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
to

291 results found

Culley F, Swieboda D, Guo Y, Thwaites R, Nadel S, Openshaw Pet al., 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

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

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, 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

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

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

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, 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

Openshaw P, Global disease burden estimates of respiratory syncytial virus associated with acute respiratory infections in older adults in 015: a systemic review and meta-analysis, Journal of Infectious Diseases, ISSN: 0022-1899

Respiratory syncytial virus associated acute respiratory infection (RSV-ARI)constitutes a substantial disease burden in older adults≥65 years. We aimed to identify all studies worldwide investigating the disease burden ofRSV-ARIin this population. We estimated thecommunityincidence, hospitalisationrate and in-hospital case fatality ratio (hCFR) of RSV-ARI in older adults stratified by industrialized anddeveloping regions, with data from a systematic review ofstudies published between January 1996 and April 2018, and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015, to calculate the global and regional burdenin older adults with RSV-ARIin community and in hospital duringthat year. We estimated thenumber ofin-hospital RSV-ARIdeaths by combining hCFR with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5million(95% CI 0.3-6.9) episodes of RSV-ARIin older adults in41industrialised countries (data missing in developing countries), and of these 214,000 (~14.5%; 95% CI 100,000-459,000) were admitted to hospitals. The global number of hospital admissionsforRSV-ARI in older adults was estimated at 336,000 (UR 186,000-614,000).We further estimated about 14,000 (UR 5,000-50,000) in-hospital deaths related to RSV-ARIglobally.The hospital admission rate and hCFR were higher for those ≥65 years than those aged 50-64 years. The disease burden of RSV-ARIamong older adults is substantialwith limited data from developing countries; appropriate prevention and management strategiesare needed to reduce this burden.

Journal article

Shi T, Arnott A, Semogas I, Falsey AR, Openshaw P, Wedzicha JA, Campbell H, Nair H, RESCEU Investigatorset al., 2019, The etiological role of common respiratory viruses in acute respiratory infections in older adults: a systematic review and meta-analysis, Journal of Infectious Diseases, ISSN: 0022-1899

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9-18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4-15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3-41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7-13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0-4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report.

Journal article

Shi T, Denouel A, Tietjen AK, Lee JW, Falsey AR, Demont C, Nyawanda BO, Cai B, Fuentes R, Stoszek SK, Openshaw P, Campbell H, Nair H, RESCEU Investigatorset al., 2019, Global and regional burden of hospital admissions for pneumonia in older adults: A systematic review and meta-analysis, Journal of Infectious Diseases, ISSN: 0022-1899

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8-8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9-1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact.

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

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, 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

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

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

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, 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

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

Sheerin D, Openshaw PJ, Pollard AJ, 2017, Issues in vaccinology: Present challenges and future directions., European Journal of Immunology, Vol: 47, Pages: 2017-2025, ISSN: 0014-2980

Vaccination is a principal and highly cost-effective means of controlling infectious diseases, providing direct protection against pathogens by conferring long-lasting immunological memory and inducing population-level herd immunity. Despite rapid ongoing progress in vaccinology, there remain many obstacles to the development and deployment of novel or improved vaccines; these include the underlying science of how to induce and sustain appropriate protective immune responses as well as bureaucratic, logistic and socio-political hurdles. The failure to distribute and administer existing vaccines to at-risk communities continues to account for a large proportion of infant mortality worldwide: almost 20 million children do not have access to basic vaccines and several million still die each year as a result. While emerging epidemic or pandemic diseases pose a significant threat to global health and prosperity, there are many infectious diseases which provide a continuous or cyclical burden on healthcare systems which also need to be addressed. Gaps in knowledge of the human immune system stand in the way of developing technologies to overcome individual and pathogenic variation. The challenges in tackling infectious disease and directions that the field of preventive medicine may take to improve the current picture of global health are the focus of this review.

Journal article

Marchant A, Sadarangani M, Garand M, Dauby N, Verhasselt V, Pereira L, Bjornson G, Jones CE, Halperin SA, Edwards KM, Heath P, Openshaw PJ, Scheifele DW, Kollmann TRet al., 2017, Maternal immunisation: collaborating with mother nature, Lancet Infectious Diseases, Vol: 17, Pages: E197-E208, ISSN: 1473-3099

Maternal immunisation has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. The success of tetanus, influenza, and pertussis immunisation during pregnancy has led to consideration of additional maternal immunisation strategies to prevent group B streptococcus and respiratory syncytial virus infections, among others. However, many gaps in knowledge regarding the immunobiology of maternal immunisation prevent the optimal design and application of this successful public health intervention. Therefore, we did an innovative landscape analysis to identify research priorities. Key topics were delineated through review of the published literature, consultation with vaccine developers and regulatory agencies, and a collaborative workshop that gathered experts across several maternal immunisation initiatives—group B streptococcus, respiratory syncytial virus, pertussis, and influenza. Finally, a global online survey prioritised the identified knowledge gaps on the basis of expert opinion about their importance and relevance. Here we present the results of this worldwide landscape analysis and discuss the identified research gaps.

Journal article

Heath PT, Culley FJ, Jones CE, Kampmann B, Le Doare K, Nunes MC, Sadarangani M, Chaudhry Z, Baker CJ, Openshaw PJMet al., 2017, Group B streptococcus and respiratory syncytial virus immunisation during pregnancy: a landscape analysis, Lancet Infectious Diseases, Vol: 17, Pages: e223-e234, ISSN: 1473-3099

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.

Journal article

Cole SL, Dunning J, Kok WL, Benam KH, Benlahrech A, Repapi E, Martinez FO, Drumright L, Powell TJ, Bennett M, Elderfield R, Thomas C, MOSAIC investigators, Dong T, McCauley J, Liew FY, Taylor S, Zambon M, Barclay W, Cerundolo V, Openshaw PJ, McMichael AJ, Ho LPet al., 2017, M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza., JCI Insight, Vol: 2, ISSN: 2379-3708

In each influenza season, a distinct group of young, otherwise healthy individuals with no risk factors succumbs to life-threatening infection. To better understand the cause for this, we analyzed a broad range of immune responses in blood from a unique cohort of patients, comprising previously healthy individuals hospitalized with and without respiratory failure during one influenza season, and infected with one specific influenza A strain. This analysis was compared with similarly hospitalized influenza patients with known risk factors (total of n = 60 patients recruited). We found a sustained increase in a specific subset of proinflammatory monocytes, with high TNF-α expression and an M1-like phenotype (independent of viral titers), in these previously healthy patients with severe disease. The relationship between M1-like monocytes and immunopathology was strengthened using murine models of influenza, in which severe infection generated using different models (including the high-pathogenicity H5N1 strain) was also accompanied by high levels of circulating M1-like monocytes. Additionally, a raised M1/M2 macrophage ratio in the lungs was observed. These studies identify a specific subtype of monocytes as a modifiable immunological determinant of disease severity in this subgroup of severely ill, previously healthy patients, offering potential novel therapeutic avenues.

Journal article

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