Attenuation and immunogenicity in mice of temperature-sensitive influenza viruses expressing truncated NS1 proteins.
It was previously shown that two mutant influenza A viruses expressing C-terminally truncated forms of the NS1 protein (NS1-81 and NS1-110) were temperature sensitive in vitro. These viruses contain HA, NA and M genes derived from influenza A/WSN/33 H1N1 virus (mouse-adapted), and the remaining five genes from human influenza A/Victoria/3/75 virus. Mice intranasally infected with the NS1 mutant viruses showed undetectable levels of virus in lungs at day 3, whereas those infected with the NS1 wild-type control virus still had detectable levels of virus at this time. Nevertheless, the temperature-sensitive mutant viruses induced specific cellular and humoral immune responses similar to those induced by the wild-type virus. Mice immunized with the NS1 mutant viruses were protected against a lethal challenge with influenza A/WSN/33 virus. These results indicate that truncations in the NS1 protein resulting in temperature-sensitive phenotypes in vitro correlate with attenuation in vivo without compromising viral immunogenicity, an ideal characteristic for live attenuated viral vaccines.
Falcón
Ana M
AM
Centro Nacional de Biotecnología, CSIC, 28049 Madrid, Spain.
Fernandez-Sesma
Ana
A
Department of Microbiology, Mount Sinai School of Medicine, Box 1124, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Nakaya
Yurie
Y
Department of Microbiology, Mount Sinai School of Medicine, Box 1124, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Moran
Thomas M
TM
Department of Microbiology, Mount Sinai School of Medicine, Box 1124, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Ortín
Juan
J
Centro Nacional de Biotecnología, CSIC, 28049 Madrid, Spain.
García-Sastre
Adolfo
A
Department of Microbiology, Mount Sinai School of Medicine, Box 1124, 1 Gustave L. Levy Place, New York, NY 10029, USA.
D000818:Animals; D003673:Defective Viruses / Q000276:immunology*; D004195:Disease Models, Animal; D005814:Genes, Viral; D005818:Genetic Engineering; D007114:Immunization; D009980:Influenza A virus / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D051379:Mice; D012313:RNA / Q000378:metabolism; D013696:Temperature; D014613:Vaccines, Attenuated / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology* / Q000502:physiology; D014779:Virus Replication
D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins; D012313:RNA