Imperial College London

Dr Peter Kelleher

Faculty of MedicineDepartment of Infectious Disease

Reader in Immunology
 
 
 
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Contact

 

+44 (0)20 3315 8251p.kelleher

 
 
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Location

 

J.2.10Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

Publication Type
Year
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157 results found

Smits B, Goldacker S, Seneviratne S, Malphettes M, Longhurst H, Mohamed OE, Witt-Rautenberg C, Leeman L, Schwaneck E, Raymond I, Meghit K, Uhlmann A, Winterhalter C, van Montfrans J, Klima M, Workman S, Fieschi C, Lorenza L, Boyle S, Onyango-Odera S, Price S, Schmalzing M, Aurillac V, Prasse A, Hartmann I, Meerburg JJ, Kemner-van de Corput M, Tiddens H, Grimbacher B, Kelleher P, Patel SY, Korganow A-S, Viallard JF, Tony HP, Bethune C, Schulze-Koops H, Witte T, Huissoon A, Baxendale H, Grigoriadou S, Oksenhendler E, Burns SO, Warnatz Ket al., 2022, The efficacy and safety of systemic corticosteroids as first line treatment for granulomatous lymphocytic interstitial lung disease., J Allergy Clin Immunol

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking. OBJECTIVE: We analyzed the effect of high-dose corticosteroids (≥0.3mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, pulmonary function test (PFT) results. METHODS: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n=56) and who underwent repeated HRCT scanning or PFT during the retrospective and/or prospective phase of the STILPAD study (n=39) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n=23). HRCT scans were blinded, randomized and scored using the Hartman score. Differences between the baseline and follow up HRCT scans and PFT were analyzed. RESULTS: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. 13/18 patients, for whom extended follow-up data was available, achieved a long-term, maintenance therapy independent remission. All patients with relapse were re-treated with corticosteroids, but only 1/5 responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts. CONCLUSION: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side-effects. Low dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.

Journal article

George PM, Reed A, Desai SR, Devaraj A, Faiez TS, Laverty S, Kanwal A, Esneau C, Liu MKC, Kamal F, Man WD-C, Kaul S, Singh S, Lamb G, Faizi FK, Schuliga M, Read J, Burgoyne T, Pinto AL, Micallef J, Bauwens E, Candiracci J, Bougoussa M, Herzog M, Raman L, Ahmetaj-Shala B, Turville S, Aggarwal A, Farne HA, Dalla Pria A, Aswani AD, Patella F, Borek WE, Mitchell JA, Bartlett NW, Dokal A, Xu X-N, Kelleher P, Shah A, Singanayagam Aet al., 2022, A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae., Science Translational Medicine, Vol: 14, Pages: 1-16, ISSN: 1946-6234

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Journal article

Thomson T, Prendecki M, Gleeson S, Martin P, Spensley K, De Aguiar RC, Sandhu B, Seneschall C, Gan J, Clarke CL, Lewis S, Pickard G, Thomas D, McAdoo SP, Lightstone L, Cox A, Kelleher P, Willicombe Met al., 2022, Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients, eClinicalMedicine, Vol: 53, Pages: 1-9, ISSN: 2589-5370

BackgroundSolid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population.MethodsWe undertook a single centre cohort study of 724 kidney transplant recipients prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their first dose of vaccine.Findings586/724 (80.9%) patients were infection-naïve post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001.Post-V4, 45/239 (18.8%) infection-naïve patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type.InterpretationA significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection. As such alternative strategies are required to provide protection to this vulnerable group.FundingMW/PK received study

Journal article

Martin P, Gleeson S, Clarke C, Thomson T, Edwards H, Spensley K, Mortimer P, Mcintyre S, cox A, Pickard G, Lightstone E, Thomas D, McAdoo S, kelleher P, Prendecki M, Willicombe Met al., 2022, Comparison of immunogenicity and clinical effectiveness between BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines in people with end-stage kidney disease receiving haemodialysis: a prospective, observational cohort study, The Lancet Regional Health Europe, Vol: 21, ISSN: 2666-7762

Background:People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical effectiveness of BNT162B2 versus ChAdOx1 in haemodialysis patients.Methods:In this observational cohort study, 1021 patients were followed-up from time of vaccination until December 2021. All patients underwent weekly RT-PCR screening. Patients were assessed for nucleocapsid(anti-NP) and spike(anti-S) antibodies at timepoints after second(V2) and third(V3) vaccinations. 191 patients were investigated for T-cell responses. Vaccine effectiveness (VE) for prevention of infection, hospitalisation and mortality was evaluated using the formula VE=(1-adjustedHR)x100.Findings:45.7% (467/1021) had evidence of prior infection. There was no difference in the proportion of infection-naïve patients who seroconverted by vaccine type, but median anti-S antibody titres were higher post-BNT162b2 compared with ChAdOx1; 462(152-1171) and 78(20-213) BAU/ml respectively, p<0.001. Concomitant immunosuppressant use was a risk factor for non-response, OR 0.12[95% CI 0.05–0.25] p<0.001. Post-V3 (all BNT162b2), median anti-S antibody titres remained higher in those receiving BNT162b2 versus ChAdOx1 as primary doses; 2756(187–1246) and 1250(439–2635) BAU/ml respectively, p=0.003.Anti-S antibodies waned over time. Hierarchical levels of anti-S post-V2 predicted risk of infection; patients with no/low anti-S being at highest risk. VE for preventing infection, hospitalisation and death was 53% (95% CI 6–75), 77% (95% CI 30–92) and 93% (95% CI 59–99) respectively, with no difference seen by vaccine type.Interpretation:Serum anti-S concentrations predict risk of breakthrough infection. Anti-S responses vary dependent upon clinical features, infection history and vaccine type. Monitoring of serological responses may enable individualised approaches

Journal article

Dixon PH, Levine AP, Cebola I, Chan MMY, Amin AS, Aich A, Mozere M, Maude H, Mitchell AL, Zhang J, NIHR BioResource, Genomics England Research Consortium Collaborators, Chambers J, Syngelaki A, Donnelly J, Cooley S, Geary M, Nicolaides K, Thorsell M, Hague WM, Estiu MC, Marschall H-U, Gale DP, Williamson Cet al., 2022, GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements, Nature Communications, Vol: 13, ISSN: 2041-1723

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1,138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.

Journal article

Harding D, Rosadas C, Tsoti S, Heslegrave A, Stewart M, Kelleher W, Zetterberg H, Taylor G, Dhasmana Det al., 2022, Refining the risk of HTLV-1-associated myelopathy in people living with HTLV-1: Identification of a HAM-like phenotype in a proportion of asymptomatic carriers, Journal of NeuroVirology, ISSN: 1355-0284

Background: Up to 3.8% of human T-lymphotropic virus type-1 (HTLV-1)-infected asymptomatic carriers (AC) eventually develop HTLV-1-associated myelopathy (HAM). HAM occurs in patients with high (>1%) HTLV proviral load (PVL). However, this cut-off includes more than 50% of ACs and therefore the risk needs to be refined. As HAM is additionally characterised by an inflammatory response to HTLV-1, markers of T cell activation (TCA), β 2 -microglobulin (β 2 M) and neuronal damage were accessed for the identification of ACs at high risk of HAM. Methods: Retrospective analysis ofcross-sectional and longitudinal routine clinical data examining differences in TCA (CD4/CD25, CD4/HLA-DR, CD8/CD25 & CD8/HLA-DR), β 2 M and neurofilament light (NfL) in plasma in ACs with high or low PVL and patients with HAM. Results: Comparison between 74 low PVL ACs, 84 high PVL ACs and 58 patients with HAM revealed a significant, stepwise, increase in TCA and β 2 M. Construction of receiver operating characteristic (ROC) curves for each of these blood tests generated a profile that correctly identifies 88% of patients with HAM along with 6% of ACs. The 10 ACs with this ‘HAM-like’ profile had increased levels of NfL in plasma and two developed myelopathy during follow-up, compared to none of the 148 without this viral-immune-phenotype. Conclusions: A viral-immuno-phenotype resembling that seen in patients with HAM identifies asymptomatic carriers who are at increased risk of developing HAM and have markers of subclinical neuronal damage.

Journal article

Gerovasili V, Shah A, Singanayagam A, George PM, Njafuh R, Prendecki M, Carby M, Willicombe M, Kelleher P, Reed Aet al., 2022, Impaired Humoral and Cellular Responses to COVID-19 Vaccine in Heart and Lung Transplant Recipients, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 1476-1479, ISSN: 1073-449X

Journal article

Clement A, Greer O, Saeed Z, Kelleher P, Johnson M, Alsaieedi A, Shah Net al., 2022, How does pregnancy affect the serological response to sars-cov-2 infection over time?, RCOG World Congress 2022, Publisher: WILEY, Pages: 69-70, ISSN: 1470-0328

Objective: The immune system of pregnant women undergoes several changes over the course of pregnancy. In the past, these changes have been associated with increased susceptibility to viral respiratory infections such as SARS-CoV-1 and influenza. Our primary objective was to investigate the differences in immune response to SARS-CoV-2 infection in pregnant women compared to non-pregnant women over time.Design: This was a prospective, laboratory-based longitudinal observational study of pregnant women who have been infected with SARS-CoV-2 to determine the effects of pregnancy on the serological response post infection compared to their matched non-pregnant women.Methods: Participants were recruited between September 2020 and June 2021 who all tested positive for SARS-CoV-2 infection using PCR or serology. Changes in the SARS-CoV-2-specific IgG titres were measured in blood samples that were collected from 51 pregnant and 52 non-pregnant women of reproductive age at approximately 7–14 days, 1-month (±7 days), 4 (±1 month), and 8 (±1 month) months post-infection, respectively. A chemiluminescent immunoassay was used to assess the IgG response to SARS-CoV-2 using serum from infected participants. Antibody levels to SARS-CoV-2 spike RBD (receptor binding domain) and nucleoprotein were measured as a relative light unit (RLU).Results: We found a reduction in seroconversion rate at 7–14 days post-infection in pregnant women compared to non-pregnant women with 63.33% compared to 100%, respectively. Longitudinal assessment highlighted a significant decline in anti-spike RBD IgG (20-fold reduction) at 151 days (or 5 months and 11 days; p < 0.05) in pregnant women versus 241 days (or 8 months and 17 days; p < 0.01) in non-pregnant women. This showed that the fall in antibody levels occurred 3 months earlier in pregnant individuals.Conclusions: The data in this study demonstrat

Conference paper

Spensley K, Gleeson S, Martin P, Thomson T, Clarke C, Pickard G, Thomas D, McAdoo S, Randell P, Kelleher P, Bedi R, Lightstone E, Prendecki M, Willicombe Met al., 2022, Comparison of vaccine effectiveness against the Omicron (B.1.1.529) variant in haemodialysis patients, Kidney International Reports, Vol: 7, Pages: 1406-1409, ISSN: 2468-0249

Journal article

Cann A, Clarke C, Brown J, Thomson T, Prendecki M, Moshe M, Badhan A, Simmons B, Klaber B, Elliott P, Darzi A, Riley S, Ashby D, Martin P, Gleeson S, Willicombe M, Kelleher P, Ward H, Barclay WS, Cooke GSet al., 2022, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow assay for antibody prevalence studies following vaccination: a diagnostic accuracy study [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 6, ISSN: 2398-502X

Background: Lateral flow immunoassays (LFIAs) are able to achieve affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Methods: This was a prospective diagnostic accuracy study. Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following two doses of SARS-CoV-2 vaccine, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination and subsequent follow up. During the participants visit, finger-prick blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG was detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. A total of 186 paired samples were collected. The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay Results: The LFIA had an estimated sensitivity of 92.0% (114/124; 95% confidence interval [CI] 85.7% to 96.1%) and specificity of 93.6% (58/62; 95% CI 84.3% to 98.2%) using the Abbott assay as reference standard (using the threshold for positivity of 7.10 BAU/ml) Conclusions: Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveillance but does not meet criteria for individual testing.

Journal article

Shah A, Hull J, Moffatt M, Cookson W, Kelleher W, Cuthbertson Let al., 2022, Evidence of immunometabolic dysregulation and airway dysbiosis in athletes susceptible to respiratory illness, EBioMedicine, Vol: 79, Pages: 1-16, ISSN: 2352-3964

BackgroundRespiratory tract infection (RTI) is a leading cause of training and in-competition time-loss in athlete health. The immune factors associated with RTI susceptibility remain unclear. In this study, we prospectively characterise host immune factors in elite athletes exhibiting RTI susceptibility.MethodsPeripheral blood lymphocyte flow cytometry phenotyping and 16S rRNA microbial sequencing of oropharyngeal swabs was performed in a prospective elite athlete cohort study (n = 121). Mass cytometry, peripheral blood mononuclear cell (PBMC) stimulation and plasma metabolic profiling was performed in age-matched highly-susceptible (HS) athletes (≥4RTI in last 18 months) (n = 22) compared to non-susceptible (NS) (≤1RTI in last 18 months) (n = 23) athletes. Findings were compared to non-athletic healthy controls (HC) (n = 19).FindingsAthletes (n = 121) had a reduced peripheral blood memory T regulatory cell compartment compared to HC (p = 0.02 (95%CI:0.1,1.0)) and reduced upper airway bacterial biomass compared to HC (p = 0.032, effect size r = 0.19). HS athletes (n = 22) had lower circulating memory T regulatory cells compared to NS (n = 23) athletes (p = 0.005 (95%CI:-1.5,-0.15)) and HC (p = 0.002 (95%CI:-1.9,-0.3) with PBMC microbial stimulation assays revealing a T-helper 2 skewed immune response compared to HC. Plasma metabolomic profiling showed differences in sphingolipid pathway metabolites (a class of lipids important in infection and inflammation regulation) in HS compared to NS athletes and HC, with sphingomyelin predictive of RTI infection susceptibility (p = 0.005).InterpretationAthletes susceptible to RTI have reduced circulating memory T regulatory cells, metabolic dysregulation of the sphingolipid pathway and evidence of upper airway bacterial dysbiosis.FundingThis study was funded by the English Institute of Sport (UK).

Journal article

Chanchlani N, Lin S, Chee D, Hamilton B, Nice R, Zehra A, Bewshea C, Cipriano B, Derikx LAAP, Dunlop A, Greathead L, Griffiths RL, Ibraheim H, Kelleher P, Kok KB, Lees CW, MacDonald J, Sebastian S, Smith PJ, McDonald TJ, Irving PM, Powell N, Kennedy NA, Goodhand JR, Ahmad Tet al., 2022, Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients., Journal of Crohns & Colitis, Vol: 16, Pages: 389-397, ISSN: 1873-9946

BACKGROUND AND AIMS: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-TNF level influences serological responses, remains unknown. METHODS: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11422 (53.3% (6084) male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between 29 th January and 30 th September 2020. Data were linked to nationally-held SARS-CoV-2 PCR results to 4 th May 2021. RESULTS: Rates of PCR confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% (178/5893), adalimumab: 3.0% (152/5074), vedolizumab: 6.7% (25/375), p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index (COI) (1.94 - 9.96) vs 5.02 (2.18 - 18.70), p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI (4.39 - 68.10, p< 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels (<0.8 mg/L) were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were anti-TNF treated. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% (12/152) patients after a median time of 183.5 days (129.8 - 235.3), without differences between drugs. CONCLUSION: Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels supports a causal relationship, although confounding factors, such as combination therapy with immunomodulator, may have

Journal article

Pallett SJC, Wake R, Youngs J, Pope C, Tan NK, Taylor J, Hawkins L, Witney AA, Laing KG, Monahan IM, Akay M, Cox A, Groppelli E, Kelleher P, Miller P, Bicanic Tet al., 2021, Adjunctive viral cell culture supports treatment decision-making in patients with secondary humoral immunodeficiency and persistent SARS-CoV-2 infection, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 196, Pages: 1170-1174, ISSN: 0007-1048

Journal article

Turner SEG, Hull JH, Jackson A, Loosemore M, Ranson C, Kelleher P, Shah Aet al., 2021, Screening Identifies Suboptimal Vaccination Protection in Illness-Susceptible Elite Athletes, CLINICAL JOURNAL OF SPORT MEDICINE, Vol: 31, Pages: E470-E472, ISSN: 1050-642X

Journal article

Cuthbertson L, Turner SEG, Jackson A, Ranson C, Loosemore M, Kelleher P, Cookson WOC, Moffatt MF, Hull JH, Shah Aet al., 2021, ELITE ATHLETES SUSCEPTIBLE TO RESPIRATORY TRACT INFECTION ARE CHARACTERISED BY REDUCED CIRCULATING MEMORY T REGULATORY CELLS, UPPER AIRWAY MICROBIAL DYSBIOSIS AND DYSREGULATION OF SPHINGOLIPID METABOLISM, Publisher: BMJ PUBLISHING GROUP, Pages: A61-A62, ISSN: 0040-6376

Conference paper

Prendecki M, Thomson T, Clarke CL, Martin P, Gleeson S, De Aguiar RC, Edwards H, Mortimer P, McIntyre S, Mokreri D, Cox A, Pickard G, Lightstone L, Thomas D, McAdoo SP, Kelleher P, Willicombe Met al., 2021, responses to SARS-CoV-2 vaccines in kidney transplant recipients, LANCET, Vol: 398, Pages: 1482-1484, ISSN: 0140-6736

Journal article

Periselneris J, Schelenz S, Loebinger M, Macedo P, Adhya Z, Armstrong-James D, Kelleher WPet al., 2021, Bronchiectasis severity correlates with outcome in patients with primary antibody deficiency, THORAX, Vol: 76, Pages: 1036-1039, ISSN: 0040-6376

Journal article

Prendecki M, Clarke C, Edwards H, McIntyre S, Mortimer P, Gleeson S, Martin P, Thomson T, Randell P, Shah A, Singanayagam A, Lightstone L, Cox A, Kelleher P, Willicombe M, McAdoo SPet al., 2021, Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression., Annals of the Rheumatic Diseases, Vol: 80, Pages: 1322-1329, ISSN: 0003-4967

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.

Journal article

Breathnach AS, Duncan CJA, El Bouzidi K, Hanrath AT, Payne BAI, Randell PA, Habibi MS, Riley PA, Planche TD, Busby JS, Sudhanva M, Pallett SJC, Kelleher WPet al., 2021, Prior COVID-19 protects against reinfection, even in the absence of detectable antibodies, JOURNAL OF INFECTION, Vol: 83, Pages: 239-241, ISSN: 0163-4453

Journal article

Kelleher P, 2021, The battle of testing in COVID-19: the secrets of victory against the virus, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: E101-E103, ISSN: 0008-6363

Journal article

Froneman C, Kelleher P, Jose RJ, 2021, Pneumococcal Vaccination in Immunocompromised Hosts: An Update, VACCINES, Vol: 9

Journal article

Clarke CL, Prendecki M, Dhutia A, Gan J, Edwards C, Prout V, Lightstone L, Parker E, Marchesin F, Griffith M, Charif R, Pickard G, Cox A, McClure M, Tedder R, Randell P, Greathead L, Guckian M, McAdoo SP, Kelleher P, Willicombe Met al., 2021, Longevity of SARS-CoV-2 immune responses in hemodialysis patients and protection against reinfection, Kidney International, Vol: 99, Pages: 1470-1477, ISSN: 0085-2538

Patients with end stage kidney disease receiving in-center hemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. Following infection, patients receiving ICHD frequently develop circulating antibodies to SARS-CoV-2, even with asymptomatic infection. Here, we investigated the durability and functionality of the immune responses to SARS-CoV-2 infection in patients receiving ICHD. Three hundred and fifty-six such patients were longitudinally screened for SARS-CoV-2 antibodies and underwent routine PCR-testing for symptomatic and asymptomatic infection. Patients were regularly screened for nucleocapsid protein (anti-NP) and receptor binding domain (anti-RBD) antibodies, and those who became seronegative at six months were screened for SARS-CoV-2 specific T-cell responses. One hundred and twenty-nine (36.2%) patients had detectable antibody to anti-NP at time zero, of whom 127 also had detectable anti-RBD. Significantly, at six months, 71/111 (64.0%) and 99/116 (85.3%) remained anti-NP and anti-RBD seropositive, respectively. For patients who retained antibody, both anti-NP and anti-RBD levels were reduced significantly after six months. Eleven patients who were anti-NP seropositive at time zero, had no detectable antibody at six months; of whom eight were found to have SARS-CoV-2 antigen specific T cell responses. Independent of antibody status at six months, patients with baseline positive SARS-CoV-2 serology were significantly less likely to have PCR confirmed infection over the following six months. Thus, patients receiving ICHD mount durable immune responses six months post SARS-CoV-2 infection, with fewer than 3% of patients showing no evidence of humoral or cellular immunity.

Journal article

Turner-Stokes T, Jiang E, Johnson N, Khakhria K, Kong E, Cairns T, Clarke C, Greathead L, Griffith M, Guckian M, Kelleher P, McClure MO, Prendecki M, Rosadas C, Tedder R, Lightstone L, Willicombe M, McAdoo SP, ICHNT Renal COVID-19 Groupet al., 2021, Serological screening for COVID-19 in patients with glomerular disease, Kidney International Reports, Vol: 6, Pages: 1402-1406, ISSN: 2468-0249

Journal article

Samri A, Chalouni M, Blanco J, Behrens G, Kelleher P, Massanella M, Ahmad F, Clotet B, Plettenberg A, Katlama C, Richert L, Raffi F, Thiebaut R, Autran Bet al., 2021, Influence of the Antiretroviral Regimen on the Early Changes in Plasma HIV RNA and Immune Activation at Initiation of Antiretroviral Therapy in Naive HIV-1-Infected Patients, JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, Vol: 86, Pages: e146-e149, ISSN: 1525-4135

Journal article

Prendecki M, Clarke C, Brown J, Cox A, Gleeson S, Guckian M, Randell P, Pria AD, Lightstone L, Xu X-N, Barclay W, McAdoo SP, Kelleher P, Willicombe Met al., 2021, Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine, The Lancet, Vol: 397, Pages: 1178-1181, ISSN: 0140-6736

Journal article

Turner SEG, Loosemore M, Shah A, Kelleher P, Hull JHet al., 2021, Salivary IgA as a potential biomarker in the evaluation of respiratory tract infection risk in athletes, Journal of Allergy and Clinical Immunology: In Practice, Vol: 9, Pages: 151-159, ISSN: 2213-2198

In recent years, there has been attention focused on the value of salivary IgA (sIgA) as a potential biomarker for the identification of athletes who may be at increased risk of developing respiratory tract infection (RTI). The utility of sIgA, in this context, is based on biological plausibility and several observational studies revealing an apparent association between sIgA and RTI susceptibility. The overall published evidence evaluating the value of sIgA in this context is however conflicting, and there is currently a lack of clear guidance as to whether this marker has a place in the health surveillance and care of athletes. In this review, we critically appraise the literature assessing the potential for sIgA to be used in this context, evaluating it against 4 key biomarker characteristics, including its (1) practicality, (2) reproducibility, (3) specificity/sensitivity, and (4) potential clinical impact and relevance. This process reveals that although there is an apparent association between respiratory illness and sIgA in many studies, with some promising results, overall there remains a paucity of evidence supporting its overall value in this context. Key deficiencies in the metrics employed to endorse a valid biomarker are apparent, including a lack of reproducibility and low specificity and sensitivity in the detection of RTI susceptibility. The review outlines these issues and makes future recommendations.

Journal article

Miguens Blanco J, Borghese F, McHugh N, Kelleher P, Sengupta R, Marchesi J, Abraham Set al., 2020, Longitudinal profiling of the gut microbiome in patients with psoriatic arthritis and ankylosing spondylitis: a multicentre, prospective, observational study, BMC Rheumatology, Vol: 4, Pages: 1-10, ISSN: 2520-1026

Background : Psoriasis is a chronic inflammatory disease of the skin affecting 2-3% ofUK population. 30% of people affected by psoriasis will develop a distinct form ofarthritis within 10 years of the skin condition onset. Although the pathogenesis ofpsoriatic arthritis is still unknown, there is a genetic predisposition triggered byenvironmental factors. Limited but convincing evidence link the gut microbiome topsoriatic arthritis. The Microbiome in Psoriatic ARThritis (Mi-PART) study propose is tocharacterise the microbiome-metabolic interface in patients affected by psoriaticarthritis to deepen our understanding of the pathogenesis of the disease.Methods : This is a multicentre, prospective, observational study. Psoriatic arthritis (n= 65) and ankylosing spondylitis (n = 30) patients will be recruited in addition to acontrol group of healthy volunteers (n = 30). Patients eligibility will be evaluated againstthe Criteria for Psoriatic Arthritis (CASPAR), the Bath Ankylosing Spondylitis ActivityIndex (BASDAI) and the healthy volunteers who fulfil study inclusion and exclusioncriteria.Information regarding their medical and medication history, demographics, diet andlifestyle will be collected. All the participants in the study will be asked to complete a 7-day food diary, to provide stool samples and to complete quality of life questionnaires.Routine clinical laboratory tests will be performed on blood and urine samples. Patientsand healthy volunteers with gastrointestinal symptoms, previous history of cancer,gastrointestinal surgery in the previous 6 months or alcohol abuse will be excludedfrom the study.Discussion : The aim of this trial is to characterise the microbiome of psoriatic arthritispatients and to compare it with microbiome of healthy volunteers and of patient withankylosing spondylitis in order to define if different rheumatologic conditions areassociated with characteristic microbiome profiles. Investigating the role of themicrobiome in the develop

Journal article

Prendecki M, Clarke C, Gleeson S, Greathead L, Santos E, McLean A, Randell P, Moore LSP, Mughal N, Guckian M, Kelleher P, Mcadoo SP, Willicombe Met al., 2020, Detection of SARS-CoV-2 antibodies in kidney transplant recipients., Journal of the American Society of Nephrology, Vol: 31, Pages: 1-8, ISSN: 1046-6673

Kidney transplant recipients and other patient groups receiving immunosuppression have a poor prognosis following presentation with symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.1 The immune response to SARS-CoV-2 in an immunocompromised population has not been systematically reported. Recognition that humoral immune responses against common viral infections are blunted in such patients has led to their exclusion from validation studies of serologic assays for SARS-CoV-2.2,3 In this study, we analyze the seroprevalence of SARS-CoV-2 antibodies in a transplant population. In order to ensure the accuracy of the seroprevalence rate, we also evaluate the performance of different serologic assays within this patient cohort.

Journal article

Lou H, Wojciak-Stothard B, Ruseva MM, Cook HT, Kelleher P, Pickering MC, Mongkolsapaya J, Screaton GR, Xu X-Net al., 2020, Autoantibody-dependent amplification of inflammation in SLE, Cell Death and Disease, Vol: 11, ISSN: 2041-4889

Anti-double stranded DNA antibodies (anti-dsDNA) are a hallmark of SLE but their role in disease pathogenesis is not fully resolved. Anti-dsDNA in serum are highly heterogeneous therefore in this study, we aimed to dissect the functional specificities of anti-dsDNA using a panel of human monoclonal antibodies (humAbs) generated from patients with active lupus nephritis. A total of 46 ANA reactive humAbs were isolated and divided into four broad classes based on their reactivity to histones, DNA and Crithidia. Functional analysis indicated that one subclass of antibodies bound strongly to decondensed DNA areas in neutrophil extracellular traps (NETs) and protected NETs from nuclease digestion, similar to the sera from active SLE patients. In addition, these anti-dsDNA antibodies could stimulate type I interferon responses in mononuclear phagocytic cells, or NF-kB activity in endothelial cells, by uptake of NETs-anti-NETs immune complexes and subsequently trigging inflammatory responses in an Fc-gamma receptor (Fcg-R)-dependant manner. Together our data suggest that only a subset of anti-dsDNA antibodies is capable to amplify inflammatory responses by deposit in the nephritic kidney in vivo, protecting NETs digestion as well as uptake of NETs immune complexes into Fcg-R-expressing cells in vitro.

Journal article

Turner S, Hull J, Jackson A, Ranson C, Kelleher P, Loosemore M, Shah Aet al., 2020, Evaluating salivary IgA levels as a biomarker for susceptibility to upper respiratory tract infection in elite athletes, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

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