Imperial College London

DrChristopherChiu

Faculty of MedicineDepartment of Infectious Disease

Clinical Reader in Molecular Haemato-oncology
 
 
 
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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
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33 results found

Habibi M, Thwaites R, Chang M, Jozwik A, Paras A, Kirsebom F, Varese A, Owen A, Cuthbertson L, James P, Tunstall T, Nickle D, Hansel T, Moffatt M, Johansson C, Chiu C, Openshaw Pet al., Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection, Science, ISSN: 0036-8075

Journal article

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

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

Journal article

Holzer B, Morgan SB, Martini V, Sharma R, Clark B, Chiu C, Salguero FJ, Tchilian Eet al., 2019, Immunogenicity and protective efficacy of seasonal human live attenuated cold-adapted influenza virus vaccine in pigs, Frontiers in Immunology, Vol: 10, Pages: 1-13, ISSN: 1664-3224

Influenza A virus infection is a global health threat to livestock and humans, causing substantial mortality and morbidity. As both pigs and humans are readily infected with influenza viruses of similar subtype, the pig is a robust and appropriate model for investigating swine and human disease. We evaluated the efficacy of the human cold-adapted 2017–2018 quadrivalent seasonal LAIV in pigs against H1N1pdm09 challenge. LAIV immunized animals showed significantly reduced viral load in nasal swabs. There was limited replication of the H1N1 component of the vaccine in the nose, a limited response to H1N1 in the lung lymph nodes and a low H1N1 serum neutralizing titer. In contrast there was better replication of the H3N2 component of the LAIV, accompanied by a stronger response to H3N2 in the tracheobronchial lymph nodes (TBLN). Our data demonstrates that a single administration of human quadrivalent LAIV shows limited replication in the nose and induces detectable responses to the H1N1 and H3N2 components. These data suggest that pigs may be a useful model for assessing LAIV against influenza A viruses.

Journal article

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

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

Journal article

Fourati S, Taa A, Mahmoudian M, Burkhart JG, Klen R, Henao R, Yu T, Aydin Z, Yeung KY, Ahsen ME, Almugbel R, Jahandideh S, Liang X, Nordling TEM, Shiga M, Stanescu A, Vogel R, Pandey G, Chiu C, McClain MT, Woods CW, Ginsburg GS, Elo LL, Tsalik EL, Mangravite LM, Sieberts SKet al., 2018, A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection, Nature Communications, Vol: 9, Pages: 1-11, ISSN: 2041-1723

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses.

Journal article

Ascough SC, Paterson S, Chiu C, 2018, Induction and subversion of human protective immunity: contrasting influenza and respiratory syncytial virus, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

Respiratory syncytial virus (RSV) and influenza are among the most important causes of severe respiratory disease worldwide. Despite the clinical need, barriers to developing reliably effective vaccines against these viruses have remained firmly in place for decades. Overcoming these hurdles requires better understanding of human immunity and the strategies by which these pathogens evade it. Although superficially similar, the virology and host response to RSV and influenza are strikingly distinct. Influenza induces robust strain-specific immunity following natural infection, although protection by current vaccines is short-lived. In contrast, even strain-specific protection is incomplete after RSV and there are currently no licensed RSV vaccines. Although animal models have been critical for developing a fundamental understanding of antiviral immunity, extrapolating to human disease has been problematic. It is only with recent translational advances (such as controlled human infection models and high-dimensional technologies) that the mechanisms responsible for differences in protection against RSV compared to influenza have begun to be elucidated in the human context. Influenza infection elicits high-affinity IgA in the respiratory tract and virus-specific IgG, which correlates with protection. Long-lived influenza-specific T cells have also been shown to ameliorate disease. This robust immunity promotes rapid emergence of antigenic variants leading to immune escape. RSV differs markedly, as reinfection with similar strains occurs despite natural infection inducing high levels of antibody against conserved antigens. The immunomodulatory mechanisms of RSV are thus highly effective in inhibiting long-term protection, with disturbance of type I interferon signaling, antigen presentation and chemokine-induced inflammation possibly all contributing. These lead to widespread effects on adaptive immunity with impaired B cell memory and reduced T cell generation and funct

Journal article

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

Conference paper

Turner RD, Chiu C, Churchyard GJ, Esmail H, Lewinsohn DM, Gandhi NR, Fennelly KPet al., 2017, Tuberculosis Infectiousness and Host Susceptibility, Journal of Infectious Disease, Vol: 216, Pages: S636-S643, ISSN: 1537-6613

The transmission of tuberculosis is complex. Necessary factors include a source case with respiratory disease that has developed sufficiently for Mycobacterium tuberculosis to be present in the airways. Viable bacilli must then be released as an aerosol via the respiratory tract of the source case. This is presumed to occur predominantly by coughing but may also happen by other means. Airborne bacilli must be capable of surviving in the external environment before inhalation into a new potential host—steps influenced by ambient conditions and crowding and by M. tuberculosis itself. Innate and adaptive host defenses will then influence whether new infection results; a process that is difficult to study owing to a paucity of animal models and an inability to measure infection directly. This review offers an overview of these steps and highlights the many gaps in knowledge that remain.

Journal article

Li S, Sullivan NL, Rouphael N, Yu T, Banton S, Maddur MS, McCausland M, Chiu C, Canniff J, Dubey S, Liu K, Tran V, Hagan T, Duraisingham S, Wieland A, Mehta AK, Whitaker JA, Subramaniam S, Jones DP, Sette A, Vora K, Weinberg A, Mulligan MJ, Nakaya HI, Levin M, Ahmed R, Pulendran Bet al., 2017, Metabolic Phenotypes of Response to Vaccination in Humans., Cell, Vol: 169, Pages: 862-877.e17

Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4(+) T cells yet limited CD8(+) T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.

Journal article

Openshaw PJM, Chiu C, Culley FJ, Johansson Cet al., 2017, Protective and Harmful Immunity to RSV Infection, Annual Review of Immunology, Vol: 35, Pages: 501-532, ISSN: 0732-0582

Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.

Journal article

Chiu C, 2017, Novel immunological insights in accelerating RSV vaccine development, Vaccine, Vol: 35, Pages: 459-460, ISSN: 0264-410X

Journal article

Habibi MS, Chiu C, 2016, Controlled human infection with RSV: the opportunities of experimental challenge, Vaccine, Vol: 35, Pages: 489-495, ISSN: 1873-2518

Despite the recent explosion in RSV vaccine development, there remain substantial hurdles to overcome before licensing of effective vaccines will allow widespread use, particularly in high-risk populations. Incomplete understanding of mechanisms and correlates of protection against RSV mean that, for the time being, successful RSV vaccines must directly demonstrate efficacy, which necessitates large and costly clinical trials in naturally infected patients. To mitigate the risks inherent in progressing to these late-stage trials, experimental human RSV infection studies have recently been re-established, representing the interface between pre-clinical models and observational studies of patients. Not only can they be used for early proof-of-concept clinical trials to test vaccine efficacy, but human challenge studies also offer the potential to better understand protective immunity against RSV infection to improve vaccine design and delivery. In the past, controlled human infection studies with RSV have been instrumental in elucidating the influence of factors such as route of infection and type of inoculum on the course of disease. Recently, efficacy trials of novel RSV antiviral drugs have also been successfully undertaken. Now, with advances in technology, detailed investigations of human mucosal immunity in the RSV-infected airway are possible. These have indicated defects in RSV-induced humoral and CD8+ T cell immunity that may contribute to the recurrent symptomatic infection that occurs throughout life and should be circumvented by optimal vaccines. Here, we discuss the insights derived from RSV human challenge models; the major impediments to their more widespread uptake; and their potential benefit in accelerating vaccine development, including future directions to further enhance the relevance of these models to at-risk patient populations.

Journal article

Chiu C, 2016, Seasonal influenza vaccines and hurdles to mutual protection, Clinical Microbiology and Infection, Vol: 22, Pages: S113-S119, ISSN: 1469-0691

While vaccines against seasonal influenza are available, major hurdles still exist that prevent their use having any impact on epidemic spread. Recent epidemiologic data question the appropriateness of traditional vaccination timing (prior to the winter season) in many parts of the world. Furthermore, vaccine uptake in most countries even in high-risk populations does not reach the 75% target recommended by the World Health Organization. Influenza viruses continually undergo antigenic variation, and both inactivated and live attenuated influenza vaccines confer only short-lived strain-specific immunity, so annual revaccination is required. Improving vaccine-induced immunity is therefore an important goal. A vaccine that could confer durable protection against emerging influenza strains could significantly reduce onward transmission. Therefore, further understanding of protective immunity against influenza (including broadly cross-protective immune mechanisms such as haemagglutinin stem-binding antibodies and T cells) offers the hope of vaccines that can confer the long-lived heterosubtypic immune responses required for mutual protection.

Journal article

Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, Dhariwal J, Almond M, Wong EH, Sykes A, Maybeno M, Del Rosario J, Trujillo-Torralbo MB, Mallia P, Sidney J, Peters B, Kon OM, Sette A, Johnston SL, Openshaw PJ, Chiu Cet al., 2016, Erratum: RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 7, ISSN: 2041-1723

Journal article

Currie SM, Findlay EG, McFarlane AJ, Fitch PM, Boettcher B, Colegrave N, Paras A, Jozwik A, Chiu C, Schwarze J, Davidson DJet al., 2016, Cathelicidins have direct antiviral activity against respiratory syncytial virus in vitro and protective function in vivo in mice and humans, Journal of Immunology, Vol: 196, Pages: 2699-2710, ISSN: 1550-6606

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection in infants, causing significant morbidity and mortality. No vaccine or specific, effective treatment is currently available. A more complete understanding of the key components of effective host response to RSV and novel preventative and therapeutic interventions are urgently required. Cathelicidins are host defense peptides, expressed in the inflamed lung, with key microbicidal and modulatory roles in innate host defense against infection. In this article, we demonstrate that the human cathelicidin LL-37 mediates an antiviral effect on RSV by inducing direct damage to the viral envelope, disrupting viral particles and decreasing virus binding to, and infection of, human epithelial cells in vitro. In addition, exogenously applied LL-37 is protective against RSV-mediated disease in vivo, in a murine model of pulmonary RSV infection, demonstrating maximal efficacy when applied concomitantly with virus. Furthermore, endogenous murine cathelicidin, induced by infection, has a fundamental role in protection against disease in vivo postinfection with RSV. Finally, higher nasal levels of LL-37 are associated with protection in a healthy human adult RSV infection model. These data lead us to propose that cathelicidins are a key, nonredundant component of host defense against pulmonary infection with RSV, functioning as a first point of contact antiviral shield and having additional later-phase roles in minimizing the severity of disease outcome. Consequently, cathelicidins represent an inducible target for preventative strategies against RSV infection and may inform the design of novel therapeutic analogs for use in established infection.

Journal article

Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, Dhariwal J, Almond M, Wong EHC, Sykes A, Maybeno M, Del Rosario J, Trujillo-Torralbo M, Mallia P, Sidney J, Peters B, Kon OM, Sette A, Johnston SL, Openshaw PJ, Chiu Cet al., 2015, RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 6, ISSN: 2041-1723

In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyze phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. These are more highly differentiated but express fewer cytotoxicity markers than in blood, but their abundance prior to infection correlates with protection from more severe disease.

Journal article

Habibi MS, Jozwik A, Makris S, Dunning J, Paras A, DeVincenzo JP, de Haan CA, Wrammert J, Openshaw PJ, Chiu C, The MOSAIC Investigatorset al., 2015, Impaired Antibody-mediated Protection and Defective IgA B Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus., American Journal of Respiratory and Critical Care Medicine, ISSN: 1535-4970

Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) re-infects throughout life. After >40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. Objectives: Characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B cell frequencies and antibody longevity. Measurements and Main Results: Despite moderately high levels of pre-existing serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from PCR-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects, but correlated with plasmablasts that peaked around day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, where virus-specific IgA memory B cells were readily recovered. Conclusions: This observed specific defect in IgA memory may partly explain RSV's ability to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.

Journal article

Chiu C, Openshaw PJ, 2015, Antiviral B cell and T cell immunity in the lungs, NATURE IMMUNOLOGY, Vol: 16, Pages: 18-26, ISSN: 1529-2908

Journal article

Chiu C, Ellebedy AH, Wrammert J, Ahmed Ret al., 2015, B Cell Responses to Influenza Infection and Vaccination, INFLUENZA PATHOGENESIS AND CONTROL - VOL II, Vol: 386, Pages: 381-398, ISSN: 0070-217X

Journal article

Jozwik A, Habibi M, Paras A, Guvenel A, Mallia P, Almond M, Wong E, Sykes A, Dhariwal J, Del Rosario J, Trujillo-Torralbo B, Kon OM, Johnston S, Openshaw P, Chiu Cet al., 2014, Human T-cell responses to RSV infection in the lower airway, IMMUNOLOGY, Vol: 143, Pages: 76-76, ISSN: 0019-2805

Journal article

Gonzalez LM, Jozwik AA, Habibi MS, Openshaw PJM, Chiu Cet al., 2014, Quality of antigen-specific B-cell responses as a correlate of protection against RSV, IMMUNOLOGY, Vol: 143, Pages: 75-75, ISSN: 0019-2805

Journal article

Ellebedy AH, Krammer F, Li G-M, Miller MS, Chiu C, Wrammert J, Chang CY, Davis CW, McCausland M, Elbein R, Edupuganti S, Spearman P, Andrews SF, Wilson PC, GarcĂ­a-Sastre A, Mulligan MJ, Mehta AK, Palese P, Ahmed Ret al., 2014, Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans., Proc Natl Acad Sci U S A, Vol: 111, Pages: 13133-13138

The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.

Journal article

Guvenel AK, Chiu C, Openshaw PJM, 2014, Current concepts and progress in RSV vaccine development, EXPERT REVIEW OF VACCINES, Vol: 13, Pages: 333-344, ISSN: 1476-0584

Journal article

Chiu C, McCausland M, Sidney J, Duh F-M, Rouphael N, Mehta A, Mulligan M, Carrington M, Wieland A, Sullivan NL, Weinberg A, Levin MJ, Pulendran B, Peters B, Sette A, Ahmed Ret al., 2014, Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV, PLoS Pathogens, Vol: 10, Pages: 1-12, ISSN: 1553-7366

Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other α-herpesviruses, HSV-1 and HSV-2, but also the γ-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a “pan-herpesvirus” vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this.

Journal article

Guvenal A, Jozwik A, Paras A, Openshaw P, Chiu Cet al., 2013, CD4+ T cell subsets in experimental human infection with Respiratory Syncytial Virus, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 123-123, ISSN: 0019-2805

Conference paper

Openshaw PJ, Chiu C, 2013, Protective and dysregulated T cell immunity in RSV infection, CURRENT OPINION IN VIROLOGY, Vol: 3, Pages: 468-474, ISSN: 1879-6257

Journal article

Sullivan N, McCausland M, Chiu C, Sidney J, Rouphael N, Mehta A, Mulligan M, Peters B, Sette A, Pulendran B, Ahmed Ret al., 2013, Antigen-specific T cell and B cell responses to the herpes zoster vaccine Zostavax (R) in the young and elderly, 100th Annual Meeting of the American-Association-of-Immunologists, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767

Conference paper

Chiu C, Wrammert J, Li G-M, McCausland M, Wilson PC, Ahmed Ret al., 2013, Cross-reactive humoral responses to influenza and their implications for a universal vaccine, TRANSLATIONAL IMMUNOLOGY IN ASIA-OCEANIA, Vol: 1283, Pages: 13-21, ISSN: 0077-8923

Journal article

Li G-M, Chiu C, Wrammert J, McCausland M, Andrews SF, Zheng N-Y, Lee J-H, Huang M, Qu X, Edupuganti S, Mulligan M, Das SR, Yewdell JW, Mehta AK, Wilson PC, Ahmed Ret al., 2012, Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells., Proc Natl Acad Sci U S A, Vol: 109, Pages: 9047-9052

We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.

Journal article

Palmowski MJ, Parker M, Choudhuri K, Chiu C, Callan MFC, van der Merwe PA, Cerundolo V, Gould KGet al., 2009, A Single-Chain H-2D(b) Molecule Presenting an Influenza Virus Nucleoprotein Epitope Shows Enhanced Ability at Stimulating CD8(+) T Cell Responses In Vivo, JOURNAL OF IMMUNOLOGY, Vol: 182, Pages: 4565-4571, ISSN: 0022-1767

Journal article

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