Baloxavir treatment delays influenza B virus transmission in ferrets and results in limited generation of drug-resistant variants

Clinical efficacy of the influenza antiviral baloxavir marboxil (baloxavir) is compromised by treatment-emergent variants harboring a polymerase acidic protein I38T substitution. However, the fitness of I38T-containing influenza B viruses (IBVs) remains inadequately defined. After confirming the pharmacokinetics of the compound in ferrets, animals were injected subcutaneously with 8 mg/kg of baloxavir acid (BXA) 24 h post-inoculation with recombinant BXA-sensitive (BXA- Sen , I38) or BXA-resistant (BXA- Res , I38T) B/Brisbane/60/2008 (Victoria lineage) virus. BXA treatment of donor ferrets reduced virus replication and delayed transmission of the BXA- Sen but not the BXA- Res IBV. The I38 genotype remained dominant in the BXA- Sen animals, even under BXA treatment. In competitive-mixture experiments, no transmission to aerosol-contacts was seen from BXA-treated donors coinfected with the BXA- Sen and BXA- Res B/Brisbane/60/2008 viruses. However, in parallel mixed-infections with the B/Phuket/3073/2013 (Yamagata lineage) virus background, BXA treatment failed to block airborne transmission of the BXA- Res virus and the I38T genotype generally predominated. Therefore, relative fitness of BXA- Res IBVs is complex and dependent on the virus backbone and within-host virus competition. BXA treatment of single-virus infected ferrets hampers aerosol transmission of the BXA- Sen virus and does not readily generate BXA- Res variants, while mixed-infections may result in propagation of BXA- Res IBVs of the Yamagata lineage. Our findings confirm the antiviral potency of baloxavir against IBVs while supporting optimization of the dosing regimen to maximize clinical benefit.

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Influenza B Virus Transmission in Recipients of Kidney and Lung Transplants From an Infected Donor

Transplantation Journal ◽

10.1097/tp.0b013e3181da1933 ◽

2010 ◽

Vol 90 (1) ◽

pp. 99-102 ◽

Cited By ~ 11

Author(s):

Amelia K. Le Page ◽

Gad Kainer ◽

Allan R. Glanville ◽

Elise Tu ◽

Deepak Bhonagiri ◽

...

Keyword(s):

Virus Transmission ◽

Influenza B Virus ◽

Influenza B ◽

Infected Donor ◽

B Virus ◽

Lung Transplants

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Experimental Infection Using Mouse-Adapted Influenza B Virus in a Mouse Model

Viruses ◽

10.3390/v12040470 ◽

2020 ◽

Vol 12 (4) ◽

pp. 470 ◽

Cited By ~ 1

Author(s):

Elena Prokopyeva ◽

Olga Kurskaya ◽

Ivan Sobolev ◽

Mariia Solomatina ◽

Tatyana Murashkina ◽

...

Keyword(s):

Influenza Vaccine ◽

Drug Testing ◽

Protective Efficacy ◽

Influenza B Virus ◽

Infection Model ◽

Influenza B ◽

Post Inoculation ◽

B Virus

Every year, influenza B viruses (IBVs) contribute to annual illness, and infection can lead to serious respiratory disease among humans. More attention is needed in several areas, such as increasing virulence or pathogenicity of circulating B viruses and developing vaccines against current influenza. Since preclinical trials of anti-influenza drugs are mainly conducted in mice, we developed an appropriate infection model, using an antigenically-relevant IBV strain, for furtherance of anti-influenza drug testing and influenza vaccine protective efficacy analysis. A Victoria lineage (clade 1A) IBV was serially passaged 17 times in BALB/c mice, and adaptive amino acid substitutions were found in hemagglutinin (HA) (T214I) and neuraminidase (NA) (D432N). By electron microscopy, spherical and elliptical IBV forms were noted. Light microscopy showed that mouse-adapted IBVs caused influenza pneumonia on day 6 post inoculation. We evaluated the illness pathogenicity, viral load, and histopathological features of mouse-adapted IBVs and estimated anti-influenza drugs and vaccine efficiency in vitro and in vivo. Assessment of an investigational anti-influenza drug (oseltamivir ethoxysuccinate) and an influenza vaccine (Ultrix®, SPBNIIVS, Saint Petersburg, Russia) showed effectiveness against the mouse-adapted influenza B virus.

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Mucosal Immunity against Neuraminidase Prevents Influenza B Virus Transmission in Guinea Pigs

mBio ◽

10.1128/mbio.00560-19 ◽

2019 ◽

Vol 10 (3) ◽

Cited By ~ 14

Author(s):

Meagan McMahon ◽

Ericka Kirkpatrick ◽

Daniel Stadlbauer ◽

Shirin Strohmeier ◽

Nicole M. Bouvier ◽

...

Keyword(s):

Influenza Virus ◽

Mucosal Immunity ◽

Guinea Pigs ◽

Virus Transmission ◽

Influenza Viruses ◽

Surface Glycoprotein ◽

Influenza B Virus ◽

Influenza B ◽

Intranasal Route ◽

B Virus

ABSTRACTDespite efforts to control influenza virus infection and transmission, influenza viruses still cause significant morbidity and mortality in the global human population each year. Most of the current vaccines target the immunodominant hemagglutinin surface glycoprotein of the virus. However, reduced severity of disease and viral shedding have also been linked to antibodies targeting the second viral surface glycoprotein, the neuraminidase. Importantly, antineuraminidase immunity was shown to be relatively broad, in contrast to vaccine-induced antibodies to the hemagglutinin head domain. In this study, we assessed recombinant neuraminidase protein vaccination for its ability to prevent or limit virus transmission. We vaccinated guinea pigs either intramuscularly or intranasally with a recombinant influenza B virus neuraminidase to assess whether neuraminidase vaccination via these routes could prevent transmission of the homologous virus to a naive recipient. Guinea pigs vaccinated with neuraminidase showed reduced virus titers; however, only vaccination via the intranasal route fully prevented virus transmission to naive animals. We found high levels of antineuraminidase antibodies capable of inhibiting neuraminidase enzymatic activity in the nasal washes of intranasally vaccinated animals, which may explain the observed differences in transmission. We also determined that mucosal immunity to neuraminidase impaired the transmission efficiency of a heterologous influenza B virus, although to a lesser extent. Finally, we found that neuraminidase-vaccinated animals were still susceptible to infection via the airborne and contact transmission routes. However, significantly lower virus titers were detected in these vaccinated recipients. In summary, our data suggest that supplementing vaccine formulations with neuraminidase and vaccinating via the intranasal route may broadly prevent transmission of influenza B viruses.IMPORTANCERecently, the protective effect of anti-neuraminidase immunity has been highlighted by several studies in humans and animal models. However, so far the role that anti-neuraminidase immunity plays in inhibition of virus transmission has not been explored. In addition, neuraminidase has been ignored as an antigen for influenza virus vaccines. We show here that neuraminidase-based vaccines can inhibit the transmission of influenza virus. Therefore, neuraminidase should be considered as an antigen for improved influenza virus vaccines that not only protect individuals from disease but also inhibit further spread of the virus in the population.

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Experimental Infection of Adapted Influenza B Virus in Mice Model

10.20944/preprints202002.0022.v1 ◽

2020 ◽

Author(s):

Elena Prokopyeva ◽

Olga Kurskaya ◽

Ivan Sobolev ◽

Mariia Solomatina ◽

Tatyana Murashkina ◽

...

Keyword(s):

Protective Efficacy ◽

Electron Microscopic Examination ◽

Influenza B Virus ◽

Influenza B ◽

Post Inoculation ◽

Mice Model ◽

Electron Microscopic ◽

B Virus

Over the years influenza B virus (IBV) contribute annual disease and can lead to serious respiratory disease among humans. More attention should be paid to the mammalian adaptive processes of B viruses and development of vaccines against current influenza. Because of preclinical trials of anti-influenza drugs are conducted mainly on mice, we developed adequate animal model using antigenically-relevant IBV strain for testing anti-influenza drugs and protective efficacy of flu vaccines. We serially passaged Victoria lineage (clade 1A) IBV 17 times in BALB/c mice. The adaptive amino acid substitutions were found in HA (T214I) and NA (D432N). By the electron microscopic examination, we showed spherical and elliptical shapes of IBV. Light microscopy showed that mouse-adapted B virus caused influenza pneumonia on day 6 post inoculation. We evaluated the illness pathogenicity, viral load and histopathological features of mouse-adapted IBV and estimated anti-influenza drugs and vaccine efficiency in vitro and in vivo. Assessment of investigational anti-influenza drug oseltamivir ethoxisuccinate and flu vaccine Ultrix® revealed effectivity against our mouse-adapted influenza B virus.

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Recurring Influenza B Virus Infections in Seals

Emerging Infectious Diseases ◽

10.3201/eid1903.120965 ◽

2013 ◽

Vol 19 (3) ◽

pp. 511-512 ◽

Cited By ~ 53

Author(s):

Rogier Bodewes ◽

Danny Morick ◽

Gerrie de Mutsert ◽

Nynke Osinga ◽

Theo Bestebroer ◽

...

Keyword(s):

Influenza B Virus ◽

Influenza B ◽

Virus Infections ◽

B Virus

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Molecular Epidemiology and Phylogenetic Analyses of Influenza B Virus in Thailand during 2010 to 2014

PLoS ONE ◽

10.1371/journal.pone.0116302 ◽

2015 ◽

Vol 10 (1) ◽

pp. e0116302 ◽

Cited By ~ 31

Author(s):

Nipaporn Tewawong ◽

Kamol Suwannakarn ◽

Slinporn Prachayangprecha ◽

Sumeth Korkong ◽

Preeyaporn Vichiwattana ◽

...

Keyword(s):

Molecular Epidemiology ◽

Phylogenetic Analyses ◽

Influenza B Virus ◽

Influenza B ◽

B Virus

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Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine

Vaccines ◽

10.3390/vaccines9070800 ◽

2021 ◽

Vol 9 (7) ◽

pp. 800

Author(s):

Jongsuk Mo ◽

Stivalis Cardenas-Garcia ◽

Jefferson J. S. Santos ◽

Lucas M. Ferreri ◽

C. Joaquín Cáceres ◽

...

Keyword(s):

Vaccine Candidate ◽

The Elderly ◽

Potential Interaction ◽

Respiratory Pathogen ◽

Influenza B Virus ◽

Influenza B ◽

Epitope Tag ◽

Live Attenuated Vaccine ◽

B Virus ◽

Homologous Challenge

Influenza B virus (IBV) is a major respiratory pathogen of humans, particularly in the elderly and children, and vaccines are the most effective way to control it. In previous work, incorporation of two mutations (E580G, S660A) along with the addition of an HA epitope tag in the PB1 segment of B/Brisbane/60/2008 (B/Bris) resulted in an attenuated strain that was safe and effective as a live attenuated vaccine. A third attempted mutation (K391E) in PB1 was not always stable. Interestingly, viruses that maintained the K391E mutation were associated with the mutation E48K. To explore the contribution of the E48K mutation to stability of the K391E mutation, a vaccine candidate was generated by inserting both mutations, along with attenuating mutations E580G and S660A, in PB1 of B/Bris (B/Bris PB1att 4M). Serial passages of the B/Bris PB1att 4M vaccine candidate in eggs and MDCK indicated high stability. In silico structural analysis revealed a potential interaction between amino acids at positions 48 and 391. In mice, B/Bris PB1att 4M was safe and provided complete protection against homologous challenge. These results confirm the compensatory effect of mutation E48K to stabilize the K391E mutation, resulting in a safer, yet still protective, IBV LAIV vaccine.

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