Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir

Vasiliy P. Mishin; Mira C. Patel; Anton Chesnokov; Juan De La Cruz; Ha T. Nguyen; Lori Lollis; Erin Hodges; Yunho Jang; John Barnes; Timothy Uyeki; Charles T. Davis; David E. Wentworth; Larisa V. Gubareva


Emerging Infectious Diseases. 2019;25(10):1969-1972. 

In This Article

Abstract and Introduction


Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2–98.3 nmol/L); susceptibility pattern was influenza A > B > C > D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors.


Influenza viruses are classified into 4 types: A, B, C, and D.[1] Influenza A viruses infect a wide range of species and pose threats to human and animal health. Influenza A viruses belonging to 16 hemagglutinin and 9 neuraminidase subtypes have been identified in the natural reservoir (wild birds). Zoonotic infections with avian H5N1, H5N6, and H7N9 viruses are concerning because of their high fatality rates in humans and pandemic risk.[2]

Swine are recognized as mixing vessels because influenza A viruses from multiple hosts can infect pigs and produce novel reassortants. Numerous subtypes of reassortant swine influenza A viruses are enzootic throughout North America and pose a threat to human health. For instance, H3N2 triple reassortant viruses caused a multistate outbreak affecting hundreds of persons in the United States during 2012, and a quadruple reassortant H1N1 virus caused the 2009 pandemic and now circulates as a seasonal virus.[2,3]

Influenza B viruses are considered strictly human pathogens, although occasional outbreaks in aquatic mammals have been reported.[1] Influenza C viruses are known to infect humans, pigs, camels, and dogs.[1] Unlike influenza A and B viruses, influenza C viruses typically cause mild illness. However, in recent years, severe illness in children infected by influenza C virus has raised concerns over the lack of virus-specific therapeutics and vaccines.[4] Recently discovered influenza D viruses were isolated from swine and bovines. No virologically confirmed human infections have been reported, but influenza D virus antibodies have been found in persons exposed to cattle.[1] Evolutionarily, influenza C and D viruses are more closely related to each other than to influenza A or B viruses.[1]

Antiviral drugs have been used to mitigate zoonotic virus outbreaks and are central to pandemic preparedness. However, therapeutic options remain limited and drug-resistant viruses can emerge after treatment, spontaneous mutation, or reassortment. Until recently, only matrix (M) 2 blockers and neuraminidase inhibitors (NAIs) were approved to control influenza. M2 blockers are effective only against influenza A viruses and are not recommended because of widespread resistance. NAIs are used for treatment of influenza A and B virus infections, but NAI-resistant viruses have emerged.[5] NAI-resistant seasonal influenza H1N1 viruses circulated worldwide during late 2007 through early 2009[6] and raised concerns over limited therapeutic options.

In 2014, favipiravir was licensed in Japan for restricted use in the event of a drug-resistant influenza pandemic.[7] Favipiravir is a broad-spectrum antiviral drug that inhibits viral RNA polymerase, an enzyme recognized as an attractive target because of its critical role in virus replication and high degree of conservation.[8] In 2018, another inhibitor of the viral RNA polymerase, baloxavir marboxil, was approved in Japan and the United States for treatment of influenza A and B virus infections.[9] Its active metabolite, baloxavir acid, inhibits cap-dependent endonuclease activity of polymerase acidic (PA) protein.[10] Amino acid substitutions at position 38 in the PA active site were recognized as the primary pathway to baloxavir resistance.[11] PA substitutions at this and other positions have variable impact on resistance and are rarely found in nature.[11,12] The purpose of this study was to determine the effectiveness of baloxavir against the 4 types of influenza viruses.

Preliminary results from this study were presented at the 6th International Society for Influenza and Other Respiratory Virus Diseases Antiviral Group Conference; November 13–15, 2018; Rockville, Maryland, USA.