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DeVincenzo J.P.,University of Memphis | DeVincenzo J.P.,Le Bonheur Childrens Hospital | Whitley R.J.,University of Alabama at Birmingham | Mackman R.L.,Gilead Sciences | And 14 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists. METHODS: We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores. RESULTS: Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] x hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P = 0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 x hours; P = 0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806. CONCLUSIONS: Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. Copyright © 2014 Massachusetts Medical Society.


De Vincenzo J.P.,University of Memphis | McClure M.W.,Alios BioPharma | Symons J.A.,Alios BioPharma | Fathi H.,Retroscreen Virology | And 7 more authors.
New England Journal of Medicine | Year: 2015

Background Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. Methods We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. Results A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents ¡Á hours per milliliter, respectively (P¡Ü0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P¡Ü0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose ¡ viral clearance was accelerated (P¡Ü0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. Conclusions In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. © 2015 Massachusetts Medical Society. All rights reserved.


Bagga B.,University of Tennessee Health Science Center | Bagga B.,Le Bonheur Childrens Hospital | Bagga B.,Childrens Foundation Research Center | Woods C.W.,Duke University | And 13 more authors.
Antiviral Therapy | Year: 2013

Background: Antivirals reduce inluenza viral replication and illness measures, particularly if initiated early, within 48 h of symptom onset. Whether experimental antivirals that reduce respiratory syncytial virus (RSV) load would also reduce disease is unknown. This study compares viral and disease dynamics in humans experimentally infected with inluenza or RSV. Methods: Clinical strains of RSV-A and inluenza A were inoculated intranasally into 20 and 17 healthy volunteers, respectively, on day 0. Symptom scores and nasal washes were performed twice daily, and daily mucus weights were collected. Viral loads in nasal washes were quantiied by culture (plaque assay in HEp-2 cells for RSV and by end point dilution in Madin-Darby canine kidney cells for inluenza). Results: After inluenza inoculation, inluenza viral load and illness markers increased simultaneously until day 2. Within individual subjects, peak inluenza load occurred 0.4 days (95% CI -0.4, 1.3) before peak symptoms. Inluenza viral load and disease declined thereafter. After RSV inoculation, a longer incubation period occurred prior to viral detection and symptom onset. RSV load and disease increased together until day 5. Within individual subjects, peak RSV loads occurred 0.2 days (95% CI -0.7, 1.05) before peak symptoms, after which both illness measures and viral load declined together. Conclusions: Viral and disease dynamics in experimental human infections suggest that reducing RSV load, if timed similarly to clinically-effective inluenza antivirals, might be expected to have a similar or greater window of opportunity for reducing clinical RSV disease. © 2013 International Medical Press 1359-6535 (print) 2040-2058 (online).


Wilkinson T.M.,University of Southampton | Li C.K.F.,Weatherall Institute of Molecular Medicine | Chui C.S.C.,Weatherall Institute of Molecular Medicine | Huang A.K.Y.,Weatherall Institute of Molecular Medicine | And 12 more authors.
Nature Medicine | Year: 2012

Protective immunity against influenza virus infection is mediated by neutralizing antibodies, but the precise role of T cells in human influenza immunity is uncertain. We conducted influenza infection studies in healthy volunteers with no detectable antibodies to the challenge viruses H3N2 or H1N1. We mapped T cell responses to influenza before and during infection. We found a large increase in influenza-specific T cell responses by day 7, when virus was completely cleared from nasal samples and serum antibodies were still undetectable. Preexisting CD4 +, but not CD8 +, T cells responding to influenza internal proteins were associated with lower virus shedding and less severe illness. These CD4 + cells also responded to pandemic H1N1 (A/CA/07/2009) peptides and showed evidence of cytotoxic activity. These cells are an important statistical correlate of homotypic and heterotypic response and may limit severity of influenza infection by new strains in the absence of specific antibody responses. Our results provide information that may aid the design of future vaccines against emerging influenza strains. © 2012 Nature America, Inc. All rights reserved. © 2012 Nature America, Inc. All rights reserved.


Huang K.-Y.A.,Weatherall Institute of Molecular Medicine | Huang K.-Y.A.,Chang Gung Childrens Hospital | Li C.K.-F.,Weatherall Institute of Molecular Medicine | Clutterbuck E.,University of Oxford | And 9 more authors.
Journal of Infectious Diseases | Year: 2014

Background. Antibodies play a major role in the protection against influenza virus in human. However, the antibody level is usually short-lived and the cellular mechanisms underlying influenza virus-specific antibody response to acute infection remain unclear.Methods. We studied the kinetics and magnitude of influenza virus-specific B-cell and serum antibody responses in relation to virus replication during the course of influenza infection in healthy adult volunteers who were previously seronegative and experimentally infected with seasonal influenza H1N1 A/Brisbane/59/07 virus.Results. Our data demonstrated a robust expansion of the virus-specific antibody-secreting cells (ASCs) and memory B cells in the peripheral blood, which correlated with both the throat viral load and the duration of viral shedding. The ASC response was obviously detected on day 7 post-infection when the virus was completely cleared from nasal samples, and serum hemagglutination-inhibition antibodies were still undetectable. On day 28 postinfection, influenza virus-specific B cells were further identified from the circulating compartment of isotype-switched B cells.Conclusions. Virus-specific ASCs could be the earliest marker of B-cell response to a new flu virus infection, such as H7N9 in humans. © The Author 2014.


McClain M.T.,Durham Medical Center | McClain M.T.,Duke University | Park L.P.,Durham Medical Center | Nicholson B.,Durham Medical Center | And 8 more authors.
Journal of Clinical Virology | Year: 2013

Background: Leukocyte counts and differentials are commonly acquired in patients with suspected respiratory viral infections and may contribute diagnostic information. However, most published work is limited to a single timepoint at initial presentation to a medical provider, which may correspond to widely varying points in the course of disease. Objectives: To examine the temporal development and time-dependent utility of routine leukocyte differentials in the diagnosis of respiratory viral infections. Study design: We analyzed data from recent experimental human challenges with influenza A/H3N2, human rhinovirus (HRV), and respiratory syncytial virus (RSV). Routine clinical lab cell counts and differentials were measured daily from the time period immediately prior to inoculation through the eventual resolution of symptomatic disease. Results: Approximately 50% of challenged individuals developed symptoms and viral shedding consistent with clinical disease. Subpopulations of WBC showed marked differences between symptomatic and asymptomatic individuals over time, but these changes were much more profound and consistent in influenza infection. Influenza-infected subjects develop both relative lymphopenia and relative monocytosis, both of which closely mirror symptom development in time. A lymphocyte:monocyte ratio of <2 correctly classifies 100% of influenza (but not RSV or HRV) infected subjects at the time of maximal symptoms. Conclusions: Leukocyte differentials may suggest a viral etiology in patients with upper respiratory infection, but are not sufficient to allow differentiation between common viruses. Timing of data acquisition relative to the disease course is a key component in determining the utility of these tests. © 2013.


Mann A.J.,Retroscreen Virology | Noulin N.,Retroscreen Virology | Catchpole A.,Retroscreen Virology | Stittelaar K.J.,Viroclinics Biosciences | And 15 more authors.
PLoS ONE | Year: 2014

We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and morbidity arising from infection with HPAI H5N1 virus. © 2014 Mann et al.


Woods C.W.,Duke University | Woods C.W.,Durham Veterans Affairs Medical Center | McClain M.T.,Duke University | McClain M.T.,Durham Veterans Affairs Medical Center | And 15 more authors.
PLoS ONE | Year: 2013

There is great potential for host-based gene expression analysis to impact the early diagnosis of infectious diseases. In particular, the influenza pandemic of 2009 highlighted the challenges and limitations of traditional pathogen-based testing for suspected upper respiratory viral infection. We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Of 41 inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 94% of infected cases. This gene signature is detectable as early as 29 hours post-exposure and achieves maximal accuracy on average 43 hours (p = 0.003, H1N1) and 38 hours (p-value = 0.005, H3N2) before peak clinical symptoms. In order to test the relevance of these findings in naturally acquired disease, a composite influenza A signature built from these challenge studies was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 92% accuracy. The host genomic response to Influenza infection is robust and may provide the means for detection before typical clinical symptoms are apparent. © 2013 Woods et al.


Patent
University of Southampton and Retroscreen Virology | Date: 2011-12-23

The present invention provides a screening method for identifying a peptide capable of inducing a T cell response comprising:


News Article | October 28, 2016
Site: www.prfire.com

Retroscreen Virology Group PLC, the pioneer of hVIVO Human Challenge Models of disease, has raised over £1000 for the Movember Foundation. Funds raised by the team will directly contribute towards the charity’s work with Prostate Cancer UK, the Institute of Cancer Research and a large number of global collaborative initiatives. The Movember Foundation pledges to change the face of men’s health forever and promote awareness of the lives of men affected by prostate cancer, testicular cancer and mental health issues. Since 2004, the Movember Foundation has invested in over 800 global programmes designed to address specific challenges in the arena of men’s health. Retroscreen Virology, founded in 1988, was established to commercialise the academic work of Professor John Oxford in the field of retroviruses. From humble beginnings, Retroscreen Virology has grown and expanded and to date has coordinated more than 40 clinical studies, involving in excess of 85 quarantines and over 1800 volunteers for a wide range of best in class industry, governmental and academic organisations with the focus on helping to accelerate drug and vaccine developments in respiratory disease areas. Kym Denny, CEO at Retroscreen said: “I’m delighted to say we raised over £1000 for this important charity and give my sincere congratulations to the whole team at Retroscreen for their fantastic efforts” “Movember is saving and improving the lives of men affected by health issues every day and we are proud to have participated in fundraising for this great cause.” Established in 1988, Retroscreen Virology Group PLC is a leading life sciences company in the UK. The team at Retroscreen Virology has carried out studies in influenza, the common cold (HRV) and Respiratory Syncytial Virus (RSV) and is now developing the hVIVO model to expand out into studies using patient volunteers who already have an existing condition, such as asthma or COPD. Retroscreen Virology is committed to creating the next generation of drugs and vaccines for respiratory diseases. For more information on Retroscreen Virology visit http://www.retroscreen.com/ or contact +44 (0)20 7756 1300.

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