title: Directed selection of influenza virus produces antigenic variants that match circulating human virus isolates and escape from vaccine-mediated immune protection.
abstract: Influenza vaccination does not provide 100% protection from infection, partly due to antigenic drift of the haemagglutinin (HA) protein. Low serum antibody titres increase the risk of infection. To determine whether there were additional correlates of risk, we examined the relationship between human serum immunity and antigenic variation in seasonal H3N2 influenza viruses. Seasonal H3N2 vaccine strains grown in the presence of heterogeneous human or mono-specific ferret antisera selected variants with mutations in the HA antigenic sites. Surprisingly, circulating strains infecting human subjects in the same seasons displayed mutations in the same positions, although only in one case did the change correspond to the same amino acid. Serum antibody titres were lower against both the in vitro selected and clinical isolates compared with the vaccine strains, suggesting that the mutations are relevant to vaccine failure. Antibody titres were also significantly lower in sera from infected subjects than in non-infected subjects, suggesting relatively poor responses to vaccination in the infected subjects. Collectively, the data suggest that risk from influenza infection is a result of poor response to vaccination, as well as encounter with drifted seasonal influenza virus antigenic variants. The results also show that directed selection under human immune pressure could reveal antigenic variants relevant to real-world drifted viruses, helping in annual vaccine re-formulation.
authors: David Smith Center for Immunology and Vaccine Biology, Department of Microbiology and Immunology, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.
authors: Marta L
authors: ML
authors: DeDiego
authors: David Smith Center for Immunology and Vaccine Biology, Department of Microbiology and Immunology, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.
authors: Christopher S
authors: CS
authors: Anderson
authors: Department of Biostatistics and Computational Biology, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.
authors: Hongmei
authors: H
authors: Yang
authors: Department of Biostatistics and Computational Biology, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.
authors: Jeanne
authors: J
authors: Holden-Wiltse
authors: Department of Medicine, Infectious Disease Unit, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.
authors: Theresa
authors: T
authors: Fitzgerald
authors: Department of Medicine, Infectious Disease Unit, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.
authors: John J
authors: JJ
authors: Treanor
authors: David Smith Center for Immunology and Vaccine Biology, Department of Microbiology and Immunology, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.
authors: David J
authors: DJ
authors: Topham
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000940:Antigenic Variation; D002460:Cell Line; D002675:Child, Preschool; D015331:Cohort Studies; D005289:Ferrets; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007223:Infant; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D011446:Prospective Studies; D012621:Seasons; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines
keywords: antigenic drift; circulating strains; haemagglutinin; human influenza virus; influenza virus vaccination; influenza-specific antibodies; vaccine strain