Efficacy of zanamivir against avian influenza A viruses that possess genesencoding H5N1 internal proteins and are pathogenic in mammals

In 1997, an avian H5N1 influenza virus, A/Hong Kong/156/97 (A/HK/156/97), c aused six deaths in Hong Kong, and in 1999, an avian H9N2 influenza virus i nfected two children in Hong Kong, These viruses and a third avian virus [A /Tea/HK/W312/97 (H6N1)] have six highly related genes encoding internal pro teins. Additionally, A/Chicken/HK/G9/97 (H9N2) virus has PB1 and PB2 genes that are highly related to those of A/HK/156/97 (H5N1), A/Teal/HK/W312/97 ( H6N1), and A/Quail/HK/G1/97 (H9N2) viruses. Because of their similarities w ith the H5N1 virus, these H6N1 and H9N2 viruses may have the potential for interspecies transmission. We demonstrate that these H6N1 and H9N2 viruses are pathogenic in mice but that their pathogenicities are less than that of A/HK/156/97 (H5N1). Unadapted virus replicated in lungs, but only A/HK/156 /97 (H5N1) was found in the brain. After three passages (P-3) in mouse lung s, the pathogenicity of the viruses increased, with both A/Teal/HK/W312/97 (H6N1) (P-3) and A/Quail/HK/Gl/97 (H9N2) (P-3) viruses being found in the b rain, The neuraminidase inhibitor zanamivir inhibited viral replication in Madin-Darby canine kidney cells in virus yield assays (50% effective concen tration, 8.5 to 14.0 muM) and inhibited viral neuraminidase activity (50% i nhibitory concentration, 5 to 10 nM), Twice daily intranasal administration of zanamivir (50 and 100 mg/kg of body weight) completely protected infect ed mice from death. At a dose of 10 mg/kg, zanamivir completely protected m ice from infection with H9N2 viruses and increased the mean survival day an d the number of survivors infected with H6N1 and H5N1 viruses. Zanamivir, a t all doses tested, significantly reduced the virus titers in the lungs and completely blocked the spread of virus to the brain. Thus, zanamivir is ef ficacious in treating avian influenza viruses that can be transmitted to ma mmals.