PB2 and PA genes control the expression of the temperature-sensitive phenotype of cold-adapted B/USSR/60/69 influenza master donor virus

Kiseleva, Irina; Voeten, J.T.M.; Teley, Lisette C. P.; Larionova, Natalie; Cruijsen, Sandra K. M. Drieszen-van der; Basten, Stephanie M. C.; Heldens, Jacco; Bosch, Han van den; Rudenko, Larisa

doi:10.1099/vir.0.017996-0

Cited by 39 publications

(26 citation statements)

References 16 publications

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“…Reversion mutations are underlined. Modifications introduced to attenuate the virus are in boldface.bData from reference 25.cData from reference 70 (sequence information not publicly available; only the number of mutations per segment is given).…”

Section: Resultsmentioning

confidence: 99%

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Development of an Alternative Modified Live Influenza B Virus Vaccine

Santos

Finch

Sutton

et al. 2017

J Virol

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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.

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Section: Resultsmentioning

confidence: 99%

“…cData from reference 70 (sequence information not publicly available; only the number of mutations per segment is given).…”

Section: Resultsmentioning

confidence: 99%

Development of an Alternative Modified Live Influenza B Virus Vaccine

Santos

Finch

Sutton

et al. 2017

J Virol

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“…The master donor viruses A/Leningrad/134/17/57 (H2N2) and B/USSR/60/69, which are the basis of LAIV, were obtained by repeated passages in embryonated chicken eggs at low temperature (25-26°C), which rendered them cold-adapted (ca), temperature-sensitive (ts) and attenuated (att) [1,8,10]. These master donor viruses are used to generate reassortant influenza viruses that contain the surface glycoproteins haemagglutinin and neuraminidase of currently circulating influenza viruses, while the ca/ts/att phenotype is inherited from the master donor virus.…”

Section: Introductionmentioning

confidence: 99%

Master donor viruses A/Leningrad/134/17/57 (H2N2) and B/USSR/60/69 and derived reassortants used in live attenuated influenza vaccine (LAIV) do not display neurovirulent properties in a mouse model

Voeten¹,

Kiseleva

Glansbeek³

et al. 2010

Arch Virol

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“…Importantly, mutations in other gene segments, including PB2, PA, NP, M, and NS, are often seen (15)(16)(17)(18). In particular, polymerase subunits PB2 and PA control replication in different host cells and at different temperatures (19). Some mutations in the M gene segment have been associated with transmission (20), while NP mutations control the interactions with MxA, a host-derived antiviral molecule (21).…”

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confidence: 99%

Equine and Canine Influenza H3N8 Viruses Show Minimal Biological Differences Despite Phylogenetic Divergence

Feng

Gonzalez

Deng

et al. 2015

J Virol

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The A/H3N8 canine influenza virus (CIV) emerged from A/H3N8 equine influenza virus (EIV) around the year 2000 through the transfer of a single virus from horses to dogs. We defined and compared the biological properties of EIV and CIV by examining their genetic variation, infection, and growth in different cell cultures, receptor specificity, hemagglutinin (HA) cleavage, and infection and growth in horse and dog tracheal explant cultures. Comparison of sequences of viruses from horses and dogs revealed mutations that may be linked to host adaptation and tropism. We prepared infectious clones of representative EIV and CIV strains that were similar to the consensus sequences of viruses from each host. The rescued viruses, including HA and neuraminidase (NA) double reassortants, exhibited similar degrees of long-term growth in MDCK cells. Different host cells showed various levels of susceptibility to infection, but no differences in infectivity were seen when comparing viruses. All viruses preferred ␣2-3-over ␣2-6-linked sialic acids for infections, and glycan microarray analysis showed that EIV and CIV HA-Fc fusion proteins bound only to ␣2-3-linked sialic acids. Cleavage assays showed that EIV and CIV HA proteins required trypsin for efficient cleavage, and no differences in cleavage efficiency were seen. Inoculation of the viruses into tracheal explants revealed similar levels of infection and replication by each virus in dog trachea, although EIV was more infectious in horse trachea than CIV. IMPORTANCEInfluenza A viruses can cross species barriers and cause severe disease in their new hosts. Infections with highly pathogenic avian H5N1 virus and, more recently, avian H7N9 virus have resulted in high rates of lethality in humans. Unfortunately, our current understanding of how influenza viruses jump species barriers is limited. Our aim was to provide an overview and biological characterization of H3N8 equine and canine influenza viruses using various experimental approaches, since the canine virus emerged from horses approximately 15 years ago. We showed that although there were numerous genetic differences between the equine and canine viruses, this variation did not result in dramatic biological differences between the viruses from the two hosts, and the viruses appeared phenotypically equivalent in most assays we conducted. These findings suggest that the crossspecies transmission and adaptation of influenza viruses may be mediated by subtle changes in virus biology. Influenza A viruses are maintained in aquatic birds as intestinal infections, occasionally transfer to and become established as respiratory infections in mammals, including humans, and sometimes spread from one mammal to another (1, 2). Mammalian hosts that have been commonly seen to maintain avian-derived viruses include swine, horses, humans, mink, seals, and, recently, dogs (2-5). Host transfers between different birds, from birds to mammals, or between different mammalian hosts are relatively common but mostly result in single infe...

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PB2 and PA genes control the expression of the temperature-sensitive phenotype of cold-adapted B/USSR/60/69 influenza master donor virus

Cited by 39 publications

References 16 publications

Development of an Alternative Modified Live Influenza B Virus Vaccine

Development of an Alternative Modified Live Influenza B Virus Vaccine

Master donor viruses A/Leningrad/134/17/57 (H2N2) and B/USSR/60/69 and derived reassortants used in live attenuated influenza vaccine (LAIV) do not display neurovirulent properties in a mouse model

Equine and Canine Influenza H3N8 Viruses Show Minimal Biological Differences Despite Phylogenetic Divergence

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