Imperial College London

Peter Openshaw - Professor of Experimental Medicine

Faculty of MedicineNational Heart & Lung Institute

Senior Consul, Professor of Experimental Medicine
 
 
 
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Contact

 

+44 (0)20 7594 3854p.openshaw Website CV

 
 
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Assistant

 

Ms Gale Lewis +44 (0)20 7594 0944

 
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Location

 

353Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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326 results found

Guvenel A, Jozwik A, Ascough S, Ung SK, Paterson S, Kalyan M, Bergstrom E, Kar S, Habibi MS, Paras A, Zhu J, Park M, Dhariwal J, Almond M, Wong EHC, Sykes A, Del Rosario J, Trujillo-Torralbo M, Mallia P, Sidney J, Peters B, Kon OM, Sette A, Johnston SL, Openshaw PJ, Chiu Cet al., 2020, Epitope-specific airway-resident CD4+ T-cell dynamics during experimental human RSV infection, Journal of Clinical Investigation, Vol: 130, Pages: 523-538, ISSN: 0021-9738

Background: Respiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T-cells play a key role in antiviral immunity, but they have been little studied in the human lung. Methods: Healthy adult volunteers were inoculated intranasally with RSV A Memphis 37. CD4+ T-cells in blood and lower airway were analysed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding. Results: Activated CD4+ T-cell frequencies in bronchoalveolar lavage correlated strongly with local CXCL10 levels. Thirty-nine epitopes were identified, predominantly towards the 3’ end of the viral genome. Five novel MHC-II tetramers were made using an immunodominant F-EFY epitope restricted to HLA-DR4, -DR9 and -DR11 (combined allelic frequency: 15% in Europeans) and G- DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labelling revealed enrichment of resident memory CD4+ T-cells (TRM) cells in the lower airway; these TRM displayed progressive differentiation, down-regulation of co- stimulatory molecules and elevated CXCR3 expression as infection evolved. Conclusion: Human infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of TRM recognising novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines.

Journal article

Samanta R, Dunning J, Taylor A, Chilvers ER, Chambers RC, Openshaw PJ, Summers Cet al., 2020, Severe Respiratory Failure in Adult Influenza Infection Is Characterised by Mechanisms Relating to Pulmonary Endothelial Leak and Interferon Gamma Induced Translational Silencing, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Moore SC, Penrice-Randall R, Alruwaili M, Randle N, Armstrong S, Hartley C, Haldenby S, Dong X, Alrezaihi A, Almsaud M, Bentley E, Clark J, García-Dorival I, Gilmore P, Han X, Jones B, Luu L, Sharma P, Shawli G, Sun Y, Zhao Q, Pullan ST, Carter DP, Bewley K, Dunning J, Zhou E-M, Solomon T, Beadsworth M, Cruise J, Crook DW, Matthews DA, Davidson AD, Mahmood Z, Aljabr W, Druce J, Vipond R, Ng L, Renia L, Openshaw PJM, Baillie JK, Carroll MW, Stewart J, Darby A, Semple M, Turtle L, Hiscox JAet al., 2020, Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism, Viruses, Vol: 12, ISSN: 1999-4915

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Sequencing the viral genome as the outbreak progresses is important, particularly in the identification of emerging isolates with different pathogenic potential and to identify whether nucleotide changes in the genome will impair clinical diagnostic tools such as real-time PCR assays. Although single nucleotide polymorphisms and point mutations occur during the replication of coronaviruses, one of the biggest drivers in genetic change is recombination. This can manifest itself in insertions and/or deletions in the viral genome. Therefore, sequencing strategies that underpin molecular epidemiology and inform virus biology in patients should take these factors into account. A long amplicon/read length-based RT-PCR sequencing approach focused on the Oxford Nanopore MinION/GridION platforms was developed to identify and sequence the SARS-CoV-2 genome in samples from patients with or suspected of COVID-19. The protocol, termed Rapid Sequencing Long Amplicons (RSLAs) used random primers to generate cDNA from RNA purified from a sample from a patient, followed by single or multiplex PCRs to generate longer amplicons of the viral genome. The base protocol was used to identify SARS-CoV-2 in a variety of clinical samples and proved sensitive in identifying viral RNA in samples from patients that had been declared negative using other nucleic acid-based assays (false negative). Sequencing the amplicons revealed that a number of patients had a proportion of viral genomes with deletions.

Journal article

Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, Seth S, Egan C, Hardwick HE, Halpin S, Girvan M, Donohue C, Pritchard M, Patel LB, Ladhani S, Sigfrid L, Sinha IP, Olliaro PL, Nguyen-Van-Tam JS, Horby PW, Merson L, Carson G, Dunning J, Openshaw PJM, Baillie JK, Harrison EM, Docherty AB, Semple MGet al., 2020, Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study, BMJ, Vol: 370

Objective To characterise the clinical features of children and young people admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to coronavirus disease 2019 (covid-19) (MIS-C).Design Prospective observational cohort study with rapid data gathering and near real time analysis.Setting 260 hospitals in England, Wales, and Scotland between 17 January and 3 July 2020, with a minimum follow-up time of two weeks (to 17 July 2020).Participants 651 children and young people aged less than 19 years admitted to 138 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory confirmed SARS-CoV-2.Main outcome measures Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C.Results Median age was 4.6 (interquartile range 0.3-13.7) years, 35% (225/651) were under 12 months old, and 56% (367/650) were male. 57% (330/576) were white, 12% (67/576) South Asian, and 10% (56/576) black. 42% (276/651) had at least one recorded comorbidity. A systemic mucocutaneous-enteric cluster of symptoms was identified, which encompassed the symptoms for the WHO MIS-C criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month (odds ratio 3.21, 95% confidence interval 1.36 to 7.66; P=0.008), age 10-14 years (3.23, 1.55 to 6.99; P=0.002), and black ethnicity (2.82, 1.41 to 5.57; P=0.003). Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children

Journal article

Openshaw P, Thwaites R, 2019, The respiratory mucosa: Front and center in RSV disease, American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 1340-1342, ISSN: 1073-449X

Journal article

Swieboda D, Guo Y, Sagawe S, Thwaites RS, Nadel S, Openshaw PJM, Culley FJet al., 2019, OMIP-062: A 14-Color, 16-antibody panel for immunophenotyping human innate yymphoid, myeloid and T cells in small volumes of whole blood and pediatric airway samples, Cytometry Part A, Vol: 95, Pages: 1231-1235, ISSN: 1552-4949

This 14‐color, 16‐antibody OMIP was designed for enumeration of leukocyte responses in pediatric samples, where sample volumes and cell numbers can be very low. Leukocytes identified by this panel include all major members of the innate lymphoid cell (ILC) family (ILC1s, ILC2s, and ILC3s), natural killer cells (NK cells), granulocytes (neutrophils and eosinophils), T‐cells (CD4+ and CD8+), mucosal‐associated invariant T cells (MAIT cells) and NKT‐like cells. The protocol was optimized using small volumes of peripheral blood and validated in airway samples obtained from children (< 2 years of age) admitted to a pediatric intensive care unit (PICU). Given this backdrop, this OMIP is widely applicable to clinical research using low volume or paucicellular samples, such as studies of innate and adaptive immune responses in infants and children, with potential clinical application in diagnostics and monitoring of patients by pediatricians.

Journal article

Jha A, Dunning J, Tunstall T, Thwaites R, Hoang L, The MOSAIC Investigators, Kon OM, Zambon MC, Hansel TT, Openshaw Pet al., 2019, Patterns of systemic and local inflammation in patients with asthma hospitalised with influenza, European Respiratory Journal, Vol: 54, ISSN: 0903-1936

BackgroundPatients with asthma are at risk of hospitalisation with influenza, but the reasons for this predisposition are unknown.Study settingA prospective observational study of adults with PCR-confirmed influenza in 11 UK hospitals, measuring nasal, nasopharyngeal and systemic immune mediators and whole-blood gene expression.ResultsOf 133 admissions, 40 (30%) had previous asthma; these were more often female (70% vs 38.7%, OR 3.69, 95% CI 1.67 to 8.18, P = 0.0012), required less mechanical ventilation (15% vs 37.6%, χ2 6.78, P=0.0338) and had shorter hospital stays (mean 8.3 vs 15.3 d, P=0.0333) than those without. In patients without asthma, severe outcomes were more frequent in those given corticosteroids (OR=2.63, 95% CI=1.02-6.96, P=0.0466) or presenting >4 days after disease onset (OR 5.49, 95% CI 2.28–14.03, P=0.0002). Influenza vaccination in at-risk groups (including asthma) were lower than intended by national policy and the early use of antiviral medications were less than optimal. Mucosal immune responses were equivalent between groups. Those with asthma had higher serum IFN-α but lower serum TNF, IL-5, IL-6, CXCL8, CXCL9, IL-10, IL-17 and CCL2 levels (all P<0.05); both groups had similar serum IL-13, total IgE, periostin and blood eosinophil gene expression levels. Asthma diagnosis was unrelated to viral load, IFN-α, IFN-γ, IL-5 or IL-13 levels.ConclusionsAsthma is common in those hospitalised with influenza, but may not represent classical Type 2-driven disease. Those admitted with influenza tend to be female with mild serum inflammatory responses, increased serum IFN-α levels and good clinical outcomes.

Journal article

Culley F, Swieboda D, Guo Y, Thwaites R, Nadel S, Openshaw Pet al., 2019, 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, Cytometry Part A, ISSN: 1552-4949

Journal article

Coultas JA, Smyth R, Openshaw PJ, 2019, Respiratory syncytial virus (RSV): a scourge from infancy to old age, Thorax, Vol: 74, Pages: 986-993, ISSN: 0040-6376

Respiratory syncytial virus (RSV) is the most common single cause of respiratory hospitalisation of infants and is the second largest cause of lower respiratory infection mortality worldwide. In adults, RSV is an under-recognised cause of deterioration in health, particularly in frail elderly persons. Infection rates typically rise in late autumn and early winter causing bronchiolitis in infants, common colds in adults and insidious respiratory illness in the elderly. Virus detection methods optimised for use in children have low detection rate in adults, highlighting the need for better diagnostic tests. There are many vaccines under development, mostly based on the surface glycoprotein F which exists in two conformations (prefusion and postfusion). Much of the neutralising antibody appears to be to the prefusion form. Vaccines being developed include live attenuated, subunit, particle based and live vectored agents. Different vaccine strategies may be appropriate for different target populations: at-risk infants, school-age children, adult caregivers and the elderly. Antiviral drugs are in clinical trial and may find a place in disease management. RSV disease is one of the major remaining common tractable challenges in infectious diseases and the era of vaccines and antivirals for RSV is on the near horizon.

Journal article

Ascough S, Vlachantoni I, Kalyan M, Haijema B-J, Wallin-Weber S, Dijkstra-Tiekstra M, Ahmed MS, van Roosmalen M, Grimaldi R, Zhang Q, Leenhouts K, Openshaw PJ, Chiu Cet al., 2019, Local and systemic immunity against RSV induced by a novel intranasal vaccine: A randomised, double- blind, placebo-controlled trial, American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 481-492, ISSN: 1073-449X

RATIONALE: Needle-free intranasal vaccines offer major potential advantages, especially against pathogens entering via mucosal surfaces. As yet, there is no effective vaccine against respiratory syncytial virus (RSV), a ubiquitous pathogen of global importance that preferentially infects respiratory epithelial cells; new strategies are urgently required. OBJECTIVES: Here, we report the safety and immunogenicity of a novel mucosal RSV F protein vaccine linked to an immunostimulatory bacterium-like particle (BLP). METHODS: In this phase I, randomised, double-blind placebo-controlled trial, 48 healthy volunteers aged 18-49 years were randomly assigned to receive placebo or SynGEM (low- or high-dose) intranasally by prime-boost administration. The primary outcome was safety and tolerability, with secondary objectives assessing virus-specific immunogenicity. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in adverse events between placebo and vaccinated groups. SynGEM induced systemic plasmablast responses and significant, durable increases in RSV-specific serum antibody in healthy seropositive adults. Volunteers given low-dose SynGEM (140 µg F, 2mg BLP) required a boost at day 28 to achieve plateau responses with a maximum fold-change of 2.4, whereas high-dose recipients (350 µg F, 5mg BLP) achieved plateau responses with a fold-change of 1.5 after first vaccination that remained elevated up to 180 days post-vaccination irrespective of further boosting. Palivizumab-like antibodies were consistently induced, but F protein site Ø-specific antibodies were not detected and virus-specific nasal IgA responses were heterogeneous, with strongest responses in individuals with lower pre-existing antibody levels. CONCLUSIONS: SynGEM is thus the first non-replicating intranasal RSV subunit vaccine to induce persistent antibody responses in human volunteers. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02958540.

Journal article

Li Y, Reeves RM, Wang X, Bassat Q, Brooks WA, Cohen C, Moore DP, Nunes M, Rath B, Campbell H, Nair H, Acacio S, Alonso WJ, Antonio M, Ayora Talavera G, Badarch D, Baillie VL, Barrera-Badillo G, Bigogo G, Broor S, Bruden D, Buchy P, Byass P, Chipeta J, Clara W, Dang D-A, de Freitas Lazaro Emediato CC, de Jong M, Diaz-Quinonez JA, Do LAH, Fasce RA, Feng L, Ferson MJ, Gentile A, Gessner BD, Goswami D, Goyet S, Grijalva CG, Halasa N, Hellferscee O, Hessong D, Homaira N, Jara J, Kahn K, Khuri-Bulos N, Kotloff KL, Lanata CF, Lopez O, Lopez Bolanos MR, Lucero MG, Lucion F, Lupisan SP, Madhi SA, McCracken JP, Mekgoe O, Moraleda C, Moyes J, Mulholland K, Munywoki PK, Naby F, Thanh HN, Nicol MP, Nokes DJ, Noyola DE, Onozuka D, Palani N, Poovorawan Y, Rahman M, Ramaekers K, Romero C, Schlaudecker EP, Schweiger B, Seidenberg P, Simoes EAF, Singleton R, Sistla S, Sturm-Ramirez K, Suntronwong N, Sutanto A, Tapia MD, Thamthitiwat S, Thongpan I, Tillekeratne G, Tinoco YO, Treurnicht FK, Turner C, Turner P, van Doorn R, Van Ranst M, Visseaux B, Waicharoen S, Wang J, Yoshida L-M, Zar HJ, Shi T, Zhang S, Openshaw P, Wedzicha J, Falsey A, Miller M, Beutels P, Bont L, Pollard A, Molero E, Martinon-Torres F, Heikkinen T, Meijer A, Fischer TK, van den Berge M, Giaquinto C, Mikolajczyk R, Hackett J, Dillon L, Tafesse E, Cai B, Knirsch C, Lopez AG, Dieussaert I, Dermateau N, Leach A, Stoszek SK, Gallichan S, Kieffer A, Demont C, Denouel A, Cheret A, Gavart S, Aerssens J, Wyffels V, Cleenewerck M, Fuentes R, Rosen Bet al., 2019, Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis, LANCET GLOBAL HEALTH, Vol: 7, Pages: E1031-E1045, ISSN: 2214-109X

Journal article

Nauwelaers I, Talts T, Galiano M, Openshaw Pet al., 2019, Deep sequencing of respiratory syncytial virus links viral diversity to disease severity, Publisher: OXFORD UNIV PRESS, Pages: S13-S13

Conference paper

Progatzky F, Jha A, Wane M, Thwaites RS, Makris S, Shattock RJ, Johansson C, Openshaw PJ, Bugeon L, Hansel TT, Dallman MJet al., 2019, Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice and humans, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 342-345.e7, ISSN: 0091-6749

We compared live zebrafish, mouse and human nasal challenge responses to the TLR7/8 agonist resiquimod (R848). We found remarkably similar induction of mediators in the three species, offering novel mucosal models of innate anti-viral immunity.

Journal article

Singhania A, Graham CM, Gabrysova L, Moreira-Teixeira L, Stavropoulos E, Pitt JM, Chakravarty P, Warnatsch A, Branchett WJ, Conejero L, Lin J-W, Davidson S, Wilson MS, Bancroft G, Langhorne J, Frickel E, Sesay AK, Priestnall SL, Herbert E, Ioannou M, Wang Q, Humphreys IR, Dodd J, Openshaw PJM, Mayer-Barber KD, Jankovic D, Sher A, Lloyd CM, Baldwin N, Chaussabel D, Papayannopoulos V, Wack A, Banchereau JF, Pascual VM, O'Garra Aet al., 2019, Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases, Nature Communications, Vol: 10, ISSN: 2041-1723

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4+ effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.

Journal article

Jha A, Thwaites R, Tunstall T, Kon OM, Shattock R, Openshaw P, Hansel Tet al., 2019, Enhanced in vivo vivo mucosal interferon and chemokine responses to a single stranded RNA analogue (R848) in participants with asthma, ERJ Open Research, Vol: 5, ISSN: 2312-0541

Background: Viruses play an important role in asthma exacerbations and are detected by Toll-like receptors (TLRs). Better characterization of mucosal innate immunity to viral triggers may help understand dysregulated host responses in asthma.Aims & Objectives: A synthetic analogue of single-stranded RNA (ssRNA) and TLR7/8 agonist resiquimod (R848) was administered in vivo to study the effect of allergy and asthma on nasal mucosal innate immune responses.Methods: Nasal spray with saline and R848 was administered to healthy non-allergic (n=12), allergic rhinitis (n=12) and allergic asthma (n=11) participants. Immune mediators from nasal and blood samples, nasal mucosal gene expression and peripheral differential cell counts were measured.Results: R848 was well tolerated with no evidence of systemic immune activation. R848 significantly induced nasal mucosal IFN-a2a, IFN-?, pro-inflammatory cytokines (TNF-a, IL-2, IL-12p70) and chemokines (CXCL10, CCL2, CCL3, CCL4 and CCL13) compared to saline. Participants with allergic rhinitis and asthma had increased IFN-a2a, CCL3 and CCL13 relative to healthy participants, whilst those with asthma alone had increased gene expression of interferon stimulated genes DDX58, MX1 and IFIT3. Nasal R848 administration was associated with a decrease in blood eosinophils at 4h and decrease in peripheral lymphocytes at 24h, a finding restricted to participants with allergic rhinitis and asthma.Conclusions: These results confirm the suitability of nasal delivery of R848 as a non-invasive tool to assess mucosal innate immunity and highlights a key role for asthma in determining host responses to viral RNA analogues.

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, MOSAIC Investigators, Moffatt MF, O'Garra A, Openshaw PJMet al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908

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.

Journal article

Wiseman DJ, Kamal F, Finney L, Ritchie AI, Gent J, Edwards MR, Johnston SL, Donaldson GC, Openshaw PJ, Wedzicha JAet al., 2019, Respiratory Syncytial Virus (RSV) Detection Is Associated with an Increased Inflammatory Response in Stable (non-Exacerbating) Chronic Obstructive Pulmonary Disease (COPD) Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Helbig C, Williamson C, Fundberg J, Openshaw PJM, Fogdell-Hahn Aet al., 2018, Men and women in immunology: Closing the gap on gender parity?, European Journal of Immunology, Vol: 48, Pages: 1776-1779, ISSN: 0014-2980

Journal article

Mazur NI, Higgins D, Nunes MC, Melero JA, Langedijk AC, Horsley N, Buchholz UJ, Openshaw PJ, McLellan JS, Englund JA, Mejias A, Karron RA, Simões EA, Knezevic I, Ramilo O, Piedra PA, Chu HY, Falsey AR, Nair H, Kragten-Tabatabaie L, Greenough A, Baraldi E, Papadopoulos NG, Vekemans J, Polack FP, Powell M, Satav A, Walsh EE, Stein RT, Graham BS, Bont LJ, Respiratory Syncytial Virus Network ReSViNET Foundationet al., 2018, The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates, Lancet Infectious Diseases, Vol: 18, Pages: e295-e311, ISSN: 1473-3099

The global burden of disease caused by respiratory syncytial virus (RSV) is increasingly recognised, not only in infants, but also in older adults (aged ≥65 years). Advances in knowledge of the structural biology of the RSV surface fusion glycoprotein have revolutionised RSV vaccine development by providing a new target for preventive interventions. The RSV vaccine landscape has rapidly expanded to include 19 vaccine candidates and monoclonal antibodies (mAbs) in clinical trials, reflecting the urgency of reducing this global health problem and hence the prioritisation of RSV vaccine development. The candidates include mAbs and vaccines using four approaches: (1) particle-based, (2) live-attenuated or chimeric, (3) subunit, (4) vector-based. Late-phase RSV vaccine trial failures highlight gaps in knowledge regarding immunological protection and provide lessons for future development. In this Review, we highlight promising new approaches for RSV vaccine design and provide a comprehensive overview of RSV vaccine candidates and mAbs in clinical development to prevent one of the most common and severe infectious diseases in young children and older adults worldwide.

Journal article

Swieboda D, Thwaites R, Nadel S, Hansel T, Openshaw P, Culley Fet al., 2018, The role of innate lymphoid cells in early life lung infection, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Barclay W, Openshaw P, 2018, The 1918 Influenza Pandemic: one hundred years of progress, but where now?, Lancet Respiratory Medicine, Vol: 6, ISSN: 2213-2600

Journal article

Schwarze J, Openshaw P, Jha A, Del Giacco SR, Firinu D, Tsilochristou O, Roberts G, Selby A, Akdis C, Agache I, Custovic A, Heffler E, Pinna G, Khaitov M, Nikonova A, Papadopoulos N, Akhlaq A, Nurmatov U, Renz H, Sheikh A, Skevaki Cet al., 2018, Influenza burden, prevention and treatment in asthma - a scoping review by the EAACI Influenza in Asthma Task Force, Allergy, Vol: 73, Pages: 1151-1181, ISSN: 0105-4538

To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma. This article is protected by copyright. All rights reserved.

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, OGarra A, Openshaw PJMet al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, Vol: 19, Pages: 625-635, ISSN: 1529-2916

Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.

Journal article

Thwaites RS, Gunawardana NC, Broich V, Mann EH, Ahnström J, Campbell GA, Lindsley S, Singh N, Tunstall T, Lane DA, Openshaw PJ, Hawrylowicz CM, Hansel TTet al., 2018, Biphasic activation of complement and fibrinolysis during the human nasal allergic response, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1892-1895.e6, ISSN: 0091-6749

Complement, coagulation and fibrinolysis contribute to the pathology of many respiratory diseases. Here we detail the biphasic activation of these pathways following nasal allergen challenge. Understanding these mechanisms may lead to therapeutic insight in common respiratory diseases.

Journal article

Thwaites RS, Coates M, Ito K, Ghazaly M, Feather C, Abdulla F, Tunstall T, Jain P, Cass L, Rapeport G, Hansel TT, Nadel S, Openshaw PJet al., 2018, Reduced nasal viral load and IFN responses in infants with RSV bronchiolitis and respiratory failure, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 1074-1084, ISSN: 1073-449X

RATIONALE: Respiratory syncytial virus (RSV) bronchiolitis is a major cause of morbidity and mortality in infancy. Severe disease is thought to result from uncontrolled viral replication, an excessive immune response, or both. OBJECTIVES: To determine RSV load and immune mediator levels in nasal mucosal lining fluid by serial sampling of nasal fluids from cases of moderate and severe bronchiolitis over the course of infection. METHODS: Infants with viral bronchiolitis necessitating admission (n=55) were recruited from a paediatric centre during 2016/17. Of these, 30 were RSV infected (18 'moderate', and 12 mechanically ventilated 'severe'). Nasal fluids were sampled frequently over time using nasosorption devices and nasophayngeal aspiration (NPA). Hierarchical clustering of time weighted averages (TWA) was performed to investigate cytokine and chemokine levels, and gene expression profiling was conducted. MEASUREMENTS AND MAIN RESULTS: Unexpectedly, cases of severe RSV bronchiolitis had lower nasal viral loads and reduced interferon (IFN)-γ and CCL5/RANTES levels compared to those with moderate disease, especially when allowance was made for disease duration (all P<0.05). Reduced cytokine/chemokine levels in severe disease were also seen in children with other viral infections. Gene expression analysis of NPA samples (n=43) confirmed reduced type-I IFN gene expression in severe bronchiolitis accompanied by enhanced expression of MUC5AC and IL17A. CONCLUSIONS: Infants with severe RSV bronchiolitis have lower nasal viral load, IP-10/CXCL10 and type-I IFNs levels compared to moderately ill children, but enhanced MUC5AC and IL17A gene expression in nasal cells.

Journal article

Thwaites RS, Jarvis HC, Singh N, Jha A, Pritchard A, Fan H, Tunstall T, Nanan J, Nadel S, Kon OM, Openshaw PJ, Hansel TTet al., 2018, Absorption of nasal and bronchial fluids: precision sampling of the human respiratory mucosa and laboratory processing of samples, Jove-Journal of Visualized Experiments, Vol: 131, ISSN: 1940-087X

The methods of nasal absorption (NA) and bronchial absorption (BA) use synthetic absorptive matrices (SAM) to absorb the mucosal lining fluid (MLF) of the human respiratory tract. NA is a non-invasive technique which absorbs fluid from the inferior turbinate, and causes minimal discomfort. NA has yielded reproducible results with the ability to frequently repeat sampling of the upper airway. By comparison, alternative methods of sampling the respiratory mucosa, such as nasopharyngeal aspiration (NPA) and conventional swabbing, are more invasive and may result in greater data variability. Other methods have limitations, for instance, biopsies and bronchial procedures are invasive, sputum contains many dead and dying cells and requires liquefaction, exhaled breath condensate (EBC) contains water and saliva, and lavage samples are dilute and variable. BA can be performed through the working channel of a bronchoscope in clinic. Sampling is well tolerated and can be conducted at multiple sites in the airway. BA results in MLF samples being less dilute than bronchoalveolar lavage (BAL) samples. This article demonstrates the techniques of NA and BA, as well as the laboratory processing of the resulting samples, which can be tailored to the desired downstream biomarker being measured. These absorption techniques are useful alternatives to the conventional sampling techniques used in clinical respiratory research.

Journal article

Petrarca L, Midulla F, Openshaw PJ, 2018, Vaccination policies in Europe: Common goals, diverse approaches and public doubts., European Journal of Immunology, Vol: 48, Pages: 10-12, ISSN: 0014-2980

Journal article

Jha A, Thwaites RS, Tunstall T, Kon OM, Shattock RJ, Openshaw PJ, Hansel TTet al., 2018, Human Nasal Challenge with TLR7/8 Agonist Resiquimod (R848) Induces Mucosal Interferon-alpha, with Increased Responsiveness in Asthmatic Volunteers, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Vlachantoni I, Ascough S, Grimaldi R, Leenhouts K, Chiu C, Openshaw Pet al., 2017, PHASE 1 TRIAL OF AN INTRANASAL RESPIRATORY SYNCYTIAL VIRUS (RSV) SUBUNIT CANDIDATE VACCINE: SAFETY RESULTS FROM THE MUC-SYNGEM STUDY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A43-A44, ISSN: 0040-6376

Conference paper

Tripp RA, Power UF, Openshaw PJM, Kauvar LMet al., 2017, Respiratory Syncytial Virus (RSV): Targeting the G Protein Provides a New Approach for an Old Problem., Journal of Virology, Vol: 92, ISSN: 1098-5514

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the US <5 years old. In the elderly (>65 years old), RSV results in ∼175,000 hospitalizations annually in the US with worldwide incidence ∼34 million. There is no approved RSV vaccine and treatments are limited. Recently, a Phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely prevention of moderate-to-severe RSV-associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent Phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in pre-term infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (mAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has re-emerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human mAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This mAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab.

Journal article

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