title: ISCOMATRIX™ adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans.
abstract: In a previously reported phase I clinical trial, subjects vaccinated with two doses of an unadjuvanted H7N9 virus like particle (VLP) vaccine responded poorly (15.6% seroconversion rates with 45μg hemagglutinin (HA) dose). In contrast, 80.6% of subjects receiving H7N9 VLP vaccine (5μg HA) with ISCOMATRIX™ adjuvant developed hemagglutination-inhibition (HI) responses. To better understand the role of adjuvant, complete antibody epitope repertoires of post-vaccination sera were investigated using Whole Genome Fragment Phage Display Library (GFPDL). In addition, antibody affinity maturation following vaccination was measured against HA1 and HA2 antigenic domains using real time Surface Plasmon Resonance (SPR) based kinetic assays. Unadjuvanted H7N9-VLP vaccine generated primarily antibodies targeting the C-terminus of the HA1 domain, predicted to be mostly buried on the native HA spikes, while adjuvanted VLP vaccine generated antibodies against large epitopes in the HA1 spanning the receptor binding domain (RBD). SPR analysis using a functional H7-HA1 domain demonstrated that sera from adjuvanted H7N9-VLP vaccine induced higher total binding antibodies and significantly higher antibody affinity maturation to HA1 compared to sera from unadjuvanted vaccine. Total antibody binding and affinity to the HA1 (but not HA2) domain correlated with HI and neutralization titers. This study demonstrates that ISCOMATRIX™ adjuvanted vaccine promotes higher quality antibody immune response against avian influenza in naïve humans.
authors.affiliation: Division of Viral Products, CBER, FDA, Silver Spring, MD 20993, USA.
authors.forename: Ka Yan
authors.initials: KY
authors.lastname: Chung
authors.affiliation: Division of Viral Products, CBER, FDA, Silver Spring, MD 20993, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Coyle
authors.affiliation: Novavax, Gaithersburg, MD 20878, USA.
authors.forename: Dewal
authors.initials: D
authors.lastname: Jani
authors.affiliation: Division of Viral Products, CBER, FDA, Silver Spring, MD 20993, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: King
authors.affiliation: Division of Viral Products, CBER, FDA, Silver Spring, MD 20993, USA.
authors.forename: Rukmini
authors.initials: R
authors.lastname: Bhardwaj
authors.affiliation: Novavax, Gaithersburg, MD 20878, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Fries
authors.affiliation: Novavax, Gaithersburg, MD 20878, USA.
authors.forename: Gale
authors.initials: G
authors.lastname: Smith
authors.affiliation: Novavax, Gaithersburg, MD 20878, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Glenn
authors.affiliation: Division of Viral Products, CBER, FDA, Silver Spring, MD 20993, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
authors.affiliation: Division of Viral Products, CBER, FDA, Silver Spring, MD 20993, USA. Electronic address: surender.khurana@fda.hhs.gov.
authors.forename: Surender
authors.initials: S
authors.lastname: Khurana
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood*; D000915:Antibody Affinity; D002784:Cholesterol / Q000008:administration & dosage*; D004338:Drug Combinations; D000939:Epitopes / Q000276:immunology; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D019151:Peptide Library; D010743:Phospholipids / Q000008:administration & dosage*; D012503:Saponins / Q000008:administration & dosage*; D020349:Surface Plasmon Resonance; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D004338:Drug Combinations; D000939:Epitopes; C493786:ISCOMATRIX; D007252:Influenza Vaccines; D019151:Peptide Library; D010743:Phospholipids; D012503:Saponins; D058425:Vaccines, Virus-Like Particle; D002784:Cholesterol
keywords: Adjuvant; Antibody affinity; Epitope; H7N7; H7N9; Hemagglutinin; ISCOMATRIX (ISCO); Influenza; Neutralization; Pandemic; Phage display; Vaccine; Virus