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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Influenza A virus

PROVIDER: GSE180642 | GEO | 2021/07/23

REPOSITORIES: GEO

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Project description:Influenza B virus (IBV) strains are one of the components of seasonal influenza vaccines in both trivalent and quadrivalent formulations. The vast majority of these vaccines are produced in embryonated chickens' eggs. While optimized backbones for vaccine production in eggs exist and are in use for influenza A viruses, no such backbones exist for IBVs, resulting in unpredictable production yields. To generate an optimal vaccine seed virus backbone, we have compiled a panel of 71 IBV strains from 1940 to present day, representing the known temporal and genetic variability of IBV circulating in humans. This panel contains strains from the B/Victoria/2/87-like lineage, B/Yamagata/16/88-like lineage and the ancestral lineage that preceded their split to provide a diverse set that would help to identify a suitable backbone which can be used in combination with hemagglutinin (HA) and neuraminidase (NA) glycoproteins from any IBV strain to be incorporated into the seasonal vaccine. We have characterized and ranked the growth profiles of the 71 IBV strains and the best performing strains were used for co-infection of eggs, followed by serial passaging to select for high-growth reassortant viruses. After serial passaging, we selected 10 clonal isolates based on their growth profiles assessed by hemagglutination and plaque-forming units. We then generated reverse genetics systems for the three clones that performed best in growth curves. The selected backbones were then used to generate different reassortant viruses with HA/NA combinations from high and low titer yielding wild type IBV. When the growth profiles of the recombinant reassortant viruses were tested, the low titer yielding HA/NA viruses with the selected backbones yielded higher titers similar to those from high titer yielding HA/NA combinations. The use of these IBV backbones with improved replication in eggs might increase yields for the influenza B virus components of seasonal influenza virus vaccines.

Project description:Influenza B virus (FLUBV) is a major respiratory pathogen of humans. Seasonal influenza vaccines include either one or both FLUBV lineage strains, Victoria, and Yamagata. Vaccine mismatch occurs frequently, particularly in countries where vaccines contain only one of the lineages. We have previously described the safety and efficacy of modified live attenuated FLUBV vaccines based on either virus with rearranged genomes (FluB-RAM and FluB-RANS) or carrying a PB1 segment with a combination of temperature sensitive mutations and a C-terminal HA tag (FluB-att). We compared side by side the immunological responses in female and male DBA/2J mice vaccinated with either one of these vaccines and those with isogenic backgrounds encoding a chimeric HA segment carrying an N-terminal peptide encoding the IgA inducing peptide (IGIP). Recombinant viruses with or without the IGIP modification were genetically stable over multiple passages in eggs. In mice, introduction of IGIP improved attenuation of the vaccine candidates, particularly for the FluB-RAM/IGIP compared with the non-IGIP FluB-RAM counterpart. In a prime-boost regime, mice were completely protected against lethal challenge with a homologous FLUBV strain. Recombinant viruses induced antibodies against HA considered of protective value. Antibodies against NA and NP were readily detected. Compared to male mice and regardless of the vaccine used, female mice showed a clear trend towards enhanced humoral and cross-reactive IgG and IgA anti-HA responses as well as against NA and NP. The presence of IGIP in the vaccine resulted in an overall trend towards reduced anti-HA responses but enhanced anti-NA and anti-NP responses, particularly of the IgA isotype. Mucosal and serological responses two weeks after challenge showed similar trends with clear differences observed based on sex, vaccine backbone, and whether the vaccine carried the IGIP modification. These findings are significant for the development of universal influenza vaccines.

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

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