Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022

Authors

Ha T. Nguyen, National Center for Immunization and Respiratory Diseases
Anton Chesnokov, National Center for Immunization and Respiratory Diseases
Juan De La Cruz, National Center for Immunization and Respiratory Diseases
Philippe Noriel Q. Pascua, National Center for Immunization and Respiratory Diseases
Vasiliy P. Mishin, National Center for Immunization and Respiratory Diseases
Yunho Jang, National Center for Immunization and Respiratory Diseases
Joyce Jones, National Center for Immunization and Respiratory Diseases
Han Di, National Center for Immunization and Respiratory Diseases
Andrei A. Ivashchenko, ChemDiv, Inc.
Mary Lea Killian, USDA APHIS National Veterinary Services Laboratories
Mia K. Torchetti, USDA APHIS National Veterinary Services Laboratories
Kristina Lantz, USDA APHIS National Veterinary Services Laboratories
David E. Wentworth, National Center for Immunization and Respiratory Diseases
Charles T. Davis, National Center for Immunization and Respiratory Diseases
Alexandre V. Ivachtchenko, ChemDiv, Inc.
Larisa V. Gubareva, National Center for Immunization and Respiratory DiseasesFollow

Date of this Version

9-1-2023

Citation

Antiviral Research 217 (2023) 105679

doi:10.1016/j.antiviral.2023.105679

Comments

U.S. government work

Abstract

Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A(H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1,015 sequences of HPAI A(H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4b A(H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors, baloxavir and the investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A(H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.