title: A Synthetic Influenza Virus Vaccine Induces a Cellular Immune Response That Correlates with Reduction in Symptomatology and Virus Shedding in a Randomized Phase Ib Live-Virus Challenge in Humans.
abstract: 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-v-specific 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. (This study has been registered at ClinicalTrials.gov under registration no. NCT01226758 and at hra.nhs.uk under EudraCT no. 2009-014716-35.).
authors.affiliation: SEEK, Central Point, London, United Kingdom.
authors.forename: Olga
authors.initials: O
authors.lastname: Pleguezuelos
authors.affiliation: SEEK, Central Point, London, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Robinson
authors.affiliation: SEEK, Central Point, London, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández
authors.affiliation: SEEK, Central Point, London, United Kingdom.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Stoloff
authors.affiliation: Retroscreen Virology Ltd., Queen Mary BioEnterprises, Innovation Centre, London, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Mann
authors.affiliation: Retroscreen Virology Ltd., Queen Mary BioEnterprises, Innovation Centre, London, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gilbert
authors.affiliation: Retroscreen Virology Ltd., Queen Mary BioEnterprises, Innovation Centre, London, United Kingdom.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Balaratnam
authors.affiliation: Clinical Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Wilkinson
authors.affiliation: Retroscreen Virology Ltd., Queen Mary BioEnterprises, Innovation Centre, London, United Kingdom.
authors.forename: Rob
authors.initials: R
authors.lastname: Lambkin-Williams
authors.affiliation: Retroscreen Virology Ltd., Queen Mary BioEnterprises, Innovation Centre, London, United Kingdom Blizzard Institute, Queen Mary College, University of London, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Oxford
authors.affiliation: SEEK, Central Point, London, United Kingdom wilson.wanderley@seekacure.com.
authors.forename: Wilson
authors.initials: W
authors.lastname: Caparrós-Wanderley
mesh_terms: D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D007111:Immunity, Cellular; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control* / Q000821:virology; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D019562:Viral Load; D017201:Virus Shedding / Q000276:immunology*; D055815:Young Adult
chemical_list: D007252:Influenza Vaccines; D010919:Placebos; D007371:Interferon-gamma