title: Infection of mice with a human influenza A/H3N2 virus induces protective immunity against lethal infection with influenza A/H5N1 virus.
abstract: The transmission of highly pathogenic avian influenza (HPAI) A viruses of the H5N1 subtype from poultry to man and the high case fatality rate fuels the fear for a pandemic outbreak caused by these viruses. However, prior infections with seasonal influenza A/H1N1 and A/H3N2 viruses induce heterosubtypic immunity that could afford a certain degree of protection against infection with the HPAI A/H5N1 viruses, which are distantly related to the human influenza A viruses. To assess the protective efficacy of such heterosubtypic immunity mice were infected with human influenza virus A/Hong Kong/2/68 (H3N2) 4 weeks prior to a lethal infection with HPAI virus A/Indonesia/5/05 (H5N1). Prior infection with influenza virus A/Hong Kong/2/68 reduced clinical signs, body weight loss, mortality and virus replication in the lungs as compared to naive mice infected with HPAI virus A/Indonesia/5/05. Priming by infection with respiratory syncytial virus, a non-related virus did not have a beneficial effect on the outcome of A/H5N1 infections, indicating that adaptive immune responses were responsible for the protective effect. In mice primed by infection with influenza A/H3N2 virus cytotoxic T lymphocytes (CTL) specific for NP(366-374) epitope ASNENMDAM and PA(224-232) SCLENFRAYV were observed. A small proportion of these CTL was cross-reactive with the peptide variant derived from the influenza A/H5N1 virus (ASNENMEVM and SSLENFRAYV respectively) and upon challenge infection with the influenza A/H5N1 virus cross-reactive CTL were selectively expanded. These CTL, in addition to those directed to conserved epitopes, shared by the influenza A/H3N2 and A/H5N1 viruses, most likely contributed to accelerated clearance of the influenza A/H5N1 virus infection. Although also other arms of the adaptive immune response may contribute to heterosubtypic immunity, the induction of virus-specific CTL may be an attractive target for development of broad protective vaccines. Furthermore the existence of pre-existing heterosubtypic immunity may dampen the impact a future influenza pandemic may have.
authors.affiliation: Department of Virology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: J H C M
authors.initials: JH
authors.lastname: Kreijtz
authors.forename: R
authors.initials: R
authors.lastname: Bodewes
authors.forename: J M A
authors.initials: JM
authors.lastname: van den Brand
authors.forename: G
authors.initials: G
authors.lastname: de Mutsert
authors.forename: C
authors.initials: C
authors.lastname: Baas
authors.forename: G
authors.initials: G
authors.lastname: van Amerongen
authors.forename: R A M
authors.initials: RA
authors.lastname: Fouchier
authors.forename: A D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: G F
authors.initials: GF
authors.lastname: Rimmelzwaan
mesh_terms: D000818:Animals; D001717:Birds; D001835:Body Weight; D005260:Female; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D005585:Influenza in Birds / Q000821:virology; D007251:Influenza, Human / Q000821:virology; D008168:Lung / Q000821:virology; D051379:Mice; D018184:Paramyxoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology