Tackling the Influenza Virus

Dr. Kawaoka has received several research awards since joining the SVM:

2002—The Hideo Noguchi Memorial Award for Medicine (Japan)

2006—The Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology in Japan, Prizes for Science and Technology

2006—Robert-Koch-Preis (Germany)

2007— Japan Prize of Agricultural Science/Yomiuri Agriculture Prize

Influenza viruses cause annual, local epidemics and rare global outbreaks (pandemics), as witnessed with the 2009 H1N1 pandemic or the 1918 pandemic that killed more than 50 million people worldwide. In addition, avian influenza viruses occasionally infect humans, often with fatal consequences; for example, more than 60% of humans infected with highly pathogenic avian H5N1 influenza (“bird flu”) viruses succumb to the infection. The medical and economic impact of influenza virus infections is thus substantial. Dr. Yoshi Kawaoka, a professor of pathobiological sciences at the UW School of Veterinary Medicine, has dedicated his career to studying this pathogen, which has led to seminal milestone achievements that have altered our understanding of influenza virus pathogenicity mechanisms.

In 1999, Dr. Kawaoka developed a novel technology (‘reverse genetics’) that allows the generation of influenza viruses entirely from plasmids, and can be used to introduce any mutation into the genome of influenza viruses (Neumann et al., PNAS, 1999). This technology is now used for the generation of tailor-made influenza vaccines, such as FluMist, a live attenuated influenza virus vaccine. Because of the high efficiency of reverse genetics, a live attenuated 2009 H1N1 pandemic vaccine generated with this technology was the first on the market. Highly pathogenic avian H5N1 influenza viruses kill chicken embryos, in which influenza vaccines are typically propagated. Based on concepts established by Dr. Kawaoka (Kawaoka & Webster, PNAS, 1988), reverse genetics allowed the generation of attenuated ‘bird flu’ viruses that can be grown in eggs. The World Health Organization (WHO) has adopted this concept, resulting in the production and stock-piling of vaccines to highly pathogenic avian H5N1 influenza viruses.

Dr. Kawaoka’s work has also led to identification of several pathogenicity markers of influenza viruses, some of which are now used by the World Organization for Animal Health (OIE) and the US Department of Agriculture (USDA) to identify highly pathogenic influenza

virus strains. Examples include the sequence at the hemagglutinin cleavage site (Kawaoka & Webster, PNAS, 1988) or the nature of a single amino acid in the influenza virus polymerase complex (Hatta et al., Science, 2001), both of which are critical determinants of influenza virulence in mammalian species. Moreover, Dr. Kawaoka’s studies provided explanations for the unparalleled virulence of the 1918 pandemic virus (Kobasa et al, Nature, 2004; Kobasa et al., Nature, 2007). In addition, Dr. Kawaoka’s studies demonstrated the presence of receptors for avian influenza viruses in the lower respiratory tract of humans (Shinya et al., Nature, 2006), and identified adapting mutations in some highly pathogenic avian H5N1 viruses that facilitate their binding to human-type receptors (Yamada et al., Nature, 2006); these two features likely contribute to the high mortality rate of human infections with highly pathogenicity avian H5N1 viruses. Recently, Dr. Kawaoka has played a critical role in the characterization of the 2009 H1N1 pandemic virus (Neumann et al., Nature, 2009; Itoh et al., Nature, 2009). The rapid characterization of this virus was critical for the fast development of vaccines to this virus, and has therefore been recognized by the National Institutes of Allergy and Infectious Diseases (NIAID) as one of the Top 10 scientific advances of 2009.

Two classes of antiviral compounds (ion channel and neuraminidase inhibitors) are available to prevent or treat influenza virus infections. However, many influenza virus strains are now resistant to ion channel inhibitors, and Dr. Kawaoka has demonstrated that the rate of resistance to neuraminidase inhibitors is significantly higher than previously thought (Kiso et al., Lance, 2004). Moreover, Dr. Kawaoka reported the emergence of highly pathogenic avian H5N1 viruses resistant to neuraminidase inhibitors (Mai et al., Nature, 2005). In one approach to identify novel targets for antiviral treatment, Dr. Kawaoka has therefore screened the Drosophila genome for genes that are critical for influenza virus infection (Hao et al., Nature, 2008). In another approach, Dr. Kawaoka used electronmicroscopy to study the architecture of the influenza virus replication complex in order to understand virus assembly (Noda et al., Nature, 2006). Collectively, knowledge obtained from such studies may open the door for the rational design of novel drugs to influenza viruses. In summary, Dr. Kawaoka has made seminal contributions to influenza virus research, which have critically advanced our understanding of these viruses, and have revolutionized influenza virus vaccine development and production.