scholarly journals FluB-RAM and FluB-RANS: Genome Rearrangement as Safe and Efficacious Live Attenuated Influenza B Virus Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 897
Author(s):  
Stivalis Cardenas-Garcia ◽  
C. Joaquín Cáceres ◽  
Aarti Jain ◽  
Ginger Geiger ◽  
Jong-Suk Mo ◽  
...  
Keyword(s):  
Genome Rearrangement ◽  
Natural Infection ◽  
The Elderly ◽  
Respiratory Pathogen ◽  
Influenza B Virus ◽  
Influenza B ◽  
B Virus ◽  
Cellular Immune

Influenza B virus (IBV) is considered a major respiratory pathogen responsible for seasonal respiratory disease in humans, particularly severe in children and the elderly. Seasonal influenza vaccination is considered the most efficient strategy to prevent and control IBV infections. Live attenuated influenza virus vaccines (LAIVs) are thought to induce both humoral and cellular immune responses by mimicking a natural infection, but their effectiveness has recently come into question. Thus, the opportunity exists to find alternative approaches to improve overall influenza vaccine effectiveness. Two alternative IBV backbones were developed with rearranged genomes, rearranged M (FluB-RAM) and a rearranged NS (FluB-RANS). Both rearranged viruses showed temperature sensitivity in vitro compared with the WT type B/Bris strain, were genetically stable over multiple passages in embryonated chicken eggs and were attenuated in vivo in mice. In a prime-boost regime in naïve mice, both rearranged viruses induced antibodies against HA with hemagglutination inhibition titers considered of protective value. In addition, antibodies against NA and NP were readily detected with potential protective value. Upon lethal IBV challenge, mice previously vaccinated with either FluB-RAM or FluB-RANS were completely protected against clinical disease and mortality. In conclusion, genome re-arrangement renders efficacious LAIV candidates to protect mice against IBV.

scholarly journals FluB-RAM and FluB-RANS: Genome re-arrangement as safe and efficacious live attenuated influenza B virus vaccines.

2021 ◽  
Author(s):  
Stivalis Cardenas-Garcia ◽  
C. Joaquín Cáceres ◽  
Aarti Jain ◽  
Ginger Geiger ◽  
Jong-Suk Mo ◽  
...  
Keyword(s):  
Natural Infection ◽  
The Elderly ◽  
Respiratory Pathogen ◽  
Influenza B Virus ◽  
Influenza B ◽  
B Virus ◽  
Cellular Immune ◽  
And Control

Influenza B virus (IBV) is considered a major respiratory pathogen responsible for seasonal respiratory disease in humans, particularly severe in children and the elderly. Seasonal influenza vaccination is considered the most efficient strategy to prevent and control IBV infections. Live attenuated influenza virus vaccines (LAIVs) are thought to induce both humoral and cellular immune responses by mimicking a natural infection, but their effectiveness have recently come into question. Thus, the opportunity exists to find alternative approaches to improve overall influenza vaccine effectiveness. Two alternative IBV backbones were developed with re-arranged genomes, re-arranged M (FluB-RAM) and a re-arranged NS (FluB-RANS). Both re-arranged viruses showed temperature sensitivity in vitro compared to the WT type B/Bris strain, were genetically stable over multiple passages in embryonated chicken eggs and were attenuated in vivo in mice. In a prime-boost regime in naïve mice, both re-arranged viruses induced antibodies against HA with hemagglutination inhibition titers considered of protective value. In addition, antibodies against NA and NP were readily detected with potential protective value. Upon lethal IBV challenge, mice previously vaccinated with either FluB-RAM or FluB-RANS were completely protected against clinical disease and mortality. In conclusion, genome re-arrangement renders efficacious LAIV candidates to protect mice against IBV.

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

Vaccines ◽  
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.

scholarly journals Influenza B Virus NS1-Truncated Mutants: Live-Attenuated Vaccine Approach

2008 ◽  
Vol 82 (21) ◽  
pp. 10580-10590 ◽  
Author(s):  
Rong Hai ◽  
Luis Martínez-Sobrido ◽  
Kathryn A. Fraser ◽  
Juan Ayllon ◽  
Adolfo García-Sastre ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
Type I ◽  
Live Attenuated Vaccine ◽  
Live Virus ◽  
B Virus

ABSTRACT Type B influenza viruses can cause substantial morbidity and mortality in the population, and vaccination remains by far the best means of protection against infections with these viruses. Here, we report the construction of mutant influenza B viruses for potential use as improved live-virus vaccine candidates. Employing reverse genetics, we altered the NS1 gene, which encodes a type I interferon (IFN) antagonist. The resulting NS1 mutant viruses induced IFN and, as a consequence, were found to be attenuated in vitro and in vivo. The absence of pathogenicity of the NS1 mutants in both BALB/c and C57BL/6 PKR−/− mice was confirmed. We also provide evidence that influenza B virus NS1 mutants induce a self-adjuvanted immune response and confer effective protection against challenge with both homologous and heterologous B virus strains in mice.

scholarly journals The NB Protein of Influenza B Virus Is Not Necessary for Virus Replication In Vitro

2003 ◽  
Vol 77 (10) ◽  
pp. 6050-6054 ◽  
Author(s):  
Masato Hatta ◽  
Yoshihiro Kawaoka
Keyword(s):  
Cell Culture ◽  
Virus Replication ◽  
Wild Type Virus ◽  
Influenza B Virus ◽  
Influenza B ◽  
Type Virus ◽  
Wild Type ◽  
B Virus

ABSTRACT The NB protein of influenza B virus is thought to function as an ion channel and therefore would be expected to have an essential function in viral replication. Because direct evidence for its absolute requirement in the viral life cycle is lacking, we generated NB knockout viruses by reverse genetics and tested their growth properties both in vitro and in vivo. Mutants not expressing NB replicated as efficiently as the wild-type virus in cell culture, whereas in mice they showed restricted growth compared with findings for the wild-type virus. Thus, the NB protein is not essential for influenza B virus replication in cell culture but promotes efficient growth in mice.

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

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 470 ◽  
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.

scholarly journals Development of an Alternative Modified Live Influenza B Virus Vaccine

2017 ◽  
Vol 91 (12) ◽  
Author(s):  
Jefferson J. S. Santos ◽  
Courtney Finch ◽  
Troy Sutton ◽  
Adebimpe Obadan ◽  
Isabel Aguirre ◽  
...  
Keyword(s):  
Influenza A ◽  
The United States ◽  
Influenza B Virus ◽  
Influenza B ◽  
Temperature Sensitive ◽  
Complete Protection ◽  
C Terminus ◽  
B Virus

ABSTRACT Influenza B virus (IBV) is considered a major human pathogen, responsible for seasonal epidemics of acute respiratory illness. Two antigenically distinct IBV hemagglutinin (HA) lineages cocirculate worldwide with little cross-reactivity. Live attenuated influenza virus (LAIV) vaccines have been shown to provide better cross-protective immune responses than inactivated vaccines by eliciting local mucosal immunity and systemic B cell- and T cell-mediated memory responses. We have shown previously that incorporation of temperature-sensitive (ts) mutations into the PB1 and PB2 subunits along with a modified HA epitope tag in the C terminus of PB1 resulted in influenza A viruses (IAV) that are safe and effective as modified live attenuated (att) virus vaccines (IAV att). We explored whether analogous mutations in the IBV polymerase subunits would result in a stable virus with an att phenotype. The PB1 subunit of the influenza B/Brisbane/60/2008 strain was used to incorporate ts mutations and a C-terminal HA tag. Such modifications resulted in a B/Bris att strain with ts characteristics in vitro and an att phenotype in vivo. Vaccination studies in mice showed that a single dose of the B/Bris att candidate stimulated sterilizing immunity against lethal homologous challenge and complete protection against heterologous challenge. These studies show the potential of an alternative LAIV platform for the development of IBV vaccines. IMPORTANCE A number of issues with regard to the effectiveness of the LAIV vaccine licensed in the United States (FluMist) have arisen over the past three seasons (2013–2014, 2014–2015, and 2015–2016). While the reasons for the limited robustness of the vaccine-elicited immune response remain controversial, this problem highlights the critical importance of continued investment in LAIV development and creates an opportunity to improve current strategies so as to develop more efficacious vaccines. Our laboratory has developed an alternative strategy, the incorporation of 2 amino acid mutations and a modified HA tag at the C terminus of PB1, which is sufficient to attenuate the IBV. As a LAIV, this novel vaccine provides complete protection against IBV strains. The availability of attenuated IAV and IBV backbones based on contemporary strains offers alternative platforms for the development of LAIVs that may overcome current limitations.

scholarly journals Mouse-adapted influenza B virus for in vitro and in vivo assessment of therapeutic and preventive efficacy of antiviral drugs

2019 ◽  
Vol 11 (4) ◽  
pp. 53-64
Author(s):  
E. A. Prokopyeva ◽  
O. G. Kurskaya ◽  
M. V. Solomatina ◽  
I. A. Sobolev ◽  
Т. A. Murashkina ◽  
...  
Keyword(s):  
Antiviral Drugs ◽  
Influenza B Virus ◽  
Influenza B ◽  
B Virus ◽  
Preventive Efficacy ◽  
In Vivo Assessment

scholarly journals A New Master Donor Virus for the Development of Live-Attenuated Influenza B Virus Vaccines

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1278
Author(s):  
Chantelle L. White ◽  
Kevin Chiem ◽  
Daniel R. Perez ◽  
Jefferson Santos ◽  
Stivalis Cardenas Garcia ◽  
...  
Keyword(s):  
The Elderly ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
Temperature Sensitive ◽  
Direct Exposure ◽  
Variable Surface ◽  
Ann Arbor

Influenza B viruses (IBV) circulate annually, with young children, the elderly and immunocompromised individuals being at high risk. Yearly vaccinations are recommended to protect against seasonally influenza viruses, including IBV. Live attenuated influenza vaccines (LAIV) provide the unique opportunity for direct exposure to the antigenically variable surface glycoproteins as well as the more conserved internal components. Ideally, LAIV Master Donor Viruses (MDV) should accurately reflect seasonal influenza strains. Unfortunately, the continuous evolution of IBV have led to significant changes in conserved epitopes compared to the IBV MDV based on B/Ann Arbor/1/1966 strain. Here, we propose a recent influenza B/Brisbane/60/2008 as an efficacious MDV alternative, as its internal viral proteins more accurately reflect those of circulating IBV strains. We introduced the mutations responsible for the temperature sensitive (ts), cold adapted (ca) and attenuated (att) phenotype of B/Ann Arbor/1/1966 MDV LAIV into B/Brisbane/60/2008 to generate a new MDV LAIV. In vitro and in vivo analysis demonstrated that the mutations responsible of the ts, ca, and att phenotype of B/Ann Arbor/1/1966 MDV LAIV were able to infer the same phenotype to B/Brisbane/60/2008, demonstrating its potential as a new MDV for the development of LAIV to protect against contemporary IBV strains.

scholarly journals A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Ning Chai ◽  
Lee R. Swem ◽  
Summer Park ◽  
Gerald Nakamura ◽  
Nancy Chiang ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Antiviral Effect ◽  
Therapeutic Benefit ◽  
Influenza B Virus ◽  
Influenza B ◽  
Lethal Challenge ◽  
Enrichment Technique ◽  
B Virus

Abstract Influenza B virus (IBV) causes annual influenza epidemics around the world. Here we use an in vivo plasmablast enrichment technique to isolate a human monoclonal antibody, 46B8 that neutralizes all IBVs tested in vitro and protects mice against lethal challenge of all IBVs tested when administered 72 h post infection. 46B8 demonstrates a superior therapeutic benefit over Tamiflu and has an additive antiviral effect in combination with Tamiflu. 46B8 binds to a conserved epitope in the vestigial esterase domain of hemagglutinin (HA) and blocks HA-mediated membrane fusion. After passage of the B/Brisbane/60/2008 virus in the presence of 46B8, we isolated three resistant clones, all harbouring the same mutation (Ser301Phe) in HA that abolishes 46B8 binding to HA at low pH. Interestingly, 46B8 is still able to protect mice against lethal challenge of the mutant viruses, possibly owing to its ability to mediate antibody-dependent cellular cytotoxicity (ADCC).

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

2021 ◽  
Author(s):  
Jongsuk Mo ◽  
Stivalis Cardenas-Garcia ◽  
Jefferson J. S. Santos ◽  
Lucas M. Ferreri ◽  
C. Joaquín Cáceres ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
The Elderly ◽  
Serial Passage ◽  
Potential Interaction ◽  
Respiratory Pathogen ◽  
Influenza B Virus ◽  
Influenza B ◽  
Epitope Tag ◽  
Live Attenuated Vaccine ◽  
B Virus

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 a 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 for 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 passage 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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