Imperial College London

ProfessorChristopherChiu

Faculty of MedicineDepartment of Infectious Disease

Professor of Infectious Diseases
 
 
 
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Contact

 

+44 (0)20 3313 2301c.chiu Website

 
 
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Location

 

8N.15Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

66 results found

Wagstaffe HR, Thwaites RS, Reynaldi A, Sidhu JK, McKendry R, Ascough S, Papargyris L, Collins AM, Xu J, Lemm N-M, Siggins MK, Chain BM, Killingley B, Kalinova M, Mann A, Catchpole A, Davenport MP, Openshaw PJM, Chiu Cet al., 2024, Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults., Sci Immunol, Vol: 9

Human infection challenge permits in-depth, early, and pre-symptomatic characterization of the immune response, enabling the identification of factors that are important for viral clearance. Here, we performed intranasal inoculation of 34 young adult, seronegative volunteers with a pre-Alpha severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Of these participants, 18 (53%) became infected and showed an interferon-dominated mediator response with divergent kinetics between nasal and systemic sites. Peripheral CD4+ and CD8+ T cell activation and proliferation were early and robust but showed distinct kinetic and phenotypic profiles; antigen-specific T cells were largely CD38+Ki67+ and displayed central and effector memory phenotypes. Both mucosal and systemic antibodies became detectable around day 10, but nasal antibodies plateaued after day 14 while circulating antibodies continued to rise. Intensively granular measurements in nasal mucosa and blood allowed modeling of immune responses to primary SARS-CoV-2 infection that revealed CD8+ T cell responses and early mucosal IgA responses strongly associated with viral control, indicating that these mechanisms should be targeted for transmission-reducing intervention.

Journal article

Corti N, Chiu C, Cox RJ, Demont C, Devaster J-M, Engelhardt OG, Gorringe A, Hassan K, Hoefnagel M, Kamerling I, Krut O, Lane C, Liebers R, Luke C, Van Molle W, Morel S, Neels P, Roestenberg M, Rubbrecht M, Klaas Smits W, Stoughton D, Talaat K, Vehreschild MJGT, Wildfire A, Meln I, Olesen OFet al., 2024, Regulatory workshop on challenge strain development and GMP manufacture - A stakeholder meeting report., Biologicals

Within the Innovative Health Initiative (IHI) Inno4Vac CHIMICHURRI project, a regulatory workshop was organised on the development and manufacture of challenge agent strains for Controlled Human Infection Model (CHIM) studies. Developers are often uncertain about which GMP requirements or regulatory guidelines apply but should be guided by the 2022 technical white paper "Considerations on the Principles of Development and Manufacturing Qualities of Challenge Agents for Use in Human Infection Models" (published by hVIVO, Wellcome Trust, HIC-Vac consortium members). Where those recommendations cannot be met, regulators advise following the "Principles of GMP" until definitive guidelines are available. Sourcing wild-type virus isolates is a significant challenge for developers. Still, it is preferred over reverse genetics challenge strains for several reasons, including implications and regulations around genetically modified organisms (GMOs). Official informed consent guidelines for collecting isolates are needed, and the characterisation of these isolates still presents risks and uncertainty. Workshop topics included ethics, liability, standardised clinical endpoints, selection criteria, sharing of challenge agents, and addressing population heterogeneity concerning vaccine response and clinical course. The organisers are confident that the workshop discussions will contribute to advancing ethical, safe, and high-quality CHIM studies of influenza, RSV and C. difficile, including adequate regulatory frameworks.

Journal article

Smith C, Smith E, Rydlova A, Varro R, Hinton JCD, Gordon MA, Choy RKM, Liu X, Pollard AJ, Chiu C, Cooke GS, Gibani MMet al., 2024, Protocol for the Challenge Nontyphoidal Salmonella (CHANTS) Study: a first-in-human, in-patient, double-blind, randomised, safety and dose-escalation controlled human infection model in the United Kingdom, BMJ Open, Vol: 14, ISSN: 2044-6055

Introduction: Invasive non-typhoidal Salmonella (iNTS) serovars are a major cause of community-acquired bloodstream infections in sub-Saharan Africa (SSA). In this setting, Salmonella enterica serovar Typhimurium accounts for two-thirds of infections and is associated with an estimated case fatality rate of 15%–20%. Several iNTS vaccine candidates are in early-stage assessment which—if found effective—would provide a valuable public health tool to reduce iNTS disease burden. The CHANTS study aims to develop a first-in-human Salmonella Typhimurium controlled human infection model, which can act as a platform for future vaccine evaluation, in addition to providing novel insights into iNTS disease pathogenesis.Methods and analysis: This double-blind, safety and dose-escalation study will randomise 40–80 healthy UK participants aged 18–50 to receive oral challenge with one of two strains of S. Typhimurium belonging to the ST19 (strain 4/74) or ST313 (strain D23580) lineages. 4/74 is a global strain often associated with diarrhoeal illness predominantly in high-income settings, while D23580 is an archetypal strain representing invasive disease-causing isolates found in SSA. The primary objective is to determine the minimum infectious dose (colony-forming unit) required for 60%–75% of participants to develop clinical or microbiological features of systemic salmonellosis. Secondary endpoints are to describe and compare the clinical, microbiological and immunological responses following challenge. Dose escalation or de-escalation will be undertaken by continual-reassessment methodology and limited within prespecified safety thresholds. Exploratory objectives are to describe mechanisms of iNTS virulence, identify putative immune correlates of protection and describe host–pathogen interactions in response to infection.Ethics and dissemination: Ethical approval has been obtained from the NHS Health Research Authority (London—Fulh

Journal article

Smith C, Smith E, Chiu C, Hinton J, Perez Sepulveda B, Gordon M, Choy RKM, Hill PWS, Meiring JE, Darton TC, Carey ME, Cooke G, Gibani MM, CHANTS Consortiumet al., 2023, The Challenge Non-Typhoidal Salmonella (CHANTS) Consortium: Development of a non-typhoidal Salmonella controlled human infection model: Report from a consultation group workshop, 05 July 2022, London, UK [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 8, ISSN: 2398-502X

Invasive non-typhoidal Salmonella disease (iNTS) is a major cause of morbidity and mortality globally, particularly as a cause of bloodstream infection in children and immunocompromised adults in sub-Saharan Africa. Vaccines to prevent non-typhoidal Salmonella (NTS) would represent a valuable public health tool in this setting to avert cases and prevent expansion of antimicrobial resistance. Several NTS and combination typhoidal-NTS vaccine candidates are in early-stage development, although the pathway to licensure is unclear due to challenges in conducting large phase III field trials. Controlled human infection models (CHIM) present an opportunity to accelerate vaccine development for a range of enteric pathogens. Several recent typhoidal Salmonella CHIMs have been conducted safely and have played pivotal roles in progressing vaccine candidates to pre-qualification and licensure. The Challenge Non-Typhoidal Salmonella (CHANTS) consortium has been formed with funding from the Wellcome Trust, to deliver the first NTS CHIM, which can act as a platform for future vaccine evaluation. This paper reports the conclusions of a consultation group workshop convened with key stakeholders. The aims of this meeting were to: (1) define the rationale for an NTS CHIM (2) map the NTS vaccine pipeline (3) refine study design and (4) establish potential future use cases.

Journal article

Zhou J, Singanayagam A, Goonawardane N, Moshe M, Sweeney F, Sukhova K, Killingley B, Kalinova M, Mann A, Catchpole A, Barer MR, Ferguson NM, Chiu C, Barclay WSet al., 2023, Viral emissions into the air and environment after SARS-CoV-2 human challenge: a phase 1, open label, first-in-human study, The Lancet Microbe, Vol: 4, Pages: e579-e590, ISSN: 2666-5247

BackgroundEffectively implementing strategies to curb SARS-CoV-2 transmission requires understanding who is contagious and when. Although viral load on upper respiratory swabs has commonly been used to infer contagiousness, measuring viral emissions might be more accurate to indicate the chance of onward transmission and identify likely routes. We aimed to correlate viral emissions, viral load in the upper respiratory tract, and symptoms, longitudinally, in participants who were experimentally infected with SARS-CoV-2.MethodsIn this phase 1, open label, first-in-human SARS-CoV-2 experimental infection study at quarantine unit at the Royal Free London NHS Foundation Trust, London, UK, healthy adults aged 18–30 years who were unvaccinated for SARS-CoV-2, not previously known to have been infected with SARS-CoV-2, and seronegative at screening were recruited. Participants were inoculated with 10 50% tissue culture infectious dose of pre-alpha wild-type SARS-CoV-2 (Asp614Gly) by intranasal drops and remained in individual negative pressure rooms for a minimum of 14 days. Nose and throat swabs were collected daily. Emissions were collected daily from the air (using a Coriolis μ air sampler and directly into facemasks) and the surrounding environment (via surface and hand swabs). All samples were collected by researchers, and tested by using PCR, plaque assay, or lateral flow antigen test. Symptom scores were collected using self-reported symptom diaries three times daily. The study is registered with ClinicalTrials.gov, NCT04865237.FindingsBetween March 6 and July 8, 2021, 36 participants (ten female and 26 male) were recruited and 18 (53%) of 34 participants became infected, resulting in protracted high viral loads in the nose and throat following a short incubation period, with mild-to-moderate symptoms. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Viral RNA was de

Journal article

Fink DL, Callaby H, Luintel A, Beynon W, Bond H, Lim EY, Gkrania-Klotsas E, Heskin J, Bracchi M, Rathish B, Milligan I, O'Hara G, Rimmer S, Peters JR, Payne L, Mody N, Hodgson B, Lewthwaite P, Lester R, Woolley SD, Sturdy A, Whittington A, Johnson L, Jacobs N, Quartey J, Ai Payne B, Crowe S, Elliott IA, Harrison T, Cole J, Beard K, Cusack T-P, Jones I, Banerjee R, Rampling T, Specialist and High Consequence Infectious Diseases Centres Network for Monkeypox, Dunning Jet al., 2023, Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study., Lancet Infectious Diseases, Vol: 23, Pages: 589-597, ISSN: 1473-3099

BACKGROUND: The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. METHODS: In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. FINDINGS: 156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30-44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3 (IQR 349-828).

Journal article

Temple DS, Hegarty-Craver M, Furberg RD, Preble EA, Bergstrom E, Gardener Z, Dayananda P, Taylor L, Lemm NM, Papargyris L, McClain MT, Nicholson BP, Bowie A, Miggs M, Petzold E, Woods CW, Chiu C, Gilchrist KHet al., 2023, Wearable sensor-based detection of influenza in presymptomatic and asymptomatic individuals, Journal of Infectious Diseases, Vol: 227, Pages: 864-872, ISSN: 0022-1899

BACKGROUND: The COVID-19 pandemic highlighted the need for early detection of viral infections in symptomatic and asymptomatic individuals to allow for timely clinical management and public health interventions. METHODS: Twenty healthy adults were challenged with an influenza A (H3N2) virus and prospectively monitored from 7 days before through 10 days after inoculation, using wearable electrocardiogram and physical activity sensors (Clinical Trial: NCT04204493; https://clinicaltrials.gov/ct2/show/NCT04204993). This framework allowed for responses to be accurately referenced to the infection event. For each participant, we trained a semi-supervised multivariable anomaly detection model on data acquired before inoculation and used it to classify the post-inoculation dataset. RESULTS: Inoculation with this challenge virus was well-tolerated with an infection rate of 85%. With the model classification threshold set so that no alarms were recorded in the 170 healthy days recorded, the algorithm correctly identified 16 of 17 (94%) positive presymptomatic and asymptomatic individuals, on average 58 hours post inoculation and 23 hrs before the symptom onset. CONCLUSION: The data processing and modeling methodology show promise for the early detection of respiratory illness. The detection algorithm is compatible with data collected from smartwatches using optical techniques but needs to be validated in large heterogeneous cohorts in normal living conditions.

Journal article

Cable J, Sun J, Cheon IS, Vaughan AE, Castro IA, Stein SR, López CB, Gostic KM, Openshaw PJM, Ellebedy AH, Wack A, Hutchinson E, Thomas MM, Langlois RA, Lingwood D, Baker SF, Folkins M, Foxman EF, Ward AB, Schwemmle M, Russell AB, Chiu C, Ganti K, Subbarao K, Sheahan TP, Penaloza-MacMaster P, Eddens Tet al., 2023, Respiratory viruses: New frontiers-a Keystone Symposia report., Annals of the New York Academy of Sciences, Vol: 1522, Pages: 60-73, ISSN: 0077-8923

Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS-CoV-2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever-evolving viruses that develop resistance, leaving therapy efficacy either short-lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Respiratory Viruses: New Frontiers." Researchers presented new insights into viral biology and virus-host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

Journal article

Stafford A, Rimmer S, Gilchrist M, Sun K, Davies EP, Waddington CS, Chiu C, Armstrong-James D, Swaine T, Davies F, Gomez CHM, Kumar V, ElHaddad A, Awad Z, Smart C, Mora-Peris B, Muir D, Randell P, Peters J, Chand M, Warrell CE, Rampling T, Cooke G, Dhanji S, Campbell V, Davies C, Osman S, Abbara Aet al., 2023, Use of cidofovir in a patient with severe mpox and uncontrolled HIV infection, LANCET INFECTIOUS DISEASES, Vol: 23, Pages: E218-E226, ISSN: 1473-3099

Journal article

Barnes MVC, Mandla A, Smith E, Maskuniitty M, Openshaw PJM, HIC-Vac meeting contributorset al., 2023, Human infection challenge in the pandemic era and beyond, HIC-Vac annual meeting report, 2022, Immunotherapy Advances, Vol: 3, ISSN: 2732-4303

HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting.

Journal article

Piggin M, Smith E, Mankone P, Ndegwa L, Gbesemete D, Pristera P, Bahrami-Hessari M, Johnson H, Catchpole AP, Openshaw PJM, Chiu C, Read RC, Ward H, Barker Cet al., 2022, The role of public involvement in the design of the first SARS-CoV-2 human challenge study during an evolving pandemic, Epidemics: the journal of infectious disease dynamics, Vol: 41, Pages: 1-6, ISSN: 1755-4365

High quality health care research must involve patients and the public. This ensures research is important, relevant and acceptable to those it is designed to benefit. The world’s first human challenge study with SARS-CoV-2 undertook detailed public involvement to inform study design despite the urgency to review and establish the study. The work was integral to the UK Research Ethics Committee review and approval of the study. Discussion with individuals from ethnic minorities within the UK population supported decision-making around the study exclusion criteria. Public review of study materials for consent processes led to the addition of new information, comparisons and visual aids to help volunteers consider the practicalities and risks involved in participating. A discussion exploring the acceptability of a human challenge study with SARS-CoV-2 taking place in the UK, given the current context of the pandemic, identified overall support for the study. Public concern for the wellbeing of trial participants, as a consequence of isolation, was identified. We outline our approach to public involvement and its impact on study design.

Journal article

Schott BH, Wang L, Zhu X, Harding AT, Ko ER, Bourgeois JS, Washington EJ, Burke TW, Anderson J, Bergstrom E, Gardener Z, Paterson S, Brennan RG, Chiu C, McClain MT, Woods CW, Gregory SG, Heaton NS, Ko DCet al., 2022, Single-cell genome-wide association reveals a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus, Cell Genomics, Vol: 2, ISSN: 2666-979X

During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and susceptibility. We applied this method to influenza A virus (IAV), the cause of four pandemics since the start of the 20th century. scHi-HOST leverages single-cell RNA sequencing (scRNA-seq) to simultaneously assign genetic identity to cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral burden, and identify expression quantitative trait loci. Integration of scHi-HOST with human challenge and experimental validation demonstrated that a missense variant in endoplasmic reticulum aminopeptidase 1 (ERAP1; rs27895) increased IAV burden in cells and human volunteers. rs27895 exhibits population differentiation, likely contributing to greater permissivity of cells from African populations to IAV. scHi-HOST is a broadly applicable method and resource for decoding infectious-disease genetics.

Journal article

Dayananda P, Chiu C, Openshaw P, 2022, Controlled human infection challenge studies with RSV., Current Topics in Microbiology and Immunology, Editors: Ahmed, Akira, Casadevall, Galan, Garcia-Sastre, Malissen, Rappuoli, Pages: 1-28

Despite considerable momentum in the development of RSV vaccines and therapeutics, there remain substantial barriers to the development and licensing of effective agents, particularly in high-risk populations. The unique immunobiology of RSV and lack of clear protective immunological correlates has held back RSV vaccine development, which, therefore, depends on large and costly clinical trials to demonstrate efficacy. Studies involving the deliberate infection of human volunteers offer an intermediate step between pre-clinical and large-scale studies of natural infection. Human challenge has been used to demonstrate the potential efficacy of vaccines and antivirals while improving our understanding of the protective immunity against RSV infection. Early RSV human infection challenge studies determined the role of routes of administration and size of inoculum on the disease. However, inherent limitations, the use of highly attenuated/laboratory-adapted RSV strains and the continued evolutionary adaptation of RSV limits extrapolation of results to present-day vaccine testing. With advances in technology, it is now possible to perform more detailed investigations of human mucosal immunity against RSV in experimentally infected adults and, more recently, older adults to optimise the design of vaccines and novel therapies. These studies identified defects in RSV-induced humoral and CD8+ T cell immunity that may partly explain susceptibility to recurrent RSV infection. We discuss the insights from human infection challenge models, ethical and logistical considerations, potential benefits, and role in streamlining and accelerating novel antivirals and vaccines against RSV. Finally, we consider how human challenges might be extended to include relevant at-risk populations.

Book chapter

Williams E, Craig K, Chiu C, Davies H, Ellis S, Emerson C, Jamrozik E, Jefford M, Kang G, Kapulu M, Kolstoe SE, Littler K, Lockett A, Elena Rey, Messer J, McShane H, Saenz C, Selgelid MJ, Shah S, Smith PG, Yamazaki Net al., 2022, Ethics review of COVID-19 human challenge studies: A joint HRA/WHO workshop, Vaccine, Vol: 40, Pages: 3484-3489, ISSN: 0264-410X

This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop discusses the ethics review of the first COVID-19 human challenge studies, undertaken in the midst of the pandemic. It reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies and create the frameworks to ensure rigorous and timely review of these studies. This report evaluates the utility of the WHO's international guidance document Key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) as a practical resource for the ethics review of COVID-19 human challenge studies. It also assesses the UK HRA's approach to these complex ethics reviews, including the formation of a Specialist Ad-Hoc Research Ethics Committee (REC) for COVID-19 Human Challenge Studies to review all current and future COVID-19 human challenge studies. In addition, the report outlines the reflections of REC members and researchers regarding the ethics review process of the first COVID-19 human challenge studies. Finally, it considers the potential ongoing scientific justification for COVID-19 human challenge studies, particularly in relation to next-generation vaccines and optimisation of vaccination schedules. Overall, there was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Workshop members suggested that the WHO Key Criteria could be practically implemented to support researchers and ethics reviewers, including in the training of ethics committee members. In future, a wider audience may be engaged by the original document and potential additional materials, informed by the experiences of those involved in the first COVID-19 human challenge studies outlined

Journal article

Ascough S, Dayananda P, Kalyan M, Kuong SU, Gardener Z, Bergstrom E, Paterson S, Kar S, Avadhan V, Thwaites R, Uruchurtu ASS, Ruckwardt TJ, Chen M, Nair D, Derrien-Colemyn A, Graham BS, Begg M, Hessel E, Openshaw P, Chiu Cet al., 2022, Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge model, The Lancet Healthy Longevity, Vol: 3, Pages: E405-E416, ISSN: 2666-7568

BackgroundRespiratory viral infections are typically more severe in older adults. Older adults are more vulnerable to infection and do not respond effectively to vaccines due to a combination of immunosenescence, so-called inflamm-ageing, and accumulation of comorbidities. Although age-related changes in immune responses have been described, the causes of this enhanced respiratory disease in older adults remain poorly understood. We therefore performed volunteer challenge with respiratory syncytial virus (RSV) in groups of younger and older adult volunteers. The aim of this study was to establish the safety and tolerability of this model and define age-related clinical, virological, and immunological outcomes.MethodsIn this human infection challenge pilot study, adults aged 18–55 years and 60–75 years were assessed for enrolment using protocol-defined inclusion and exclusion criteria. Symptoms were documented by self-completed diaries and viral load determined by quantitative PCR of nasal lavage. Peripheral blood B cell frequencies were measured by enzyme-linked immunospot and antibodies against pre-fusion and post-fusion, NP, and G proteins in the blood and upper respiratory tract were measured. The study was registered with ClinicalTrials.gov, NCT03728413.Findings381 adults aged 60–75 years (older cohort) and 19 adults aged 18–55 years (young cohort) were assessed for enrolment using protocol-defined inclusion and exclusion criteria between Nov 12, 2018, and Feb 26, 2020. 12 healthy volunteers aged 60–75 years and 21 aged 18–55 years were inoculated intranasally with RSV Memphis-37. Nine (67%) of the 12 older volunteers became infected, developing mild-to-moderate upper respiratory tract symptoms that resolved without serious adverse events or sequelae. Viral load peaked on day 6 post-inoculation and symptoms peaked between days 6 and 8. Increases in circulating IgG-positive and IgA-positive antigen-specific plasmablasts, serum

Journal article

Stewart A, Sinclair E, Ng JC-F, O'Hare JS, Page A, Serangeli I, Margreitter C, Orsenigo F, Longman K, Frampas C, Costa C, Lewis H-M, Kasar N, Wu B, Kipling D, Openshaw PJM, Chiu C, Baillie JK, Scott JT, Semple MG, Bailey MJ, Fraternali F, Dunn-Walters DKet al., 2022, Pandemic, epidemic, endemic: B cell repertoire analysis reveals unique anti-viral responses to SARS-CoV-2, Ebola and respiratory syncytial virus, Frontiers in Immunology, Vol: 13, Pages: 1-15, ISSN: 1664-3224

Immunoglobulin gene heterogeneity reflects the diversity and focus of the humoral immune response towards different infections, enabling inference of B cell development processes. Detailed compositional and lineage analysis of long read IGH repertoire sequencing, combining examples of pandemic, epidemic and endemic viral infections with control and vaccination samples, demonstrates general responses including increased use of IGHV4-39 in both Zaire Ebolavirus (EBOV) and COVID-19 patient cohorts. We also show unique characteristics absent in Respiratory Syncytial Virus or yellow fever vaccine samples: EBOV survivors show unprecedented high levels of class switching events while COVID-19 repertoires from acute disease appear underdeveloped. Despite the high levels of clonal expansion in COVID-19 IgG1 repertoires there is a striking lack of evidence of germinal centre mutation and selection. Given the differences in COVID-19 morbidity and mortality with age, it is also pertinent that we find significant differences in repertoire characteristics between young and old patients. Our data supports the hypothesis that a primary viral challenge can result in a strong but immature humoral response where failures in selection of the repertoire risk off-target effects.

Journal article

Cable J, Rappuoli R, Klemm EJ, Kang G, Mutreja A, Wright GJ, Pizza M, Castro SA, Hoffmann JP, Alter G, Carfi A, Pollard AJ, Krammer F, Gupta RK, Wagner CE, Machado V, Modjarrad K, Corey L, Gilbert PB, Dougan G, Lurie N, Bjorkman PJ, Chiu C, Nemes E, Gordon SB, Steer AC, Rudel T, Blish CA, Sandberg JT, Brennan K, Klugman KP, Stuart LM, Madhi SA, Karp CLet al., 2022, Innovative vaccine approaches-a Keystone Symposia report, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, Vol: 1511, Pages: 59-86, ISSN: 0077-8923

Journal article

Killingley B, Mann AJ, Kalinova M, Boyers A, Goonawardane N, Zhou J, Lindsell K, Hare SS, Brown J, Frise R, Smith E, Hopkins C, Noulin N, Londt B, Wilkinson T, Harden S, McShane H, Baillet M, Gilbert A, Jacobs M, Charman C, Mande P, Nguyen-Van-Tam JS, Semple MG, Read RC, Ferguson NM, Openshaw PJ, Rapeport G, Barclay WS, Catchpole AP, Chiu Cet al., 2022, Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults, Nature Medicine, Vol: 28, Pages: 1031-1041, ISSN: 1078-8956

Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18–29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study’s primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2–4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative cor

Journal article

McKendry R, Lemm N-M, Papargyris L, Chiu Cet al., 2022, Human Challenge Studies with Coronaviruses Old and New., Curr Top Microbiol Immunol, ISSN: 0070-217X

Coronavirus infections have been known to cause disease in animals since as early as the 1920s. However, only seven coronaviruses capable of causing human disease have been identified thus far. These Human Coronaviruses (HCoVs) include the causes of the common cold, but more recent coronaviruses that have emerged (i.e. SARS-CoV, MERS-CoV and SARS-CoV-2) are associated with much greater morbidity and mortality. HCoVs have been relatively under-studied compared to other common respiratory infections, as historically they have presented with mild symptoms. This has led to a relatively limited understanding of their animal reservoirs, transmission and determinants of immune protection. To address this, human infection challenge studies with HCoVs have been performed that enable a detailed clinical and immunological analysis of the host response at specific time points under controlled conditions with standardised viral inocula. Until recently, all such human challenge studies were conducted with common cold HCoVs, with the study of SARS-CoV and MERS-CoV unacceptable due to their greater pathogenicity. However, with the emergence of SARS-CoV-2 and the COVID-19 pandemic during which severe outcomes in young healthy adults have been rare, human challenge studies with SARS-CoV-2 are now being developed. Two SARS-CoV-2 human challenge studies in the UK studying individuals with and without pre-existing immunity are underway. As well as providing a platform for testing of antivirals and vaccines, such studies will be critical for understanding the factors associated with susceptibility to SARS-CoV-2 infection and thus developing improved strategies to tackle the current as well as future HCoV pandemics. Here, we summarise the major questions about protection and pathogenesis in HCoV infection that human infection challenge studies have attempted to answer historically, as well as the knowledge gaps that aim to be addressed with contemporary models.

Journal article

Killingley B, Mann A, Kalinova M, Boyers A, Goonawardane N, Zhou J, Lindsell K, Hare SS, Brown J, Frise R, Smith E, Hopkins C, Noulin N, Londt B, Wilkinson T, Harden S, McShane H, Baillet M, Gilbert A, Jacobs M, Charman C, Mande P, Nguyen-Van-Tam JS, Semple MG, Read RC, Ferguson NM, Openshaw PJ, Rapeport G, Barclay WS, Catchpole AP, Chiu Cet al., 2022, Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge

<jats:title>Abstract</jats:title> <jats:p>To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID<jats:sub>50</jats:sub> of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log<jats:sub>10</jats:sub> copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown. ClinicalTrials.gov identifier: NCT04865237.</jats:p>

Journal article

Cuthbertson L, James P, Habibi MS, Thwaites RS, Paras A, Chiu C, Openshaw PJM, Cookson WOC, Moffatt MFet al., 2022, Resilience of the respiratory microbiome in controlled adult RSV challenge study, European Respiratory Journal, Vol: 59, ISSN: 0903-1936

Journal article

Barker C, Collet K, Gbesemete D, Piggin M, Watson D, Pristerà P, Lawerence W, Smith E, Bahrami-Hessari M, Johnson H, Baker K, Qavi A, McGrath C, Chiu C, Read RC, Ward Het al., 2022, Public attitudes to a human challenge study with SARS-CoV-2: a mixed-methods study., Wellcome Open Res, Vol: 7, ISSN: 2398-502X

Background: Human challenge studies involve the deliberate exposure of healthy volunteers to an infectious micro-organism in a highly controlled and monitored way. They are used to understand infectious diseases and have contributed to the development of vaccines. In early 2020, the UK started exploring the feasibility of establishing a human challenge study with SARS-CoV-2. Given the significant public interest and the complexity of the potential risks and benefits, it is vital that public views are considered in the design and approval of any such study and that investigators and ethics boards remain accountable to the public. Methods: Mixed methods study comprising online surveys conducted with 2,441 UK adults and in-depth virtual focus groups with 57 UK adults during October 2020 to explore the public's attitudes to a human challenge study with SARS-CoV-2 taking place in the UK. Results: There was overall agreement across the surveys and focus groups that a human challenge study with SARS-CoV-2 should take place in the UK. Transparency of information, trust and the necessity to provide clear information on potential risks to study human challenge study participants were important. The perceived risks of taking part included the risk of developing long-term effects from COVID, impact on personal commitments and mental health implications of isolation. There were a number of practical realities to taking part that would influence a volunteer's ability to participate (e.g. Wi-Fi, access to exercise, outside space and work, family and pet commitments). Conclusions: The results identified practical considerations for teams designing human challenge studies. Recommendations were grouped: 1) messaging to potential study participants, 2) review of the protocol and organisation of the study, and 3) more broadly, making the study more inclusive and relevant. This study highlights the value of public consultation in research, particularly in fields attracting public intere

Journal article

Rapeport G, Chiu C, McShane H, 2021, SARS-CoV-2 Human Challenge Studies. Reply., N Engl J Med, Vol: 385

Journal article

Grzesiak E, Bent B, McClain MT, Woods CW, Tsalik EL, Nicholson BP, Veldman T, Burke TW, Gardener Z, Bergstrom E, Turner RB, Chiu C, Doraiswamy PM, Hero A, Henao R, Ginsburg GS, Dunn Jet al., 2021, Assessment of the Feasibility of Using Noninvasive Wearable Biometric Monitoring Sensors to Detect Influenza and the Common Cold Before Symptom Onset, JAMA NETWORK OPEN, Vol: 4, ISSN: 2574-3805

Journal article

She X, Zhai Y, Henao R, Woods CW, Chiu C, Ginsburg GS, Song PXK, Hero AOet al., 2021, Adaptive multi-channel event segmentation and feature extraction for monitoring health outcomes, IEEE Transactions on Biomedical Engineering, Vol: 68, Pages: 2377-2388, ISSN: 0018-9294

Objective: To develop a multi-channel device event segmentation and feature extraction algorithm that is robust to changes in data distribution. Methods: We introduce an adaptive transfer learning algorithm to classify and segment events from non-stationary multi-channel temporal data. Using a multivariate hidden Markov model (HMM) and Fisher's linear discriminant analysis (FLDA) the algorithm adaptively adjusts to shifts in distribution over time. The proposed algorithm is unsupervised and learns to label events without requiring a priori information about true event states. The procedure is illustrated on experimental data collected from a cohort in a human viral challenge (HVC) study, where certain subjects have disrupted wake and sleep patterns after exposure to an H1N1 influenza pathogen. Results: Simulations establish that the proposed adaptive algorithm significantly outperforms other event classification methods. When applied to early time points in the HVC data, the algorithm extracts sleep/wake features that are predictive of both infection and infection onset time. Conclusion: The proposed transfer learning event segmentation method is robust to temporal shifts in data distribution and can be used to produce highly discriminative event-labeled features for health monitoring. Significance: Our integrated multisensor signal processing and transfer learning method is applicable to many ambulatory monitoring applications.

Journal article

Rapeport G, Smith E, Gilbert A, Catchpole A, McShane H, Chiu Cet al., 2021, SARS-CoV-2 human challenge studies - establishing the model during an evolving pandemic, New England Journal of Medicine, Vol: 385, Pages: 961-964, ISSN: 0028-4793

Journal article

Paterson S, Kar S, Ung SK, Gardener Z, Bergstrom E, Ascough S, Kalyan M, Zyla J, Maertzdorf J, Mollenkopf H-J, Weiner J, Jozwik A, Jarvis H, Jha A, Nicholson BP, Veldman T, Woods CW, Mallia P, Kon OM, Kaufmann SHE, Openshaw PJ, Chiu Cet al., 2021, Innate-like gene expression of lung-resident memory CD8+ T-cells during experimental human influenza, American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 826-841, ISSN: 1073-449X

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T cells recognizing peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection.Objectives: To investigate the kinetics, phenotypes, and function of influenza virus–specific CD8+ resident memory T (Trm) cells in the lower airway and infer the molecular pathways associated with their response to infection in vivo.Methods: Healthy volunteers, aged 18–55, were inoculated intranasally with influenza A/California/4/09(H1N1). Blood, upper airway, and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed by using self-reported diaries, and the nasal viral load was assessed by using quantitative PCR. T-cell responses were analyzed by using a three-color FluoroSpot assay, flow cytometry with MHC I–peptide tetramers, and RNA sequencing, with candidate markers being confirmed by using the immunohistochemistry results for endobronchial biopsy specimens.Measurements and Main Results: After challenge, 57% of participants became infected. Preexisting influenza-specific CD8+ T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8+ T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8+ T cells in BAL fluid and blood by using RNA sequencing revealed 3,928 differentially expressed genes, including all major Trm-cell markers. However, gene set enrichment analysis of BAL-fluid CD8+ T cells showed primarily innate cell–related pathways and, during infection, included upregulation of innate chemokines (Cxcl1, Cxcl10, and Cxcl16) that were also expressed by CD8+ cells in bronchial tissues.Conclusions: CD8+ Trm cells in the human lung display innate-like gene and protein expression that demonstrates blur

Journal article

Felt SA, Sun Y, Jozwik A, Paras A, Habibi MS, Nickle D, Anderson L, Achouri E, Feemster KA, Cardenas AM, Turi KN, Chang M, Hartert TV, Sengupta S, Chiu C, Lopez CBet al., 2021, Detection of respiratory syncytial virus defective genomes in nasal secretions is associated with distinct clinical outcomes, Nature Microbiology, Vol: 6, Pages: 672-681, ISSN: 2058-5276

Respiratory syncytial virus (RSV) causes respiratory illness in children, immunosuppressed individuals and the elderly. However, the viral factors influencing the clinical outcome of RSV infections remain poorly defined. Defective viral genomes (DVGs) can suppress virus replication by competing for viral proteins and by stimulating antiviral immunity. We studied the association between detection of DVGs of the copy-back type and disease severity in three RSV A-confirmed cohorts. In hospitalized children, detection of DVGs in respiratory samples at or around the time of admission associated strongly with more severe disease, higher viral load and a stronger pro-inflammatory response. Interestingly, in experimentally infected adults, the presence of DVGs in respiratory secretions differentially associated with RSV disease severity depending on when DVGs were detected. Detection of DVGs early after infection associated with low viral loads and mild disease, whereas detection of DVGs late after infection, especially if DVGs were present for prolonged periods, associated with high viral loads and severe disease. Taken together, we demonstrate that the kinetics of DVG accumulation and duration could predict clinical outcome of RSV A infection in humans, and thus could be used as a prognostic tool to identify patients at risk of worse clinical disease.

Journal article

Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, Fairfield C, Carter E, Abrams S, Short C, Thaventhiran T, Bergstrom E, Gardener Z, Ascough S, Chiu C, Docherty AB, Hunt D, Crow YJ, Solomon T, Taylor GP, Turtle L, Harrison EM, Dunning J, Semple MG, Baillie JK, Openshaw PJMet al., 2021, Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19, Science Immunology, Vol: 6, Pages: 1-17, ISSN: 2470-9468

While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.

Journal article

Cuthbertson L, James P, Habibi M, Thwaites R, Paras A, Chiu C, Openshaw P, Cookson W, Moffatt Met al., 2020, The Effect of RSV Infection on the Respiratory Microbiome of Adults

<jats:title>Abstract</jats:title> <jats:p>Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection in infants. It is being increasingly recognised as a cause of morbidity and mortality in the elderly. Microbial dysbiosis in the respiratory tract has been hypothesized to predispose individuals to severe RSV infection. This study explores changes in the bacterial community over the course of a controlled human challenge study. From 37 healthy adult patients exposed to a challenge inoculum of RSV, throat swabs were collected daily for 10 days during quarantine and on days 14 and 28 post quarantine. Swabs were processed for bacterial and viral quantification and 16S rRNA gene sequencing. Over the course of the study three clinical outcomes were observed; clinical cold (n = 17), asymptomatic infection (n = 6) or no infection (n = 14). These three outcome groups had no significant differences in the bacterial load, diversity or community composition at baseline. Over the twenty-eight days following RSV inoculation no significant changes in the bacterial community were observed between the outcome groups.This study of healthy adults revealed no major changes in the bacterial community of the respiratory tracts following RSV inoculation, suggesting that this microbial community is resilient to viral perturbations.</jats:p>

Journal article

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