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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.

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.

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.

Barnes E.,University of Oxford | Flanagan P.,University of Oxford | Brown A.,University of Oxford | Robinson N.,University of Oxford | And 12 more authors.
Journal of Infectious Diseases | Year: 2010

A xenotropic murine leukemia virus-related virus (XMRV) has recently been reported in association with prostate cancer and chronic fatigue syndrome, with a prevalence of up to 3.7% in the healthy population. We looked for XMRV in 230 patients with human immunodeficiency virus type 1 or hepatitis C infection. XMRV was undetectable in plasma or peripheral blood mononuclear cells by polymerase chain reaction targeting XMRV gag or env. T cell responses to XMRV Gag were undetectable in peripheral blood mononuclear cells by ex vivo gamma interferon enzyme-linked immunospot assay. In our cohorts, XMRV was not enriched in patients with blood-borne or sexually transmitted infections fromthe United Kingdom and Western Europe. © 2010 by the Infectious Diseases Society of America. All rights reserved.

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.

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