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

Mo, Jong-Suk; Cardenas-Garcia, Stivalis; Santos, Jefferson; Ferreri, Lucas; Cáceres, C. Joaquín; Geiger, Ginger; Pérez, Daniel R.; Rajão, Daniela S.

doi:10.3390/vaccines9070800

Cited by 5 publications

(11 citation statements)

References 39 publications

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“…The humoral responses induced by the rearranged virus vaccines were analyzed utilizing serum samples obtained at 19 days post-boost (19 dpb) from a subset of 4 mice/group (2 males, 2 females, except in the FluB-RAM group with 1 male and 2 female serum samples). Please note that we included HI data from FluB att as it was part of the same study, although it was reported elsewhere [39]; these data were included for comparison purposes. Boost vaccination led to HI titers above 40, the predictive limit of protection (Figure 2C) with either rearranged virus.…”

Section: Qualitative Differences In Humoral Responses Among Different Vaccine Groupsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Qualitative Differences In Humoral Responses Among Different Vaccine Groupsmentioning

confidence: 99%

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

et al. 2021

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“…Lethality of Phu/13 and FL/4/06 in Mice Prior to Mouse-Adapting Influenza viruses do not typically cause disease in mice. However, lethal challenge strains of influenza are often optimal for vaccine and therapeutics studies [26,29,[32][33][34]. Therefore, mouse-adapting is used to produce a disease model for use in laboratory studies [23,26].…”

Section: Resultsmentioning

confidence: 99%

“…Despite this, the inability to naturally cause infections in many mouse strains has led to difficulty of developing easily accessible small animal disease models for IBV vaccine and therapeutic research. The process of mouse-adapting IBV has been used to define in vivo pathogenic determinants [24][25][26] and for development of lethal strains for use in vaccine and therapeutics studies [32][33][34]36]. However, performing mouse-adapting series can be costly and may not produce consistent or repeatable results.…”

Section: Discussionmentioning

confidence: 99%

Expanding Mouse-Adapted Yamagata-like Influenza B Viruses in Eggs Enhances In Vivo Lethality in BALB/c Mice

Pekarek

Petro-Turnquist

Rubrum

et al. 2022

Viruses

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Despite the yearly global impact of influenza B viruses (IBVs), limited host range has been a hurdle to developing a readily accessible small animal disease model for vaccine studies. Mouse-adapting IBV can produce highly pathogenic viruses through serial lung passaging in mice. Previous studies have highlighted amino acid changes throughout the viral genome correlating with increased pathogenicity, but no consensus mutations have been determined. We aimed to show that growth system can play a role in mouse-adapted IBV lethality. Two Yamagata-lineage IBVs were serially passaged 10 times in mouse lungs before expansion in embryonated eggs or Madin–Darby canine kidney cells (London line) for use in challenge studies. We observed that virus grown in embryonated eggs was significantly more lethal in mice than the same virus grown in cell culture. Ten additional serial lung passages of one strain again showed virus grown in eggs was more lethal than virus grown in cells. Additionally, no mutations in the surface glycoprotein amino acid sequences correlated to differences in lethality. Our results suggest growth system can influence lethality of mouse-adapted IBVs after serial lung passaging. Further research can highlight improved mechanisms for developing animal disease models for IBV vaccine research.

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“…The PB1 plasmids containing the re-arranged M (PB1BM2) and re-arranged NS (PB1BNS2) and the M and NS plasmids encoding early stops codons have been previously described 18 . The PB1 plasmid containing the temperature sensitive mutations and C-terminal HA tag (pDP-PB1att) was previously described 21,29 . The plasmid pDP_B/Bris-PB1_Nluc (B/Bris) was produced carrying a chimeric PB1 gene segment from B/Brisbane/60/2008 (B/Bris) WT with an in-frame C-terminal nanoluciferase ORF (Nluc) between the C-terminal end of the PB1 ORF and the 3'UTR.…”

Section: Recombinant Plasmidsmentioning

confidence: 99%

Modified Live Attenuated Influenza B Virus Vaccines and Sex-driven Differences on Humoral Immune Responses in the DBA/2J Mouse Model

Pérez¹,

Cardenas-Garcia²,

Cáceres³

et al. 2022

Preprint

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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 backbones containing a chimeric HA segment carrying an N-terminal 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 regimen, mice were completely protected against lethal challenge with a homologous FLUBV strain. Recombinant viruses induced neutralizing antibodies with hemagglutination inhibition titers ≥40. 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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Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine

Cited by 5 publications

References 39 publications

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

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

Expanding Mouse-Adapted Yamagata-like Influenza B Viruses in Eggs Enhances In Vivo Lethality in BALB/c Mice

Modified Live Attenuated Influenza B Virus Vaccines and Sex-driven Differences on Humoral Immune Responses in the DBA/2J Mouse Model

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