High-yield reassortant influenza vaccine production virus has a mutation at an HLA-A 2.1-restricted CD8+ CTL epitope on the NS1 protein.
Current influenza virus vaccines are prepared using high-yield reassortant virus strains obtained from a mixed infection of the new virus strain and a prototype high-yielding virus strain. The high-titered reassortant virus strain used as vaccine seed virus possesses the recent virus HA and NA and contains the internal genes from the high-growing prototype parent. We established a human CD8(+) cytotoxic T cell (CTL) line, 10-2C2, which recognizes an HLA-A2.1-restricted influenza A virus H1, H2, H3 cross-reactive T cell epitope on amino acids 122-130 of the NS1 protein, and unexpectedly we observed that there was decreased lysis of target cells infected with the A/Texas/36/91 (H1N1) vaccine virus strain compared to the lysis of target cells infected with the prototype A/PR/8/34 (H1N1) virus. RT-PCR results showed that the A/Texas vaccine virus strain contained a quasispecies. Approximately 50% of viral RNA of the NS1 gene had a nucleotide substitution that resulted in the N --> K amino acid change at the sixth position of the nonamer peptide. Current influenza vaccines are inactivated and do not contain the NS1 protein; however, future influenza vaccines may include live attenuated vaccines and with this mutation a live virus would fail to induce a CD8(+) CTL response to this epitope in individuals with HLA-A2.1, a very common allele, and potentially have reduced efficacy.
Terajima
M
M
Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Jameson
J
J
Norman
J E
JE
Cruz
J
J
Ennis
F A
FA
D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000821:virology*; D005814:Genes, Viral; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007252:Influenza Vaccines; D008969:Molecular Sequence Data; D009154:Mutation; D009975:Orthomyxoviridae / Q000235:genetics*; D016865:Reassortant Viruses / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics*
D015234:HLA-A Antigens; C085820:INS1 protein, influenza virus; D007252:Influenza Vaccines; D017361:Viral Nonstructural Proteins