Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018

Takashita, Emi; Kawakami, Chiharu; Morita, Hiroko; Ogawa, Rie; Fujisaki, Seiichiro; Saijo, Masayuki; Miura, Hideka; Nakamura, Kenzo; Kishida, Noriko; Kuwahara, Tomoko; Mitamura, Keiko; Abe, Takashi; Ichikawa, Masataka; Yamazaki, Masahiko; Watanabe, Shinji; Odagiri, Takato

doi:10.2807/1560-7917.es.2019.24.3.1800698

Cited by 91 publications

(61 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Six to nine in vitro passages of A/WSN/33 (H1N1) virus in the presence of baloxavir revealed that an I38T substitution in PA conferred 22-to 41-fold reduced susceptibility to baloxavir . The PA I38T substitution occurs infrequently in naturally occurring A(H1N1)pdm09, A(H3N2), and B viruses (0%-0.02%) (Stevaert et al 2013;Takashita et al 2019b), suggesting that this substitution emerges as a result of treatment.…”

Section: Resistancementioning

confidence: 99%

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Takashita

2020

Cold Spring Harb Perspect Med

Self Cite

View full text Add to dashboard Cite

Section: Resistancementioning

confidence: 99%

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Takashita

2020

Cold Spring Harb Perspect Med

Self Cite

View full text Add to dashboard Cite

“…Mutant viruses resistant to FAV are rarely isolated in vitro and in vivo with one exceptional case 3 . Although detection of viruses that exhibit reduced susceptibility to NA inhibitors or baloxavir marboxil in immunocompetent patients has frequently been reported 1,[4][5][6][7][8][9] , such viruses usually do not dominate susceptible viruses with the exception of the worldwide spread of oseltamivir-resistant H1N1 virus in the 2007-2008 season. Recently, broadly protective human monoclonal antibodies (mAbs) against conserved regions of HA, including the receptorbinding site (RBS) and stem region, have been evaluated [10][11][12][13][14][15][16] and studies for their clinical application are being conducted [17][18][19][20] .…”

mentioning

confidence: 99%

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

2020

View full text Add to dashboard Cite

Prolonged treatment of immunocompromised influenza patients with viral neuraminidase (NA) inhibitors is required, because the immune system of such patients fails to eradicate the viruses. Here, we attempted to eradicate influenza virus from the respiratory organs of nude mice, which is a model of immunocompromised hosts, by using combination therapy of the viral polymerase inhibitor favipiravir and monoclonal antibodies (mAbs) against the receptorbinding site (RBS) and stem of viral hemagglutinin (HA). Although monotherapy or combination therapy of two antivirals (two mAbs or favipiravir plus a mAb) suppressed virus replication, they failed to eradicate viruses from nude mice. In contrast, the triple combination therapy of favipiravir plus anti-Stem and anti-RBS mAbs completely stopped virus replication in nude mice, resulting in virus clearance. Triple combination approaches should be considered for the treatment of human immunocompromised patients with severe influenza.

show abstract

“…In the case of antivirals, their effectiveness is dependent on being administered within 48 h after appearance of symptoms [59, 60]. Importantly, antiviral-resistant strains have been described [1, 24–26]. Consequently, these prevention and treatment methods still leave substantial public health vulnerabilities.…”

Section: Discussionmentioning

confidence: 99%

“…In terms of antivirals, three major classes of drugs are FDA-approved for the treatment of influenza infections: NA inhibitors (oseltamivir, zanamivir and peramivir), matrix protein 2 (M2) inhibitors (amantadine and rimantadine), and the polymerase acid (PA) endonuclease inhibitor (Baloxavir marboxil or Xofluza) [1, 23]. However, influenza antiviral drugs have several limitations, including the lack of antiviral activity of M2 inhibitors against IBV, the emergence of drug resistant variants [24–26], and a limited antiviral effect due to rapid metabolism and elimination of the inhibitor [27–30]. Thus, there is an urgent need to find alternative approaches for the prevention and treatment of influenza infections in humans.…”

Section: Introductionmentioning

confidence: 99%

A broad and potent H1-specific human monoclonal antibody produced in plants prevents influenza virus infection and transmission in guinea pigs

Park

Piepenbrink

et al. 2020

Preprint

View full text Add to dashboard Cite

Although seasonal influenza vaccines block most predominant influenza types and subtypes, humans still remain vulnerable to waves of seasonal and new potential pandemic influenza viruses for which no immunity may exist because of viral antigenic drift and/or shift, respectively. Previously, we have described a human monoclonal antibody (hMAb), KPF1, which was produced in human embryonic kidney 293T cells (KPF1-HEK) with broad and potent neutralizing activity against H1N1 influenza A viruses (IAV) in vitro, and prophylactic and therapeutic activities in vivo. In this study, we produced hMAb KPF1 in tobacco plants (KPF1-Antx) and demonstrate how the plant-produced KPF1-Antx hMAb possesses similar biological activity compared with the mammalian produced KPF1-HEK hMAb. KPF1-Antx hMAb shows broad binding to recombinant HA proteins and H1N1 IAV, including A/California/04/2009 (pH1N1) in vitro, that are comparable to those observed with KPF1-HEK hMAb. Importantly, prophylactic administration of KPF1-Antx hMAb to guinea pigs prevented pH1N1 infection and transmission in both prophylactic and therapeutic experiments, substantiating its clinical potential to prevent and treat H1N1 infections. Collectively, this study demonstrates, for the first time, that plant-produced influenza hMAbs have similar in vitro and in vivo biological properties to those produced in mammalian cells. Because of the many advantages of plant-produced hMAbs, such as rapid batch production, low cost, and the absence of mammalian cell products, they represent an alternative strategy for the production of immunotherapeutics for the treatment of influenza viral infections, including emerging seasonal and/or pandemic strains.

show abstract

Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018

Cited by 91 publications

References 5 publications

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

A broad and potent H1-specific human monoclonal antibody produced in plants prevents influenza virus infection and transmission in guinea pigs

Contact Info

Product

Resources

About