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Colloca S.,Okairos Inc. | Barnes E.,Peter Medawar Building for Pathogen Research | Barnes E.,National Health Research Institute | Folgori A.,Okairos Inc. | And 23 more authors.
Science Translational Medicine | Year: 2012

Replication-defective adenovirus vectors based on human serotype 5 (Ad5) induce protective immune responses against diverse pathogens and cancer in animal models, as well as elicit robust and sustained cellular immunity in humans. However, most humans have neutralizing antibodies to Ad5, which can impair the immunological potency of such vaccines. Here, we show that rare serotypes of human adenoviruses, which should not be neutralized in most humans, are far less potent as vaccine vectors than Ad5 in mice and nonhuman primates, casting doubt on their potential efficacy in humans. To identify novel vaccine carriers suitable for vaccine delivery in humans, we isolated and sequenced more than 1000 adenovirus strains from chimpanzees (ChAd). Replication-defective vectors were generated from a subset of these ChAd serotypes and screened to determine whether they were neutralized by human sera and able to grow in human cell lines. We then ranked these ChAd vectors by immunological potency and found up to a thousandfold variation in potency for CD8+ T cell induction in mice. These ChAd vectors were safe and immunologically potent in phase 1 clinical trials, thereby validating our screening approach. These data suggest that the ChAd vectors developed here represent a large collection of non - cross-reactive, potent vectors that may be exploited for the development of new vaccines.


PubMed | Peter Medawar Building for Pathogen Research, Imperial College London, National and Kapodistrian University of Athens, Chelsea and Westminster Hospital and 3 more.
Type: Journal Article | Journal: PLoS pathogens | Year: 2016

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/l or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of exhaustion or immune checkpoint markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.


Matthews P.C.,Peter Medawar Building for Pathogen Research | Matthews P.C.,University of Oxford | Geretti A.M.,University of Liverpool | Goulder P.J.R.,Peter Medawar Building for Pathogen Research | And 4 more authors.
Journal of Clinical Virology | Year: 2014

Human immunodeficiency virus (HIV), Hepatitis B (HBV) and Hepatitis C (HCV) are blood-borne viruses with potentially shared routes of transmission. In high-income settings, the impact of antiretroviral therapy (ART) on survival has unmasked chronic liver disease from viral hepatitis B or hepatitis C as a leading cause of morbidity and mortality in individuals with HIV infection. It is now feared that progressive liver disease may threaten the success of ART programmes in developing countries, where HCV or HBV testing and monitoring are not yet systematic among HIV-infected patients and ART use is generally blind to these co-infections. We set out to review recent data from Sub-Saharan Africa, in order to build a detailed and up-to-date picture of the epidemiology and emerging impact of HBV and HCV coinfection in countries at the heart of the HIV pandemic. There is a preponderance of HIV/HBV coinfection compared to HIV/HCV in this region, and significant caveats exist regarding the accuracy of published HCV seroprevalence surveys. Morbidity and mortality of coinfection is significant, and may be further enhanced in African populations due to the influence of host, viral and environmental factors. Careful scrutiny of the coinfection problem is vital to inform an approach to directing resources, planning public health initiatives, providing clinical care, and guiding future research. © 2014 Elsevier B.V.


Fitzmaurice K.,University of Oxford | Hurst J.,University of Oxford | Dring M.,Trinity College Dublin | Rauch A.,University of Bern | And 6 more authors.
Gut | Year: 2014

Background Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. Objective This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. Design We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. Results Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A∗03 (OR 0.36 (0.15 to 0.89), p=0.027)-B∗27 (OR 0.12 (0.03 to 0.45), p=<0.001),-DRB1∗01:01 (OR 0.2 (0.07 to 0.61), p=0.005),-DRB1∗04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1∗02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. Conclusions This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.


Matthews P.C.,University of Oxford | Matthews P.C.,Peter Medawar Building for Pathogen Research | Chue A.L.,University of Oxford | Wyllie D.,University of Oxford | And 7 more authors.
Journal of Infection | Year: 2014

Objective: Teicoplanin is widely used for the treatment of severe gram-positive infection, aiming to achieve trough serum levels of 20-60mg/L for patients with severe infection. A standard 400mg daily dose is frequently associated with sub-therapeutic levels, and we have therefore changed our routine approach to 600mg daily (following loading doses in each case). We set out to investigate the impact of this dose increase on drug levels and potential side-effects. Methods: We undertook a retrospective study of 549 consecutive adult Out-Patient Antimicrobial Treatment (OPAT) episodes treated with intravenous teicoplanin. Results: Therapeutic teicoplanin levels were more frequently achieved in patients treated with 600mg compared to 400mg daily (68% vs. 37% respectively, p<0.0001), without an increased frequency of potentially toxic levels, defined as >60mg/L (6% vs. 8% respectively, p=0.4). There was no difference in the incidence of neutropaenia, eosinophilia, thrombocytopaenia, acute renal injury or treatment cessation in patients treated with the higher teicoplanin dose. Conclusions: In the majority of stable adult patients with normal renal function, we advocate a loading regimen (600mg b.d. for two doses) followed by a 600mg daily teicoplanin dose in order to achieve therapeutic trough levels. © 2013 The British Infection Association.


Jones M.,Peter Medawar Building for Pathogen Research | Williams J.,Peter Medawar Building for Pathogen Research | Gartner K.,Peter Medawar Building for Pathogen Research | Phillips R.,Peter Medawar Building for Pathogen Research | And 7 more authors.
Journal of Virological Methods | Year: 2014

Droplet Digital PCR (ddPCR) represents a new and alternative platform to conventional quantitative-PCR (qPCR) for the quantitation of DNA templates. However, the proposed improvement in sensitivity and reproducibility offered by ddPCR is not yet fully proven, partly because the delineation between positive and negative responses is not always clear.Data are presented demonstrating the sensitivity of the ddPCR system to both reagent concentrations and choice of cut-off for defining positive and negative results. By implementing k-nearest clustering, cut-offs are produced that improve the accuracy of ddPCR where target DNA is present at low copy numbers, a key application of ddPCR. This approach is applied to human albumin and HIV-1 proviral DNA ddPCR quantitative protocols. This tool is coded in JavaScript and has been made available for free in a web browser at http://www.definetherain.org.uk. Optimisation of the analyses of raw ddPCR data using 'definetherain' indicates that low target number detection can be improved by its implementation. Further application to patient samples will help define the clinical utility of this approach. © 2014.


Thornhill J.,Imperial College London | Fidler S.,Imperial College London | Frater J.,Collaborative HIV Eradication of Reservoirs UK BRC CHERUB | Frater J.,Peter Medawar Building for Pathogen Research | And 2 more authors.
Current Opinion in Infectious Diseases | Year: 2015

Purpose of review: To explore how ethical considerations, improved diagnostics and data from clinical trials might see the lowering of some of the barriers blocking a cure for HIV infection over the next 5 years. Recent findings: Despite the recent well publicized but eventually disappointing case reports, there remains only one successful HIV cure, the 'Berlin patient'. We will review the data suggesting that more potent agents might achieve in-vivo viral activation and explore the tantalizing phenomenon of 'posttreatment control' following treatment in primary HIV infection. We will also explore how new assays and novel interventions might move the field forward. Summary: There is a need for new agents that can be safely tested to impact the viral reservoir, a more meaningful understanding of how to assay patient samples, and research into mechanisms behind how the reservoir is established and impacted by therapy. With HIV+ve individuals responding so well to antiretroviral therapy, new trials must be tested hand-in-hand with guidance from patient representatives, especially with respect to determining the acceptable risk. The road to a cure is going to be difficult, but it is vital that inevitable disappointments do not detract from the final goal, which remains worth striving for. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Prendergast A.,University of Oxford | Prendergast A.,Peter Medawar Building for Pathogen Research | Goodliffe H.,University of Oxford | Clapson M.,Imperial College London | And 6 more authors.
AIDS | Year: 2011

HIV-specific Elispot responses were investigated in 57 antiretroviral therapy-naive children, of median age 9.9 years. CD8 T-cell responses were detected in 96% children; Nef was the immunodominant protein. Responses broadened over time, but there was no association between magnitude, breadth or specificity of response and viraemia. Gag-specific CD4 T-cell responses, detectable in 26% children, correlated inversely with viraemia (R = -0.43, P < 0.001), suggesting that preservation of this cell population may be an important goal of therapeutic/vaccine strategies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Rajoriya N.,Peter Medawar Building for Pathogen Research | Fergusson J.,Peter Medawar Building for Pathogen Research | Leithead J.A.,Queen Elizabeth Hospital | Klenerman P.,Peter Medawar Building for Pathogen Research | Klenerman P.,Oxford Radcliffe Hospital
Frontiers in Immunology | Year: 2014

Discovered thirty years ago, gamma delta (γδ) T-lymphocytes remain an intriguing and enigmatic T-cell subset. Although in humans they comprise a small fraction of the total circulating T-lymphocyte pool, they represent an important T-cell subset in tissues such as the liver, with roles bridging the innate and adaptive immune systems. The associations of γδ T-lymphocytes with chronic liver disease have been explored -however there remain conflicting data as to whether these T-cells are pathogenic or protective. In patients with some forms of liver disease, their expansion in the periphery and especially in the liver may indeed help pathogen clearance, whilst in other conditions their presence may, in contrast, contribute to disease progression. γδ T cells can also express CD161, a C-type lectin, and such cells have been found to be involved in the pathogenesis of inflammatory disease. CD161+ T-cells of diverse subsets are known to be enriched in the livers of patients with chronic hepatitis C. This article serves to provide a review of the γδ T-cell population and its role in hepatitis C and other chronic liver diseases, and also explores a potential role of the CD161+ γδ T-cells in liver diseases. © 2014 Rajoriya, Fergusson, Leithead and Klenerman.


O'Hara G.A.,Peter Medawar Building for Pathogen Research | Welten S.P.M.,Leiden University | Klenerman P.,Peter Medawar Building for Pathogen Research | Arens R.,Leiden University
Trends in Immunology | Year: 2012

Typically, during viral infections, T cells encounter antigen, undergo proliferative expansion and ultimately contract into a pool of memory cells. However, after infection with cytomegalovirus, a ubiquitous β-herpesvirus, T cell populations specific for certain epitopes do not contract but instead are maintained and/or accumulate at high frequencies with a characteristic effector-memory phenotype. This feature has also been noted after other infections, for example, by parvoviruses. We discuss this so-called memory T cell inflation and the factors involved in this phenomenon. Also, we consider the potential therapeutic use of memory T cell inflation as a vaccine strategy and the associated implications for immune senescence. © 2011 Elsevier Ltd.

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