Research Centre at University College London. Conflict of interest: D. Alexander has nothing to disclose. Conflict of interest: J.K. Baillie reports grants from DHSC National Institute of Health Research UK, Medical Research Council UK, Wellcome Trust, Fiona Elizabeth Agnew Trust, Intensive Care Society and Chief Scientist Office, during the conduct of the study. Conflict of interest: R. Berka is an Associate at Faculty; Faculty has a paid partnership with NHSX to build its new AI lab to help drive digital transformation and the use of AI in the NHS. This contract has been extended for setting up the platform environment that manages the data storage for the National COVID-19 Chest Imaging Database (NCCID); the platform is being made available by Faculty at zero licence cost. In addition, Faculty is contracted to support NHS England and Improvement as well as NHSX with its data response strategy to COVID-19, which includes developing dashboards, models and simulations to provide information to central government decision-makers. Conflict of interest: O. Bertolli is an Associate at Faculty; Faculty has a paid partnership with NHSX to build its new AI lab to help drive digital transformation and the use of AI in the NHS. This contract has been extended for setting up the platform environment that manages the data storage for the National COVID-19 Chest Imaging Database (NCCID); the platform is being made available by Faculty at zero licence cost. In addition, Faculty is contracted to support NHS England and Improvement as well as NHSX with its data response strategy to COVID-19, which includes developing dashboards, models and simulations to provide information to central government decision-makers. Conflict of interest: J. Blackwood has nothing to disclose. Conflict of interest: I. Buchan reports personal fees from and acting as advisor for AstraZeneca, grants from NIHR, and is a former employee of Microsoft, outside the submitted work. Conflict of interest: C. Bloomfield reports that NCIMI is funded through support from the Industry Strategy Challenge Fund, by Innovate UK grant 104688. Conflict of interest: D. Cushnan has nothing to disclose. Conflict of interest: A. Docherty has nothing to disclose. Conflict of interest: A. Edey has nothing to disclose. Conflict of interest: A. Favaro is a Lead Data Scientist at Faculty; Faculty has a paid partnership with NHSX to build its new AI lab to help drive digital transformation and the use of AI in the NHS. This contract has been extended for setting up the platform environment that manages the data storage for the National COVID-19 Chest Imaging Database (NCCID); the platform is being made available by Faculty at zero licence cost. In addition, Faculty is contracted to support NHS England and Improvement as well as NHSX with its data response strategy to COVID-19, which includes developing dashboards, models and simulations to provide information to central government decision-makers. Conflict of interest: F. Gleeson has nothing to disclose. Conflict of interest: M. Halling-Brown is an advisor to Google Health on the MAMMOTH project, and has a Visiting Professorship with University of Surrey as part of a research collaboration with Transpara. Conflict of interest: S. Hare has nothing to disclose. Conflict of interest: E. Jefferson reports grants from Medical Research Council (MRC), Health Data Research (HDR) UK, National Institute of Health Research (NIHR), Chief Scientist Office (CSO), Engineering and Physical Sciences Research Council (EPSRC), Health Foundation, Data Lab, Scottish Government, NHS Fife Health Board and EU Horizon 2020, during the conduct of the study. Conflict of interest: A. Johnstone has nothing to disclose. Conflict of interest: M. Kirby is a Principal at Faculty; Faculty has a paid partnership with NHSX to build its new AI lab to help drive digital transformation and the use of AI in the NHS. This contract has been extended for setting up the platform environment that manages the data storage for the National COVID-19 Chest Imaging Database (NCCID); the platform is being made available by Faculty at zero licence cost. In addition, Faculty is contracted to support NHS England and Improvement as well as NHSX with its data response strategy to COVID-19, which includes developing dashboards, models and simulations to provide information to central government decision-makers. Conflict of interest: R. McStay has nothing to disclose. Conflict of interest: A. Nair reports salary reimbursement from Biomedical Research Centre UCL, and is medical advisor to Aidence BV, outside the submitted work. Conflict of interest: P.J.M. Openshaw reports personal fees for consultancy work with Janssen, J and J and Sanofi; grants from MRC, European Union, NIHR Biomedical Research Centre and Wellcome Trust, collaborative grants with GSK, personal fees from the European Respiratory Society and an NIHR Senior Investigator Award outside the submitted work; in addition, P.J.M. Openshaw was President of the British Society for Immunology; this was an unpaid appointment but travel and accommodation at some meetings was provided by the Society. Conflict of interest: G. Parker is director and shareholder of Bioxydyn Limited, outside the submitted work. Conflict of interest: G. Reilly has nothing to disclose. Conflict of interest: G. Robinson has nothing to disclose. Conflict of interest: G. Roditi has nothing to disclose. Conflict of interest: J.C.L. Rodrigues has nothing to disclose. Conflict of interest: N. Sebire has nothing to disclose. Conflict of interest: M.G. Semple reports grants from DHSC National Institute of Health Research UK, Medical Research Council UK, Health Protection Research Unit in Emerging and Zoonotic Infections, and University of Liverpool, during the conduct of the study; and is minority owner of Integrum Scientific LLC, Greensboro, NC, USA, outside the submitted work. Conflict of interest: C. Sudlow has nothing to disclose. Conflict of interest: N. Woznitza reports grants from Cancer Research UK and Roy Castle Lung Cancer Foundation, personal fees from InHealth, outside the submitted work. Conflict of interest: I. Joshi has nothing to disclose.
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- 2020
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213. Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities.
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Mehta P, Porter JC, Manson JJ, Isaacs JD, Openshaw PJM, McInnes IB, Summers C, and Chambers RC
- Subjects
- COVID-19, Coronavirus Infections complications, Coronavirus Infections virology, Disease Progression, Humans, Immunomodulation, Pandemics, Pneumonia, Viral complications, Pneumonia, Viral virology, Respiratory Distress Syndrome virology, SARS-CoV-2, COVID-19 Drug Treatment, Betacoronavirus immunology, Coronavirus Infections drug therapy, Granulocyte-Macrophage Colony-Stimulating Factor antagonists & inhibitors, Immunologic Factors therapeutic use, Pneumonia, Viral drug therapy, Respiratory Distress Syndrome prevention & control
- Abstract
The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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214. Tracheostomy in the COVID-19 era: global and multidisciplinary guidance.
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McGrath BA, Brenner MJ, Warrillow SJ, Pandian V, Arora A, Cameron TS, Añon JM, Hernández Martínez G, Truog RD, Block SD, Lui GCY, McDonald C, Rassekh CH, Atkins J, Qiang L, Vergez S, Dulguerov P, Zenk J, Antonelli M, Pelosi P, Walsh BK, Ward E, Shang Y, Gasparini S, Donati A, Singer M, Openshaw PJM, Tolley N, Markel H, and Feller-Kopman DJ
- Subjects
- COVID-19, Coronavirus Infections prevention & control, Critical Care methods, Humans, Pandemics prevention & control, Pneumonia, Viral prevention & control, SARS-CoV-2, Betacoronavirus, Coronavirus Infections therapy, Infectious Disease Transmission, Patient-to-Professional prevention & control, Internationality, Pneumonia, Viral therapy, Practice Guidelines as Topic, Tracheostomy methods
- Abstract
Global health care is experiencing an unprecedented surge in the number of critically ill patients who require mechanical ventilation due to the COVID-19 pandemic. The requirement for relatively long periods of ventilation in those who survive means that many are considered for tracheostomy to free patients from ventilatory support and maximise scarce resources. COVID-19 provides unique challenges for tracheostomy care: health-care workers need to safely undertake tracheostomy procedures and manage patients afterwards, minimising risks of nosocomial transmission and compromises in the quality of care. Conflicting recommendations exist about case selection, the timing and performance of tracheostomy, and the subsequent management of patients. In response, we convened an international working group of individuals with relevant expertise in tracheostomy. We did a literature and internet search for reports of research pertaining to tracheostomy during the COVID-19 pandemic, supplemented by sources comprising statements and guidance on tracheostomy care. By synthesising early experiences from countries that have managed a surge in patient numbers, emerging virological data, and international, multidisciplinary expert opinion, we aim to provide consensus guidelines and recommendations on the conduct and management of tracheostomy during the COVID-19 pandemic., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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215. Seasonal and pandemic influenza: 100 years of progress, still much to learn.
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Dunning J, Thwaites RS, and Openshaw PJM
- Subjects
- Animals, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Bacterial Infections epidemiology, Bacterial Infections microbiology, Coinfection, Comorbidity, Disease Outbreaks, History, 20th Century, History, 21st Century, Host-Pathogen Interactions immunology, Humans, Influenza A virus drug effects, Influenza A virus physiology, Influenza Vaccines administration & dosage, Influenza Vaccines immunology, Influenza, Human history, Influenza, Human prevention & control, Influenza, Human virology, Betainfluenzavirus drug effects, Betainfluenzavirus physiology, Virus Replication, Influenza, Human epidemiology, Pandemics history, Seasons
- Abstract
Influenza viruses are highly transmissible, both within and between host species. The severity of the disease they cause is highly variable, from the mild and inapparent through to the devastating and fatal. The unpredictability of epidemic and pandemic outbreaks is accompanied but the predictability of seasonal disease in wide areas of the Globe, providing an inexorable toll on human health and survival. Although there have been great improvements in understanding influenza viruses and the disease that they cause, our knowledge of the effects they have on the host and the ways that the host immune system responds continues to develop. This review highlights the importance of the mucosa in defence against infection and in understanding the pathogenesis of disease. Although vaccines have been available for many decades, they remain suboptimal in needing constant redesign and in only providing short-term protection. There are real prospects for improvement in treatment and prevention of influenza soon, based on deeper knowledge of how the virus transmits, replicates and triggers immune defences at the mucosal surface.
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- 2020
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216. Cancer datasets and the SARS-CoV-2 pandemic: establishing principles for collaboration.
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Palmieri C, Palmer D, Openshaw PJM, Baillie JK, Semple MG, and Turtle L
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- Betacoronavirus, COVID-19, Coronavirus Infections, Humans, New York City, Pandemics, Pneumonia, Viral, Prognosis, SARS-CoV-2, Neoplasms, Severe acute respiratory syndrome-related coronavirus
- Abstract
Competing Interests: Competing interests: None declared.
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- 2020
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217. OMIP-062: A 14-Color, 16-Antibody Panel for Immunophenotyping Human Innate Lymphoid, Myeloid and T Cells in Small Volumes of Whole Blood and Pediatric Airway Samples.
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Swieboda D, Guo Y, Sagawe S, Thwaites RS, Nadel S, Openshaw PJM, and Culley FJ
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- Child, Color, Fluorescent Antibody Technique, Humans, Immunity, Innate, Infant, Antibodies metabolism, Blood Volume physiology, Flow Cytometry methods, Immunophenotyping, Lung immunology, Lymphocytes cytology, Myeloid Cells cytology, T-Lymphocytes cytology
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- 2019
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218. Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza.
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Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, O'Garra A, and Openshaw PJM
- Abstract
In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.
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- 2019
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219. Group B streptococcus and respiratory syncytial virus immunisation during pregnancy: a landscape analysis.
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Heath PT, Culley FJ, Jones CE, Kampmann B, Le Doare K, Nunes MC, Sadarangani M, Chaudhry Z, Baker CJ, and Openshaw PJM
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- Female, Humans, Immunization statistics & numerical data, Infant, Pregnancy, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus, Human drug effects, Respiratory Syncytial Virus, Human immunology, Streptococcal Infections microbiology, Streptococcus agalactiae isolation & purification, Vaccination, Immunity, Maternally-Acquired, Immunization methods, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines administration & dosage, Streptococcal Infections prevention & control, Streptococcal Vaccines administration & dosage
- Abstract
Group B streptococcus and respiratory syncytial virus are leading causes of infant morbidity and mortality worldwide. No licensed vaccines are available for either disease, but vaccines for both are under development. Severe respiratory syncytial virus disease can be prevented by passively administered antibody. The presence of maternal IgG antibody specific to respiratory syncytial virus is associated with reduced prevalence and severity of respiratory syncytial virus disease in the first few weeks of life, whereas maternal serotype-specific anticapsular antibody is associated with protection against both early-onset and late-onset group B streptococcus disease. Therefore, vaccination in pregnancy might protect infants against both diseases. This report describes what is known about immune protection against group B streptococcus and respiratory syncytial virus, identifies knowledge gaps regarding the immunobiology of both diseases, and aims to prioritise research directions in maternal immunisation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
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- 2017
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220. Protective and Harmful Immunity to RSV Infection.
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Openshaw PJM, Chiu C, Culley FJ, and Johansson C
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- Adult, Aged, Animals, Child, Humans, Immune Evasion, Immunomodulation, Respiratory Mucosa virology, Respiratory Mucosa immunology, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Viruses immunology, Viral Vaccines immunology
- Abstract
Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.
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- 2017
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221. Vaccines in the Prevention of Viral Pneumonia.
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Fraser CS, Jha A, and Openshaw PJ
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- Humans, Pneumonia, Viral virology, Vaccines administration & dosage, Pneumonia, Viral drug therapy, Respiratory Syncytial Virus Infections drug therapy, Vaccination methods, Vaccines therapeutic use
- Abstract
Pneumonia is of great global public health importance. Viral infections play both direct and indirect parts in its cause across the globe. Influenza is a leading cause of viral pneumonia in both children and adults, and respiratory syncytial virus is increasingly recognized as causing disease at both extremes of age. Vaccination offers the best prospect for prevention but current influenza vaccines do not provide universal and durable protection, and require yearly reformulation. In the future, it is hoped that influenza vaccines will give better and universal protection, and that new vaccines can be found for other causes of viral pneumonia., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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222. RSV Takes Control of Neonatal Breg Cells: Two Hands on the Wheel.
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Openshaw PJM
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- Humans, B-Lymphocytes, Regulatory immunology
- Abstract
The viral attachment protein of RSV has many surprising features, especially its mimicry of fractalkine (CX3CL1). Zhivaki et al. (2017) now show that, in addition to using this homology to attach to ciliated cells, it activates human neonatal regulatory B cells, thereby inhibiting immunological responses., (Copyright © 2017. Published by Elsevier Inc.)
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- 2017
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223. Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus.
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Habibi MS, Jozwik A, Makris S, Dunning J, Paras A, DeVincenzo JP, de Haan CA, Wrammert J, Openshaw PJ, and Chiu C
- Subjects
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Young Adult, Antibodies, Viral immunology, B-Lymphocytes immunology, Immunoglobulin A immunology, Immunologic Memory, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Viruses immunology
- Abstract
Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection., Objectives: To characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development., Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B-cell frequencies and antibody longevity., Measurements and Main Results: Despite moderately high levels of preexisting serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from polymerase chain reaction-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects but correlated with plasmablasts that peaked around Day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, in which virus-specific IgA memory B cells were readily recovered., Conclusions: This observed specific defect in IgA memory may partly explain the ability of RSV to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.
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- 2015
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224. Natural killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation.
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Farhadi N, Lambert L, Triulzi C, Openshaw PJ, Guerra N, and Culley FJ
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- Animals, Asthma immunology, Female, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Pneumonia immunology, Pyroglyphidae immunology, Asthma etiology, Granzymes physiology, Killer Cells, Natural immunology, NK Cell Lectin-Like Receptor Subfamily K physiology, Pneumonia etiology
- Abstract
Background: The diverse roles of innate immune cells in the pathogenesis of asthma remain to be fully defined. Natural killer (NK) cells are innate lymphocytes that can regulate adaptive immune responses. NK cells are activated in asthma; however, their role in allergic airway inflammation is not fully understood., Objective: We investigated the importance of NK cells in house dust mite (HDM)-triggered allergic pulmonary inflammation. Specifically, we aimed to determine the role of the major NK-cell activating receptor NKG2D and NK-cell effector functions mediated by granzyme B., Methods: Allergic airway inflammation was induced in the airways of mice by repeated intranasal HDM extract administration and responses in wild-type and NKG2D-deficient mice were compared. Adoptive transfer studies were used to identify the cells and mechanisms involved., Results: Mice that lacked NKG2D were resistant to the induction of allergic inflammation and showed little pulmonary eosinophilia, few airway TH2 cells, and no rise in serum IgE after multiple HDM-allergen exposures. However, NKG2D was not required for pulmonary inflammation after a single inoculation of allergen. NKG2D-deficient mice showed no alteration in responses to respiratory virus infection. Transfer of wild-type NK cells (but not CD3(+) cells) into NKG2D-deficient mice restored allergic inflammatory responses only if the NK cells expressed granzyme B., Conclusions: These studies established a pivotal role for NK-cell NKG2D and granzyme B in the pathogenesis of HDM-induced allergic lung disease, and identified novel therapeutic targets for the prevention and treatment of asthma., (Copyright © 2013 The Authors. Published by Mosby, Inc. All rights reserved.)
- Published
- 2014
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225. RSV-induced bronchial epithelial cell PD-L1 expression inhibits CD8+ T cell nonspecific antiviral activity.
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Telcian AG, Laza-Stanca V, Edwards MR, Harker JA, Wang H, Bartlett NW, Mallia P, Zdrenghea MT, Kebadze T, Coyle AJ, Openshaw PJ, Stanciu LA, and Johnston SL
- Subjects
- Apoptosis, B7-H1 Antigen, Cells, Cultured, Coculture Techniques, Humans, Antigens, CD biosynthesis, CD8-Positive T-Lymphocytes immunology, Epithelial Cells virology, Immune Tolerance, Respiratory Syncytial Viruses immunology, Respiratory Syncytial Viruses pathogenicity
- Abstract
Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (PD-Ls) on antigen-presenting cells interact with receptors on T cells to regulate immune responses. The programmed death receptor-ligand 1/programmed death receptor 1 (PD-L1-PD-1) pathway is inhibitory in chronic viral infections, but its role in acute viral infections is unclear. We hypothesized that bronchial epithelial cell (BEC) expression of PD-Ls would inhibit local effector CD8(+) T cell function. We report that RSV infection of primary human BECs strongly induces PD-L1 expression. In a co-culture system of BECs with purified CD8(+) T cells, we demonstrated that RSV-infected BECs increased CD8(+) T cell activation, proliferation, and antiviral function. Blocking PD-L1 on RSV-infected BECs co-cultured with CD8(+) T cells enhanced CD8(+) T cell IFN-γ, IL-2, and granzyme B production. It also decreased the virus load of the BECs. Based on our findings, we believe therapeutic strategies that target the PD-L1-PD-1 pathway might increase antiviral immune responses to RSV and other acute virus infections.
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- 2011
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226. CD25+ natural regulatory T cells are critical in limiting innate and adaptive immunity and resolving disease following respiratory syncytial virus infection.
- Author
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Lee DC, Harker JA, Tregoning JS, Atabani SF, Johansson C, Schwarze J, and Openshaw PJ
- Subjects
- Animals, Cell Line, Female, Humans, Interferon-gamma immunology, Interleukin-2 Receptor alpha Subunit immunology, Interleukin-6 immunology, Lung immunology, Lung pathology, Mice, Mice, Inbred BALB C, Respiratory Syncytial Virus Infections pathology, Respiratory Syncytial Virus Infections virology, Respiratory Syncytial Viruses immunology, T-Lymphocytes, Regulatory virology, Adaptive Immunity, Immunity, Innate, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Viruses physiology, T-Lymphocytes, Regulatory immunology
- Abstract
Regulatory CD4(+) T cells have been shown to be important in limiting immune responses, but their role in respiratory viral infections has received little attention. Here we observed that following respiratory syncytial virus (RSV) infection, CD4(+) Foxp3(+) CD25(+) natural regulatory T-cell numbers increased in the bronchoalveolar lavage fluid, lung, mediastinal lymph nodes, and spleen. The depletion of CD25(+) natural regulatory T cells prior to RSV infection led to enhanced weight loss with delayed recovery that was surprisingly accompanied by increased numbers of activated natural killer cells in the lung and bronchoalveolar lavage fluid on day 8 postinfection. Increased numbers of neutrophils were also detected within the bronchoalveolar lavage fluid and correlated with elevated levels of myeloperoxidase as well as interleukin-6 (IL-6) and gamma interferon (IFN-gamma). CD25(+) natural regulatory T-cell depletion also led to enhanced numbers of proinflammatory T cells producing IFN-gamma and tumor necrosis factor alpha (TNF-alpha) in the lung. Despite these increases in inflammatory responses and disease severity, the viral load was unaltered. This work highlights a critical role for natural regulatory T cells in regulating the adaptive and innate immune responses during the later stages of lung viral infections.
- Published
- 2010
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227. Pulmonary V gamma 4+ gamma delta T cells have proinflammatory and antiviral effects in viral lung disease.
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Dodd J, Riffault S, Kodituwakku JS, Hayday AC, and Openshaw PJ
- Subjects
- Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic adverse effects, Animals, Cell Movement immunology, Female, Inflammation Mediators metabolism, Lung metabolism, Lung virology, Lymphocyte Activation immunology, Lymphocyte Depletion, Mice, Mice, Inbred BALB C, Receptors, Antigen, T-Cell, gamma-delta biosynthesis, Respiratory Syncytial Virus Infections pathology, Respiratory Syncytial Virus Vaccines administration & dosage, Respiratory Syncytial Virus Vaccines adverse effects, Respiratory Syncytial Virus Vaccines immunology, Severity of Illness Index, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets pathology, T-Lymphocyte Subsets virology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic adverse effects, Vaccines, Synthetic immunology, Viral Fusion Proteins administration & dosage, Viral Fusion Proteins immunology, Virus Replication immunology, Inflammation Mediators physiology, Lung immunology, Lung pathology, Receptors, Antigen, T-Cell, gamma-delta physiology, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Viruses immunology, T-Lymphocyte Subsets immunology
- Abstract
Host defenses, while effecting viral clearance, contribute substantially to inflammation and disease. This double action is a substantial obstacle to the development of safe and effective vaccines against many agents, particularly respiratory syncytial virus (RSV). RSV is a common cold virus and the major cause of infantile bronchiolitis worldwide. The role of alphabeta T cells in RSV-driven immunopathology is well studied, but little is known about the role of "unconventional" T cells. During primary RSV challenge of BALB/c mice, some Vgamma7+ gammadelta T cells were present; however, immunization with a live vaccinia vector expressing RSV F protein substantially enhanced Vgamma4+ gammadelta T cell influx after RSV infection. Harvested early, these cells produced IFN-gamma, TNF, and RANTES after ex vivo stimulation. By contrast, those recruited 5 days after challenge made IL-4, IL-5, and IL-10. Depletion of gammadelta T cells in vivo reduced lung inflammation and disease severity and slightly increased peak viral replication but did not prevent viral clearance. These studies demonstrate a novel role for gammadelta T cells in the development of immunopathology and cellular influx into the lungs after immunization and RSV challenge. Though a minor population, gammadelta T cells have a critical influence on disease and are an attractive interventional target in the alleviation of viral lung disease.
- Published
- 2009
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228. Polylactide-co-glycolide (PLG) microparticles modify the immune response to DNA vaccination.
- Author
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Helson R, Olszewska W, Singh M, Megede JZ, Melero JA, O'Hagan D, and Openshaw PJ
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Eosinophils immunology, Female, Immunization, Secondary, Injections, Intramuscular, Interleukin-4 biosynthesis, Interleukin-5 biosynthesis, Leukocyte Count, Lung immunology, Lung metabolism, Mice, Mice, Inbred BALB C, Plasmids metabolism, Polyglycolic Acid, Polylactic Acid-Polyglycolic Acid Copolymer, Polymers, Respiratory Syncytial Virus Infections virology, Respiratory Syncytial Virus Vaccines administration & dosage, Respiratory Syncytial Viruses physiology, Vaccines, DNA administration & dosage, Vaccines, DNA immunology, Viral Fusion Proteins biosynthesis, Viral Fusion Proteins genetics, Virus Replication, Lactic Acid immunology, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Viruses immunology, Vaccination
- Abstract
Priming with the major surface glycoprotein G of respiratory syncytial virus (RSV) expressed by recombinant vaccinia leads to strong Th2 responses and lung eosinophilia during viral challenge. We now show that DNA vaccination in BALB/c mice with plasmids encoding G attenuated RSV replication but also enhanced disease with lung eosinophilia and increased IL-4/5 production. However, formulating the DNA with PLG microparticles reduced the severity of disease during RSV challenge without significantly lessening protection against viral replication. PLG formulation greatly reduced lung eosinophilia and prevented the induction of IL-4 and IL-5 during challenge, accompanied by a less marked CD4+ T cell response and a restoration of the CD8+ T cell recruitment seen during infection of non-vaccinated animals. After RSV challenge, lung eosinophilia was enhanced and prolonged in mice vaccinated with DNA encoding a secreted form of G; this effect was virtually prevented by PLG formulation. Therefore, PLG microparticulate formulation modifies the pattern of immune responses induced by DNA vaccination boosts CD8+ T cell priming and attenuates Th2 responses. We speculate that PLG microparticles affect antigen uptake and processing, thereby influencing the outcome of DNA vaccination.
- Published
- 2008
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229. RSV 2005: Global impact, changing concepts, and new challenges.
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Openshaw PJ, Tregoning J, and Harker J
- Subjects
- Aged, Antiviral Agents therapeutic use, Humans, Infant, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Virus Infections epidemiology, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Infections therapy, Respiratory Syncytial Viruses immunology, Respiratory Syncytial Viruses physiology
- Published
- 2005
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230. Antiviral immune responses and lung inflammation after respiratory syncytial virus infection.
- Author
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Openshaw PJ
- Subjects
- Animals, Humans, Immunity, Mucosal drug effects, Pneumonia, Viral drug therapy, Pneumonia, Viral immunology, Respiratory Syncytial Virus Vaccines therapeutic use, Immunity, Mucosal immunology, Pneumonia, Viral virology, Respiratory Syncytial Virus Infections complications, Respiratory Syncytial Virus Infections immunology
- Abstract
Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease coincides not with the peak of viral replication but with the development of specific T and B cell responses. This immune response is apparently responsible for much of the disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. The inflammatory host response to viral infection may be relevant not only to childhood bronchiolitis, but also to obstructive lung diseases in adults.
- Published
- 2005
- Full Text
- View/download PDF
231. Childhood infections, the developing immune system, and the origins of asthma.
- Author
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Openshaw PJ, Yamaguchi Y, and Tregoning JS
- Subjects
- Age Factors, Animals, Animals, Newborn immunology, Humans, Hygiene, Infant, Newborn, Th1 Cells immunology, Th2 Cells immunology, Asthma etiology, Immune System physiology, Respiratory Syncytial Virus Infections complications
- Abstract
Asthma is an immune-mediated inflammatory condition characterized by increased responsiveness to bronchoconstrictive stimuli. Viruses have been shown to play an important role in asthma, with viral infection being present during about 85% of exacerbations. However, the role they play in the onset of asthma is more controversial. Some respiratory viral infections might be protective, but there is a strong association between respiratory syncytial virus-induced bronchiolitis in infancy and recurrent wheeze up to 12 years of age. Both the respiratory tract and the immune system undergo rapid maturation during the first year of life, and it seems that postnatal development is affected by and affects responses to viral infections. Understanding postnatal developmental changes in the immune system might help to explain the origins and pathogenesis of asthma and thus the effectiveness or ineffectiveness of specific asthma therapies.
- Published
- 2004
- Full Text
- View/download PDF
232. Protective and disease-enhancing immune responses induced by recombinant modified vaccinia Ankara (MVA) expressing respiratory syncytial virus proteins.
- Author
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Olszewska W, Suezer Y, Sutter G, and Openshaw PJ
- Subjects
- Animals, Interferon-gamma genetics, Interleukin-2 genetics, Mice, Mice, Inbred BALB C, Respiratory Syncytial Virus Vaccines administration & dosage, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Virus, Human immunology, Vaccines, Inactivated administration & dosage, Vaccines, Inactivated adverse effects, Vaccines, Inactivated immunology, Vaccines, Synthetic immunology, Viral Proteins, Interferon-gamma immunology, Interleukin-2 immunology, Respiratory Syncytial Virus Vaccines adverse effects, T-Lymphocytes immunology, Vaccinia virus immunology
- Abstract
Modified vaccinia Ankara (MVA) recombinants expressing single or multiple RSV surface proteins (F or G) are promising potential vaccines. We studied humoral and cellular responses induced by MVA-F and MVA-G in mice, comparing them to a formalin inactivated RSV preparation (FI-RSV) known to increase disease severity. MVA-F or MVA-G vaccination enhanced weight loss during RSV challenge, but did not show the lung eosinophilia seen after FI-RSV vaccination. FI-RSV induced a stronger total RSV IgG response than the MVA recombinants, but very little IgG2a. MVA recombinants induced cytokine responses biased towards IFNgamma and IL-12, while FI-RSV induced strong IL-4/5 responses in the lungs during RSV challenge. Thus, MVA vaccines induce a favourable immune profile in RSV disease but retain the potential to enhance disease.
- Published
- 2004
- Full Text
- View/download PDF
233. Respiratory syncytial virus and other pneumoviruses: a review of the international symposium--RSV 2003.
- Author
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Schmidt AC, Johnson TR, Openshaw PJ, Braciale TJ, Falsey AR, Anderson LJ, Wertz GW, Groothuis JR, Prince GA, Melero JA, and Graham BS
- Subjects
- Animals, Humans, Respiratory Syncytial Viruses pathogenicity, Respirovirus pathogenicity, Respirovirus physiology, Respiratory Syncytial Viruses immunology, Respirovirus immunology, Viral Vaccines immunology
- Abstract
The Respiratory Syncytial Virus 2003 symposium took place from 8th-11th November 2003 in Stone Mountain, Georgia, and brought together more than 200 international investigators engaged in RSV research. RSV biology, pathogenesis, and clinical data, as well as RSV vaccines and antivirals, were addressed in the meeting, and this review will aim to briefly summarize and discuss the implications of new findings. The meeting also served as the inauguration of the Robert M. Chanock Award for lifetime achievement in RSV research, an award named in honor of the person who started the field of RSV research by recovering the first human RS virus from infants with severe bronchiolitis in 1956.
- Published
- 2004
- Full Text
- View/download PDF
234. Recombinant respiratory syncytial virus lacking secreted glycoprotein G is attenuated, non-pathogenic but induces protective immunity.
- Author
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Maher CF, Hussell T, Blair E, Ring CJ, and Openshaw PJ
- Subjects
- Animals, Cell Line, Chemokine CCL2 metabolism, Cricetinae, Humans, Immunity, Mucosal, Lung virology, Mice, Mice, Inbred BALB C, Recombination, Genetic, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Vaccines administration & dosage, Respiratory Syncytial Virus, Human genetics, Viral Proteins genetics, Viral Proteins metabolism, Virus Replication, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Virus, Human pathogenicity
- Abstract
Respiratory syncytial virus (RSV) causes intense pulmonary inflammatory responses in some infected infants. The surface attachment protein 'G' of RSV has membrane-bound and secreted forms and shows homology to the CX3C chemokine fractalkine. Using recombinant techniques, we generated replication-competent recombinant clonal RSV expressing normal G proteins ('rRSV') or only the membrane-bound form of G ('Gmem rRSV'). Both recombinants grew well in HEp-2 cells, but after primary intranasal infection in mice, pulmonary Gmem rRSV replication was reduced tenfold compared to parental or rRSV; moreover, CCL2 and CCL5 production was greatly reduced and no apparent disease or pulmonary cellular infiltration was observed. However, Gmem rRSV-infected mice developed good antibody responses and were fully protected against subsequent intranasal challenge with parental virus. Even in mice sensitized to G by cutaneous infection with recombinant vaccinia expressing G, intranasal challenge with Gmem rRSV caused insignificant disease. We conclude that secreted G is a key viral product assisting virus replication in vivo, enhancing CCL2 and CCL5 production and promoting illness. Engineered RSV mutants lacking the ability to secrete G are thus promising vaccine candidates.
- Published
- 2004
- Full Text
- View/download PDF
235. Vaccines for the prevention of respiratory viral infections: problems and current status.
- Author
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Olszewska W, Helson R, and Openshaw PJ
- Subjects
- Adenoviridae Infections immunology, Adenoviridae Infections prevention & control, Common Cold immunology, Common Cold prevention & control, Humans, Influenza, Human immunology, Influenza, Human prevention & control, Metapneumovirus immunology, Paramyxoviridae Infections immunology, Paramyxoviridae Infections prevention & control, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections prevention & control, Respiratory Tract Infections immunology, Severe Acute Respiratory Syndrome immunology, Severe Acute Respiratory Syndrome prevention & control, Virus Diseases immunology, Respiratory Tract Infections prevention & control, Viral Vaccines immunology, Virus Diseases prevention & control
- Abstract
Acute respiratory virus infections cause the majority of lower respiratory tract illnesses and hospitalisations of infants and the elderly. The emergence of new respiratory viruses and a high probability that influenza will cause further pandemics highlights the necessity for developing better preventative strategies. Although there is a clear and pressing need for vaccines to prevent respiratory syncytial virus, rhinoviruses, coronaviruses, parainfluenza and human metapneumovirus, progress has been extremely slow. This review presents the current status of vaccine development for respiratory viral diseases and outlines novel approaches for the future.
- Published
- 2004
- Full Text
- View/download PDF
236. Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood.
- Author
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Culley FJ, Pollott J, and Openshaw PJ
- Subjects
- Animals, Animals, Newborn, Base Sequence, DNA Primers, Mice, Mice, Inbred BALB C, Recurrence, Age Factors, Respiratory Syncytial Virus Infections immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Infants experiencing severe respiratory syncytial virus (RSV) bronchiolitis have an increased frequency of wheeze and asthma in later childhood. Since most severe RSV infections occur between the 8th and 24th postnatal week, we examined whether age at first infection determines the balance of cytokine production and lung pathology during subsequent rechallenge. Primary RSV infection in newborn mice followed the same viral kinetics as in adults but was associated with reduced and delayed IFN-gamma responses. To study rechallenge, mice were infected at 1 day or 1, 4, or 8 weeks of age and reinfected at 12 weeks. Neonatal priming produced more severe weight loss and increased inflammatory cell recruitment (including T helper 2 cells and eosinophils) during reinfection, whereas delayed priming led to enhanced interferon gamma production and less severe disease during reinfection. These results show the crucial importance of age at first infection in determining the outcome of reinfection and suggest that the environment of the neonatal lung is a major determinant of cytokine production and disease patterns in later life. Thus, simply delaying RSV infection beyond infancy might reduce subsequent respiratory morbidity in later childhood.
- Published
- 2002
- Full Text
- View/download PDF
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