ISCOMATRIX™ adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans

• Published in: Vaccine Vol. 33; no. 32; pp. 3953 - 3962
• Main Authors: Chung, Ka Yan, Coyle, Elizabeth M., Jani, Dewal, King, Lisa R., Bhardwaj, Rukmini, Fries, Louis, Smith, Gale, Glenn, Gregory, Golding, Hana, Khurana, Surender
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 31.07.2015; Elsevier Limited
• Subjects: Adjuvant; adjuvants; Adjuvants, Immunologic - administration & dosage; Allergy and Immunology; antibodies; Antibodies, Neutralizing - blood; Antibodies, Viral - blood; Antibody Affinity; Antigens; Avian flu; avian influenza; bacteriophages; binding capacity; Cholesterol - administration & dosage; Clinical trials; Dendritic cells; Drug Combinations; Epitope; epitopes; Epitopes - immunology; genome; H7N7; H7N9; Hemagglutination Inhibition Tests; Hemagglutinin; hemagglutinins; Humans; Immune response; Immunoglobulins; Infections; Influenza; Influenza A Virus, H7N9 Subtype - immunology; Influenza Vaccines - administration & dosage; Influenza Vaccines - immunology; ISCOMATRIX (ISCO); Lymphatic system; Mammals; Neutralization; neutralization tests; Pandemic; Peptide Library; Phage display; Phospholipids - administration & dosage; Saponins - administration & dosage; seroconversion; Studies; Surface Plasmon Resonance; vaccination; Vaccine; Vaccines; Vaccines, Virus-Like Particle - administration & dosage; Vaccines, Virus-Like Particle - immunology; Virus; virus-like particle vaccines; Viruses; Epitope; Hemagglutinin; Pandemic; Vaccine; Virus; Phage display; Influenza; Antibody affinity; ISCOMATRIX (ISCO); H7N7; Adjuvant; H7N9; Neutralization
• ISSN: 0264-410X; 1873-2518; 1873-2518
• DOI: 10.1016/j.vaccine.2015.06.047

•H7N9 VLP vaccine with ISCOMATRIX™ adjuvant showed enhanced neutralizing antibody responses in humans.•Unadjuvanted H7N9-VLP vaccine generated primarily antibodies targeting the C-terminus of the globular HA1 domain.•Adjuvanted H7N9-VLP vaccine generated antibodies against large conformational epitopes in the HA1 spanning the receptor binding domain (RBD).•Adjuvanted H7N9-VLP promotes better antibody affinity maturation to HA1 than unadjuvanted vaccine that correlates with Virus neutralization.•This study shows that ISCOMATRIX™ adjuvanted vaccine promotes higher quality antibody immune response against avian influenza in humans. 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.