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Taylor P.C.,University of Warwick | Clark A.J.,University of Warwick | Marsh A.,University of Warwick | Singer D.R.J.,University of Warwick | Dilly S.J.,SEEK
Chemical Communications | Year: 2013

Magic Tag® immobilisation of bioactive molecules coupled with bacteriophage display, followed by an ELISA assay, provides a protocol that can probe interactions of drugs with putative products of alternative initiation of translation as exemplified by the binding of immobilised flecainide to protein products of genes linked to sudden cardiac death. © The Royal Society of Chemistry 2013.

Pleguezuelos O.,SEEK | Robinson S.,SEEK | Fernandez A.,SEEK | Stoloff G.A.,SEEK | And 8 more authors.
Clinical and Vaccine Immunology | Year: 2015

Current influenza vaccines elicit primarily antibody-based immunity. They require yearly revaccination and cannot be manufactured until the identification of the circulating viral strain(s). These issues remain to be addressed. Here we report a phase Ib trial of a vaccine candidate (FLU-v) eliciting cellular immunity. Thirty-two males seronegative for the challenge virus by hemagglutination inhibition assay participated in this single-center, randomized, double-blind study. Volunteers received one dose of either the adjuvant alone (placebo, n=16) or FLU-v (500 μg) and the adjuvant (n=16), both in saline. Twenty-one days later, FLU-v (n=15) and placebo (n=13) volunteers were challenged with influenza virus A/Wisconsin/67/2005 (H3N2) and monitored for 7 days. Safety, tolerability, and cellular responses were assessed pre- and postvaccination. Virus shedding and clinical signs were assessed postchallenge. FLU-v was safe and well tolerated. No difference in the prevaccination FLU-v-specific gamma interferon (IFN-γ) response was seen between groups (average±the standard error of the mean [SEM] for the placebo and FLU-v, respectively, 1.4-fold±0.2-fold and 1.6-fold±0.5-fold higher than the negative-control value). Nineteen days postvaccination, the FLU-v group, but not the placebo group, developed FLU-v-specific IFN-γ responses (8.2-fold±3.9-fold versus 1.3- fold±0.1-fold higher than the negative-control value [average±SEM] for FLU-v versus the placebo [P=0.0005]). FLU-vspecific cellular responses also correlated with reductions in both viral titers (P=0.01) and symptom scores (P=0.02) postchallenge. Increased cellular immunity specific to FLU-v correlates with reductions in both symptom scores and virus loads.

Pleguezuelos O.,SEEK | Robinson S.,SEEK | Stoloff G.A.,SEEK | Caparros-Wanderley W.,SEEK
Vaccine | Year: 2012

Objectives: Current Influenza vaccines elicit antibody mediated prophylactic immunity targeted to viral capsid antigens. Despite their global use these vaccines must be administered yearly to the population, cannot be manufactured until the circulating viral strain(s) have been identified and have limited efficacy. A need remains for Influenza vaccines addressing these issues and here we report the results of a Phase Ib trial of a novel synthetic Influenza vaccine (FLU-v) targeting T cell responses to NP, M1 and M2. Methods: Forty-eight healthy males aged 18-40 were recruited for this single-centre, randomised, double blind study. Volunteers received one single low (250. μg) or high (500. μg) dose of FLU-v, either alone or adjuvanted. Safety, tolerability and basic immunogenicity (IgG and IFN-γ responses) parameters were assessed pre-vaccination and for 21 days post-vaccination. Results: FLU-v was found to be safe and well tolerated with no vaccine associated severe adverse events. Dose-dependent IFN-γ responses >2-fold the pre-vaccination level were detected in 80% and 100% of volunteers receiving, respectively, the low and high dose adjuvanted FLU-v formulations. No formulation tested induced any significant FLU-v antibody response. Conclusion: FLU-v is safe and induces a vaccine-specific cellular immunity. Cellular immune responses are historically known to control and mitigate infection and illness during natural infection. © 2012 Elsevier Ltd.

Pleguezuelos O.,SEEK | Robinson S.,SEEK | Fernandez A.,SEEK | Stoloff G.A.,SEEK | Caparros-Wanderley W.,SEEK
Clinical and Vaccine Immunology | Year: 2015

Influenza live viral challenges in humans are valuable models for testing the efficacy of vaccines and antiviral agents. Volunteers are treated with an investigational agent, and their clinical outcomes postchallenge are compared to those of placebo-treated volunteers. Despite using a common protocol, similar recruitment criteria, and similar doses of the same challenge strain, we noticed differences in disease severity outcomes between the placebo groups from different studies. We investigated whether these differences were significant and, if so, whether any pattern and its possible causes could be identified. We compared the clinical outcomes postchallenge in placebo groups from five clinical studies carried out between 2008 and 2013. Correlations between the prechallenge heterosubtypic cellular response (gamma interferon [IFN-γ]) and postchallenge clinical outcomes were also investigated in one study. Placebo groups from studies carried out between 2009 and 2010 attained significantly reduced (P<0.05) symptom scores postchallenge compared to those of placebo groups from studies carried out in either 2008 or 2013. Also, in a 2010 study, the frequency of high-influenza heterosubtypic cellular responders prevaccination was significantly lower in the test group (FLU-v) than that in the placebo group (P≤0.04). Moreover, the increased preexisting heterosubtypic cellular response of the placebo group correlated with reductions in symptom score and viral shedding postchallenge (P< 0.023). Only postvaccination did the test group display an equivalent correlation. The last influenza pandemic coincided with a significant reduction in disease severity outcomes. This reduction also appears to correlate with increased preexisting influenza heterosubtypic cellular responses. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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