Imperial College London

PROFESSOR AJIT LALVANI

Faculty of MedicineNational Heart & Lung Institute

Chair in Infectious Diseases
 
 
 
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Contact

 

+44 (0)20 7594 0883a.lalvani

 
 
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Assistant

 

Ms Gale Lewis +44 (0)20 7594 0944

 
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Location

 

Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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257 results found

Kundu R, Sam Narean J, Wang L, Fenn J, Pillay T, Derqui N, Conibear E, Koycheva A, Davies M, Tolosa-Wright M, Hakki S, Varro R, McDermott E, Hammett S, Cutajar J, Thwaites R, Parker E, Rosados C, McClure M, Tedder R, Taylor G, Dunning J, Lalvani Aet al., 2022, Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts, Nature Communications, ISSN: 2041-1723

Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p=0.0139), and nucleocapsid-specific (p=0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n=26), when compared with those who convert to PCR-positive (n=26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.

Journal article

Lalvani A, Hakki S, Singanayagam A, Dunning J, Barnett JL, Crone MA, Freemont PS, Ferguson NMet al., 2022, Transmissibility of SARS-CoV-2 among fully vaccinated individuals - Authors' reply., Lancet Infect Dis, Vol: 22, Pages: 18-19

Journal article

Houston H, Hakki S, Pillay TD, Madon K, Derqui-Fernandez N, Koycheva A, Singanayagam A, Fenn J, Kundu R, Conibear E, Varro R, Cutajar J, Quinn V, Wang L, Narean JS, Tolosa-Wright MR, Barnett J, Kon OM, Tedder R, Taylor G, Zambon M, Ferguson N, Dunning J, Deeks JJ, Lalvani Aet al., 2021, Broadening symptom criteria improves early case identification in SARS-CoV-2 contacts., Eur Respir J

INTRODUCTION: The success of case isolation and contact tracing for the control of SARS-CoV-2 transmission depends on the accuracy and speed of case identification. We assessed whether inclusion of additional symptoms alongside three canonical symptoms (CS) - fever; cough; loss or change in smell or taste - could improve case definitions and accelerate case identification in SARS-CoV-2 contacts. METHODS: Two prospective longitudinal London-based cohorts of community SARS-CoV-2 contacts, recruited within 5 days of exposure, provided independent training and test datasets. Infected and uninfected contacts completed daily symptom diaries from the earliest possible time-points. Diagnostic information gained by adding symptoms to the CS was quantified using likelihood ratios and AUC-ROC. Improvements in sensitivity and time-to-detection were compared to penalties in terms of specificity and number-needed-to-test. RESULTS: Of 529 contacts within two cohorts, 164 (31%) developed PCR-confirmed infection and 365 (69%) remained uninfected. In the training dataset (n=168), 29% of infected contacts did not report the CS. Four symptoms (sore throat, muscle aches, headache and appetite loss) were identified as early-predictors (EP) which added diagnostic value to the CS. The broadened symptom criterion "≥1 of the CS, or ≥2 of the EP" identified PCR-positive contacts in the test dataset on average 2 days earlier after exposure (p=0.07) than "≥1 of the CS", with only modest reduction in specificity (5.7%). CONCLUSIONS: Broadening symptom criteria to include individuals with at least 2 of muscle aches, headache, appetite loss and sore throat identifies more infections and reduces time-to-detection, providing greater opportunities to prevent SARS-CoV-2 transmission.

Journal article

Singanayagam A, Hakki S, Dunning J, Madon KJ, Crone MA, Koycheva A, Derqui-Fernandez N, Barnett JL, Whitfield MG, Varro R, Charlett A, Kundu R, Fenn J, Cutajar J, Quinn V, Conibear E, Barclay W, Freemont PS, Taylor GP, Ahmad S, Zambon M, Ferguson NM, Lalvani A, Badhan A, Dustan S, Tejpal C, Ketkar AV, Narean JS, Hammett S, McDermott E, Pillay T, Houston H, Luca C, Samuel J, Bremang S, Evetts S, Poh J, Anderson C, Jackson D, Miah S, Ellis J, Lackenby Aet al., 2021, Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study, The Lancet Infectious Diseases, ISSN: 1473-3099

BackgroundThe SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community.MethodsBetween Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status.FindingsThe SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for unin

Journal article

Sgalla G, Iovene B, Bruni T, Flore MC, Porro LM, Lalvani A, Richeldi Let al., 2021, Telemedicine-enabled, Hotel-based Management of Patients with COVID-19: A Single-Center Feasibility Study, ANNALS OF THE AMERICAN THORACIC SOCIETY, Vol: 18, Pages: 1743-1746, ISSN: 1546-3222

Journal article

Halliday A, Masonou T, Tolosa-Wright MR, Guo Y, Hoang L, Parker R, Boakye A, Takwoingi Y, Badhan A, Jain P, Marwah I, Berrocal-Almanza LC, Deeks J, Beverley P, Kon OM, Lalvani Aet al., 2021, Defining the role of cellular immune signatures in diagnostic evaluation of suspected tuberculosis, Journal of Infectious Diseases, ISSN: 0022-1899

BACKGROUND: Diagnosis of paucibacillary tuberculosis (TB) including extrapulmonary TB is a significant challenge, particularly in high-income, low-incidence settings. Measurement of Mycobacterium tuberculosis (Mtb)-specific cellular immune signatures by flow cytometry discriminates active TB from latent TB infection (LTBI) in case-control studies; however, their diagnostic accuracy and clinical utility in routine clinical practice is unknown. METHODS: Using a nested case-control study design within a prospective multicenter cohort of patients presenting with suspected TB in England, we assessed diagnostic accuracy of signatures in 134 patients who tested interferon-gamma release assay (IGRA)-positive and had final diagnoses of TB or non-TB diseases with coincident LTBI. Cellular signatures were measured using flow cytometry. RESULTS: All signatures performed less well than previously reported. Only signatures incorporating measurement of phenotypic markers on functional Mtb-specific CD4 T cells discriminated active TB from non-TB diseases with LTBI. The signatures measuring HLA-DR+IFNγ + CD4 T cells and CD45RA-CCR7-CD127- IFNγ -IL-2-TNFα + CD4 T cells performed best with 95% positive predictive value (95% confidence interval, 90-97) in the clinically challenging subpopulation of IGRA-positive but acid-fast bacillus (AFB) smear-negative TB suspects. CONCLUSIONS: Two cellular immune signatures could improve and accelerate diagnosis in the challenging group of patients who are IGRA-positive, AFB smear-negative, and have paucibacillary TB.

Journal article

Lalvani A, Fenn J, Pillay TD, 2021, Probing the in-vivo reservoir of latent tuberculosis infection, LANCET MICROBE, Vol: 2, Pages: E226-E227, ISSN: 2666-5247

Journal article

Kondratiuk AL, Pillay TD, Kon OM, Lalvani Aet al., 2021, A conceptual framework to accelerate the clinical impact of evolving research into long COVID, LANCET INFECTIOUS DISEASES, Vol: 21, Pages: 756-757, ISSN: 1473-3099

Journal article

Halliday A, Jain P, Hoang L, Parker R, Tolosa-Wright M, Masonou T, Green N, Boakye A, Takwoingi Y, Hamilton S, Mandagere V, Fries A, Coin L, Deeks J, White PJ, Levin M, Beverley P, Kon OM, Lalvani Aet al., 2021, New technologies for diagnosing active TB: the VANTDET diagnostic accuracy study, Efficacy and Mechanism Evaluation, Vol: 8, Pages: 1-160, ISSN: 2050-4365

<jats:sec id="abs1-1"> <jats:title>Background</jats:title> <jats:p>Tuberculosis (TB) is a devastating disease for which new diagnostic tests are desperately needed.</jats:p> </jats:sec> <jats:sec id="abs1-2"> <jats:title>Objective</jats:title> <jats:p>To validate promising new technologies [namely whole-blood transcriptomics, proteomics, flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR)] and existing signatures for the detection of active TB in samples obtained from individuals with suspected active TB.</jats:p> </jats:sec> <jats:sec id="abs1-3"> <jats:title>Design</jats:title> <jats:p>Four substudies, each of which used samples from the biobank collected as part of the interferon gamma release assay (IGRA) in the Diagnostic Evaluation of Active TB study, which was a prospective cohort of patients recruited with suspected TB.</jats:p> </jats:sec> <jats:sec id="abs1-4"> <jats:title>Setting</jats:title> <jats:p>Secondary care.</jats:p> </jats:sec> <jats:sec id="abs1-5"> <jats:title>Participants</jats:title> <jats:p>Adults aged ≥ 16 years presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham, with suspected active TB.</jats:p> </jats:sec> <jats:sec id="abs1-6"> <jats:title>Interventions</jats:title> <jats:p>New tests using genome-wide gene expression microarray

Journal article

Hoang LT, Jain P, Pillay TD, Tolosa-Wright M, Niazi U, Takwoingi Y, Halliday A, Berrocal-Almanza LC, Deeks JJ, Beverley P, Kon OM, Lalvani Aet al., 2021, Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a prospective, multicentre cohort study, LANCET INFECTIOUS DISEASES, Vol: 21, Pages: 366-375, ISSN: 1473-3099

Journal article

Bruni T, Lalvani A, Richeldi L, 2020, Telemedicine-enabled Accelerated Discharge of Patients Hospitalized with COVID-19 to Isolation in Repurposed Hotel Rooms (vol 202, pg 508, 2020), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 1608-1609, ISSN: 1073-449X

Journal article

Bruni T, Lalvani A, Richeldi L, 2020, An Expanded COVID-19 Telemedicine Intermediate Care Model Using Repurposed Hotel Rooms Reply, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 1192-1193, ISSN: 1073-449X

Journal article

Fenton ME, Wasko K, Behl V, Froh J, Schmalenberg Met al., 2020, An Expanded COVID-19 Telemedicine Intermediate Care Model Using Repurposed Hotel Rooms, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 1190-1192, ISSN: 1073-449X

Journal article

Bruni T, Lalvani A, Richeldi L, 2020, Telemedicine-enabled accelerated discharge of patients hospitalized with COVID-19 to isolation in repurposed hotel rooms., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 508-510, ISSN: 1073-449X

Journal article

Lalvani A, Seshadri C, 2020, Understanding how BCG vaccine protects against Mycobacterium tuberculosis infection: Lessons from household contact studies, Journal of Infectious Diseases, Vol: 221, Pages: 1229-1231, ISSN: 0022-1899

Journal article

Jeon D, 2020, Latent tuberculosis infection: recent progress and challenges in South Korea, KOREAN JOURNAL OF INTERNAL MEDICINE, Vol: 35, Pages: 269-275, ISSN: 1226-3303

Journal article

Quijano-Campos JC, Williams L, Agarwal S, Tweed K, Parker R, Lalvani A, Chiu Y-D, Dorey K, Devine T, Stoneman V, Toshner M, Thillai Met al., 2020, CASPA (CArdiac Sarcoidosis in PApworth) improving the diagnosis of cardiac involvement in patients with pulmonary sarcoidosis: protocol for a prospective observational cohort study, BMJ OPEN RESPIRATORY RESEARCH, Vol: 7, ISSN: 2052-4439

Journal article

Katelaris AL, Jackson C, Southern J, Gupta RK, Drobniewski F, Lalvani A, Lipman M, Mangtani P, Abubakar Iet al., 2020, Effectiveness of BCG vaccination against Mycobacterium tuberculosis infection in adults: a cross-sectional analysis of a UK-based cohort, The Journal of Infectious Diseases, Vol: 221, Pages: 146-155, ISSN: 0022-1899

BackgroundBCG appears to reduce acquisition of Mycobacterium tuberculosis (Mtb) infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of Mtb infection in adults.MethodsWe conducted a cross-sectional analysis of data from adult contacts of tuberculosis cases participating in a UK cohort study. Vaccine effectiveness (VE) of BCG, ascertained based on presence of a scar or vaccination history, against latent tuberculosis infection (LTBI), measured via IGRA, was assessed using multivariable logistic regression. The effects of age at BCG and time since vaccination were also explored.ResultsOf 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (aOR=0.70, 95% CI 0.56-0.87, p=0.0017) yielding a VE of 30%. VE declined with time since vaccination, but there was evidence that LTBI prevalence was lower amongst vaccinated individuals even >20 years after vaccination, compared with non-vaccinated participants.ConclusionBCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against Mtb infection as well as disease. This has implications for immunisation programmes, vaccine development and tuberculosis control efforts worldwide.

Journal article

Gupta RK, Lipman M, Jackson C, Sitch A, Southern J, Drobniewski F, Deeks JJ, Tsou C-Y, Griffiths C, Davidson J, Campbell C, Stirrup O, Noursadeghi M, Kunst H, Haldar P, Lalvani A, Abubakar Iet al., 2019, Quantitative interferon gamma release assay and tuberculin skin test Results to predict incident tuberculosis: a prospective cohort study., American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 984-991, ISSN: 1073-449X

RATIONALE: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. OBJECTIVES: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the tuberculin skin test (TST) might improve prediction of incident TB. METHODS: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by re-linkage to national TB surveillance records (median follow-up 4.7 years). Incidence rates and rate ratios, sensitivities, specificities and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior BCG). MEASUREMENTS AND MAIN RESULTS: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (p<0.0001). Over three years' follow-up, there was a modest increase in positive predictive value (PPV) with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/mL vs. 3.6% for ≥4.00 IU/mL; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5mm vs. 4.3% for ≥15mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/mL vs. 23.2% for ≥4.00 IU/mL; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5mm vs. 28.1% for ≥15mm). CONCLUSIONS: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB and TST modestly increases PPV for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal article

Park M, Dave D, Russell G, Martin L, Lalvani A, Barwick T, Kon OMet al., 2019, FDG-PET/CT APPEARANCES IN MDR-TB PATIENTS WITH RESIDUAL CT ABNORMALITIES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A69-A70, ISSN: 0040-6376

Conference paper

Chaplin E, Rervitt O, Ward S, Watt A, Gardiner N, Houchen-Wolloff L, Bourne C, Singh Set al., 2019, S5 Changing the shape of rehabilitation: breathlessness rehabilitation, British Thoracic Society Winter Meeting 2019, QEII Centre, Broad Sanctuary, Westminster, London SW1P 3EE, 4 to 6 December 2019, Programme and Abstracts, Publisher: BMJ Publishing Group Ltd and British Thoracic Society

Conference paper

Berrocal-Almanza LC, Harris R, Lalor MK, Muzyamba MC, Were J, O'Connell A-M, Mirza A, Kon O-M, Lalvani A, Zenner Det al., 2019, Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study., Lancet Infectious Diseases, Vol: 19, Pages: 1191-1201, ISSN: 1473-3099

BACKGROUND: Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population. METHODS: We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System. FINDINGS: Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, an

Journal article

Gupta R, Lipman M, Jackson C, Sitch A, Southern J, Drobniewski F, Deeks J, Tsou C-Y, Griffiths C, Davidson J, Campbell C, Stirrup O, Noursadeghi M, Kunst H, Haldar P, Lalvani A, Abubakar Iet al., 2019, Do higher quantitative interferon gamma release assay or tuberculin skin test results help to predict incident tuberculosis? Data from the UK PREDICT study, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Yang Y, Walker TM, Walker AS, Wilson DJ, Peto TEA, Crook DW, Shamout F, Zhu T, Clifton DA, Arandjelovic I, Comas I, Farhat MR, Gao Q, Sintchenko V, van Soolingen D, Hoosdally S, Cruz ALG, Carter J, Grazian C, Earle SG, Kouchaki S, Fowler PW, Iqbal Z, Hunt M, Smith EG, Rathod P, Jarrett L, Matias D, Cirillo DM, Borroni E, Battaglia S, Ghodousi A, Spitaleri A, Cabibbe A, Tahseen S, Nilgiriwala K, Shah S, Rodrigues C, Kambli P, Surve U, Khot R, Niemann S, Kohl T, Merker M, Hoffmann H, Molodtsov N, Plesnik S, Ismail N, Omar SV, Thwaites G, Thuong NTT, Nhung HN, Srinivasan V, Moore D, Coronel J, Solano W, Gao GF, He G, Zhao Y, Ma A, Liu C, Zhu B, Laurenson I, Claxton P, Koch A, Wilkinson R, Lalvani A, Posey J, Gardy J, Werngren J, Paton N, Jou R, Wu M-H, Lin W-H, Ferrazoli L, de Oliveira RSet al., 2019, DeepAMR for predicting co-occurrent resistance of Mycobacterium tuberculosis, Bioinformatics, Vol: 35, Pages: 3240-3249, ISSN: 1367-4803

MotivationResistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages.ResultsWe used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization. We then proposed an end-to-end multi-task model with deep denoising auto-encoder (DeepAMR) for multiple drug classification and developed DeepAMR_cluster, a clustering variant based on DeepAMR, for learning clusters in latent space of the data. The results showed that DeepAMR outperformed baseline model and four machine learning models with mean AUROC from 94.4% to 98.7% for predicting resistance to four first-line drugs [i.e. isoniazid (INH), ethambutol (EMB), rifampicin (RIF), pyrazinamide (PZA)], multi-drug resistant TB (MDR-TB) and pan-susceptible TB (PANS-TB: MTB that is susceptible to all four first-line anti-TB drugs). In the case of INH, EMB, PZA and MDR-TB, DeepAMR achieved its best mean sensitivity of 94.3%, 91.5%, 87.3% and 96.3%, respectively. While in the case of RIF and PANS-TB, it generated 94.2% and 92.2% sensitivity, which were lower than baseline model by 0.7% and 1.9%, respectively. t-SNE visualization shows that DeepAMR_cluster captures lineage-related clusters in the latent space.Availability and implementationThe details of source code are provided at http://www.robots.ox.ac.uk/∼davidc/code.php.

Journal article

Lalvani A, Whitworth HS, 2019, Progress in interferon-gamma release assay development and applications: an unfolding story of translational research, ANNALS OF TRANSLATIONAL MEDICINE, Vol: 7, ISSN: 2305-5839

Journal article

Halliday A, Masonou T, Tolosa-Wright M, Mandagere V, Lalvani Aet al., 2019, Immunodiagnosis of active tuberculosis, Expert Review of Respiratory Medicine, Vol: 13, Pages: 521-532, ISSN: 1747-6348

Introduction: There is an unmet clinical need for improved diagnostic tests for active tuberculosis (TB) to provide high sensitivity for all cases, accelerate time to diagnosis and ensure timely and appropriate treatment. Whilst the measurement of M.tb-specific immune responses is widely used for detecting infection in the absence of TB symptoms (i.e. latent TB infection), there is currently no role for immunodiagnostics in active TB disease. This is primarily due to insufficient sensitivity, and an inability to discriminate between active disease and controlled, latent TB infection. Areas covered: In this review, we focus on recent developments in the use of immune-based tests to provide a point of care test for the rule-in or rule-out of active TB. Expert opinion: Recent studies have demonstrated that second-generation IGRAs have the potential to rule-out active TB, particularly in low burden settings. Newer technological platforms, including systems serology and flow cytometry, offer the means to measure specific M.tb specific immune signatures which have been shown to have a high level of accuracy for active TB. However, it is now crucial that new and promising test undergo validation in clinically relevant cohorts which include the full spectrum of TB patients and differential diagnoses.

Journal article

Masonou T, Hokey DA, Lahey T, Halliday A, Berrocal-Almanza LC, Wieland-Alter WF, Arbeit RD, Lalvani A, von Reyn CFet al., 2019, CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial, PLoS ONE, Vol: 14, ISSN: 1932-6203

BACKGROUND: DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo. METHODS: We analysed CD4+ T cell cytokine immune responses from 10 DAR-901 recipients, 9 BCG recipients and 9 placebo recipients from the Phase I DAR-901 MDES trial. In that study, HIV-negative, IGRA-negative participants with prior BCG immunization were randomized (double-blind) to receive three intradermal injections of DAR-901 or saline placebo or two injections of saline placebo followed by an intradermal injection of BCG. Antigen-specific functional and phenotypic CD4+ T cell responses along with effector phenotype of responder cells were measured by intracellular cytokine staining. RESULTS: DAR-901 recipients exhibited increased DAR-901 antigen-specific polyfunctional or bifunctional T cell responses compared to baseline. Vaccine specific CD4+ IFNγ, IL2, TNFα and any cytokine responses peaked at 7 days post-dose 3. Th1 responses predominated, with most responder cells exhibiting a polyfunctional effector memory phenotype. BCG induced greater CD4+ T cell responses than placebo while the more modest DAR-901 responses did not differ from placebo. Neither DAR-901 nor BCG induced substantial or sustained Th17 /Th22 cytokine responses. CONCLUSION: DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172 which was shown to prevent TB, induced low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These results suggest that induction of higher levels of CD4+ c

Journal article

Lalvani A, Berrocal Almanza L, 2019, Engaging with civil society to improve access to LTBI screening for new-entrant migrants in England: a qualitative study, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, Vol: 23, Pages: 563-570, ISSN: 1027-3719

Setting The LTBI programme offers testing and treatment to new entrant migrants from high incidence countries in England. However, the rates of LTBI testing, treatment acceptance and completion are suboptimal and appropriate access must be improved. Objective: To gain insights from the community, community-based organisations (CBOs), and public sector stakeholders on interventions that facilitate collaboration to improve health care outreach and delivery. Design Three stakeholder meetings and five focus group discussions were held using thematic analysis to identify themes arising from the participants’ perspectives. Results Four overarching themes emerged from the discussions. These were capacity, collaboration, culture and trust. These highlighted the complementary skills sets different sectors bring to collaboration, as well as the barriers that need surmounting.Stigma could be reduced by making LTBI testing routine, and community members could act as champions for health promotion raising awareness on LTBI testing, and providing a bridge between communities and primary care services. Conclusion Public service providers, community members and CBOs have a willingness to collaborate to support primary care delivery of testing for LTBI and other communicable and non-communicable diseases. Policy and commissioning support are needed to facilitate such workings.

Journal article

Takwoingi Y, Whitworth H, Rees-Roberts M, Badhan A, Partlett C, Green N, Boakye A, Lambie H, Marongiu L, Jit M, White P, Deeks JJ, Kon OM, Lalvani A, Abdoyeku D, Branley H, Chua F, Conlon C, Cooke G, Davison R, Dedicoat M, Kunst H, Lipman M, Loebingher M, Lynn W, Macallan D, Menzies S, Nathani N, O'Connell R, Post F, Pozniak A, Wiselka M, Woltmann Get al., 2019, Interferon gamma release assays for diagnostic evaluation of active tuberculosis (IDEA): test accuracy study and economic evaluation, Health Technology Assessment, Vol: 23, ISSN: 1366-5278

BackgroundInterferon gamma release assays (IGRAs) are blood tests recommended for the diagnosis of tuberculosis (TB) infection. There is currently uncertainty about the role and clinical utility of IGRAs in the diagnostic workup of suspected active TB in routine NHS clinical practice.ObjectivesTo compare the diagnostic accuracy and cost-effectiveness of T-SPOT.TB® (Oxford Immunotec, Abingdon, UK) and QuantiFERON® TB GOLD In-Tube (Cellestis, Carnegie, VIC, Australia) for diagnosis of suspected active TB and to estimate the diagnostic accuracy of second-generation IGRAs.DesignProspective within-patient comparative diagnostic accuracy study.SettingSecondary care.ParticipantsAdults (aged ≥ 16 years) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB.InterventionsThe index tests [T-SPOT.TB and QuantiFERON GOLD In-Tube (QFT-GIT)] and new enzyme-linked immunospot assays utilising novel Mycobacterium tuberculosis antigens (Rv3615c, Rv2654, Rv3879c and Rv3873) were verified against a composite reference standard applied by a panel of clinical experts blinded to IGRA results.Main outcome measuresSensitivity, specificity, predictive values and likelihood ratios were calculated to determine diagnostic accuracy. A decision tree model was developed to calculate the incremental costs and incremental health utilities [quality-adjusted life-years (QALYs)] of changing from current practice to using an IGRA as an initial rule-out test.ResultsA total of 363 patients had active TB (culture-confirmed and highly probable TB cases), 439 had no active TB and 43 had an indeterminate final diagnosis. Comparing T-SPOT.TB and QFT-GIT, the sensitivities [95% confidence interval (CI)] were 82.3% (95% CI 77.7% to 85.9%) and 67.3% (95% CI 62.1% to 72.2%), respectively, whereas specificities were 82.6% (95% CI 78.6% to 86.1%) and 80.4% (95% CI 76.1% to 84.1%), respectively. T-SPOT.TB was mor

Journal article

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