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A High-Yield Recombinant Inactivated Whole-Virion Nasal Influenza A(H1N1)pdm09 Virus Vaccine with an Attenuated PB2 Gene
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A High-Yield Recombinant Inactivated Whole-Virion Nasal Influenza A(H1N1)pdm09 Virus Vaccine with an Attenuated PB2 Gene
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Journal Article
A High-Yield Recombinant Inactivated Whole-Virion Nasal Influenza A(H1N1)pdm09 Virus Vaccine with an Attenuated PB2 Gene
2025
Overview
During the 2009 H1N1 pandemic (pdm09), the poor replication of PR8-derived vaccine strains in embryonated chicken eggs (ECEs) delayed vaccine production, necessitating costly adjuvants. To improve egg-based yield, we generated PB2-substituted H1N1 strains via reverse genetics, replacing PR8 PB2 with a PB2 lacking mammalian-adaptive mutations (dtxPB2), cognate pdm09 PB2 (19PB2), or avian PB2. All PB2-substituted strains achieved over tenfold higher titers than the conventional PR8 PB2-containing strain (rGD19), with rGD19/dtxPB2 and rGD19/19PB2 exhibiting significantly higher titers and reduced murine virulence. Among these, rGD19/19PB2 produced the highest hemagglutinin (HA) yield and, when administered intranasally as a binary ethyleneimine (BEI)-inactivated whole-virion vaccine, elicited a significantly stronger broncho-alveolar IgA response than rGD19. Both rGD19 and rGD19/19PB2 provided comparable protection against a homologous H1N1 challenge, yet only rGD19/19PB2 conferred full survival protection after a lethal heterologous H3N2 challenge. These findings show that incorporation of cognate PB2 enhances H1N1 replication in ECEs and antigen yield, reduces murine virulence, and confers robust homo- and heterosubtypic protection via intranasal immunization, underscoring the promise of PB2-modified H1N1 strains as inactivated mucosal whole-virion vaccines for future vaccine development.
Publisher
MDPI AG,MDPI
Subject
/ Animals
/ Enzymes
/ Female
/ Humans
/ Influenza A Virus, H1N1 Subtype - genetics
/ Influenza A Virus, H1N1 Subtype - immunology
/ Influenza Vaccines - administration & dosage
/ Influenza Vaccines - genetics
/ Influenza Vaccines - immunology
/ Mice
/ Mutation
/ Orthomyxoviridae Infections - immunology
/ Orthomyxoviridae Infections - prevention & control
/ Orthomyxoviridae Infections - virology
/ RNA-Dependent RNA Polymerase - genetics
/ RNA-Dependent RNA Polymerase - immunology
/ Vaccines, Attenuated - genetics
/ Vaccines, Attenuated - immunology
/ Vaccines, Inactivated - administration & dosage
/ Vaccines, Inactivated - genetics
/ Vaccines, Inactivated - immunology
/ Viruses
