Oseltamivir Is Effective against 1918 Influenza Virus Infection of Macaques but Vulnerable to Escape
Friederike Feldmann,
Darwyn Kobasa,
Carissa Embury-Hyatt,
Allen Grolla,
Tracy Taylor,
Maki Kiso,
Satoshi Kakugawa,
Jason Gren,
Steven M. Jones,
Yoshihiro Kawaoka,
Heinz Feldmann
Affiliations
Friederike Feldmann
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Darwyn Kobasa
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Carissa Embury-Hyatt
National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
Allen Grolla
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Tracy Taylor
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Maki Kiso
Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Satoshi Kakugawa
Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Jason Gren
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Steven M. Jones
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
Yoshihiro Kawaoka
Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Heinz Feldmann
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
ABSTRACT The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug. IMPORTANCE Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.
