Alternative Strategy for a Quadrivalent Live Attenuated Influenza Virus Vaccine

Wan, Zhimin; Cardenas-Garcia, Stivalis; Liu, Jing; Santos, Jefferson; Carnaccini, Silvia; Geiger, Ginger; Ferreri, Lucas; Rajão, Daniela S.; Pérez, Daniel R.

doi:10.1128/jvi.01025-18

Cited by 15 publications

(21 citation statements)

References 41 publications

(47 reference statements)

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“…In contrast, PBS-vaccinated/challenged mice showed severe body weight loss. Only one female (out of 8) and none of the male mice survived in the PBS-vaccinated/challenged group, consistent with previous studies [27,31]. (C) Post-challenge antibody titer determination.…”

Section: Qualitative Differences In Humoral Responses Among Different Vaccine Groupssupporting

confidence: 89%

“…Live attenuated vaccine platforms have been among the most explored over the years (reviewed in [24]). In addition to the coldadapted LAIVs developed in the 60's that form the basis of the current LAIVs approved for human use, alternative LAIV approaches have been developed that include modifications and deletions to the NS1 gene segment, generation of M2 deficient viruses, alternative virus backbones with temperature sensitive phenotypes, among others [25][26][27][28][29][30][31]. We have previously shown that genome re-arrangement is a suitable strategy for the development of influenza A virus LAIVs [32].…”

Section: Introductionmentioning

confidence: 99%

“…The FluB-RANS re-arrangement used a similar strategy whereby NS2 was cloned downstream of PB1 and segment 8 contains multiple mutations that precludes NS2 expression. Safety and efficacy of the FluB-RAM and FluB-RANS viruses was evaluated in DBA/2J mice [27,31,33,34]. Both vaccine candidates were immunogenic and effectively protected mice against homologous lethal IBV challenge.…”

Section: Introductionmentioning

confidence: 99%

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

Cardenas-Garcia¹,

Cáceres²,

Jain³

et al. 2021

Preprint

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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 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.

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Section: Qualitative Differences In Humoral Responses Among Different Vaccine Groupssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Cardenas-Garcia¹,

Cáceres²,

Jain³

et al. 2021

Preprint

Self Cite

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“…We have developed a LAIV strategy by incorporating ts mutations on the PB1 that can be applied similarly for both IAV and IBV [19,21,22]. This strategy has been shown to be safe and effective in mice, pigs and chickens, stimulating cross-protective immunity against antigenically distinct viruses and can be used in a quadrivalent formulation [19,20,22,[30][31][32]. In a previous study using an IBV LAIV candidate with the PB1 gene segment carrying three ts mutations K391E, E580G, S660A and a C-terminus HA tag, the K391E mutation reverted to its wild type form (E391K) during the initial passages in SPF eggs [22].…”

Section: Discussionmentioning

confidence: 99%

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

Mo¹,

Cardenas-Garcia²,

Santos³

et al. 2021

Preprint

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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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“…Influenza vaccine is the recommended approach to protect against influenza virus infection. Currently, influenza vaccines approved by the US FDA include inactivated influenza vaccine (IIV), recombinant influenza protein (RIP), and live attenuated influenza vaccine (LAIV) [1]. Studies have shown that inactivated influenza virus vaccine is wildly used and shows good safety and immunogenicity after immunization in humans [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

MiRNA Targeted NP Genome of Live Attenuated Influenza Vaccines Provide Cross-Protection against a Lethal Influenza Virus Infection

Gao

Yang²,

Liu³

et al. 2020

Vaccines

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The miRNA-based strategy has been used to develop live attenuated influenza vaccines. In this study, the nucleoprotein (NP) genome segment of the influenza virus was inserted by different perfect miRNA-192-5p target sites, and the virus was rescued by standard reverse genetics method, so as to verify the virulence and protective efficacy of live attenuated vaccine in cells and mice. The results showed there was no significant attenuation in 192t virus with one perfect miRNA-192-5p target site, and 192t-3 virus with three perfect miRNA target sites. However, 192t-6 virus with 6 perfect miRNA target sites and 192t-9 virus with 9 perfect miRNA target sites were both significantly attenuated after infection, and their virulence were similar to that of temperature-sensitive (TS) influenza A virus (IAV) which is a temperature-sensitive live attenuated influenza vaccine. Mice were immunized with different doses of 192t-6, 192t-9, and TS IAV. Four weeks after immunization, the IgG in serum and IgA in lung homogenate were increased in the 192t-6, 192t-9, and TS IAV groups, and the numbers of IFN-γ secreting splenocytes were also increased in a dose-dependent manner. Finally, 192t-6, and 192t-9 can protect the mice against the challenge of homologous PR8 H1N1 virus and heterosubtypic H3N2 influenza virus. MiRNA targeted viruses 192t-6 and 192t-9 were significantly attenuated and showed the same virulence as TS IAV and played a role in the cross-protection.

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Alternative Strategy for a Quadrivalent Live Attenuated Influenza Virus Vaccine

Cited by 15 publications

References 41 publications

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

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

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

MiRNA Targeted NP Genome of Live Attenuated Influenza Vaccines Provide Cross-Protection against a Lethal Influenza Virus Infection

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