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From Variation of Influenza Viral Proteins to Vaccine Development.

ABSTRACT: Recurrent influenza epidemics and occasional pandemics are one of the most important global public health concerns and are major causes of human morbidity and mortality. Influenza viruses can evolve through antigen drift and shift to overcome the barriers of human immunity, leading to host adaption and transmission. Mechanisms underlying this viral evolution are gradually being elucidated. Vaccination is an effective method for the prevention of influenza virus infection. However, the emergence of novel viruses, including the 2009 pandemic influenza A (H1N1), the avian influenza A virus (H7N9), and the highly pathogenic avian influenza A virus (HPAI H5N1), that have infected human populations frequently in recent years reveals the tremendous challenges to the current influenza vaccine strategy. A better vaccine that provides protection against a wide spectrum of various influenza viruses and long-lasting immunity is urgently required. Here, we review the evolutionary changes of several important influenza proteins and the influence of these changes on viral antigenicity, host adaption, and viral pathogenicity. Furthermore, we discuss the development of a potent universal influenza vaccine based on this knowledge.

SUBMITTER: Zhu W

PROVIDER: S-EPMC5536042 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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From Variation of Influenza Viral Proteins to Vaccine Development.

Zhu Wandi W Wang Chao C Wang Bao-Zhong BZ

International journal of molecular sciences 20170718 7

Recurrent influenza epidemics and occasional pandemics are one of the most important global public health concerns and are major causes of human morbidity and mortality. Influenza viruses can evolve through antigen drift and shift to overcome the barriers of human immunity, leading to host adaption and transmission. Mechanisms underlying this viral evolution are gradually being elucidated. Vaccination is an effective method for the prevention of influenza virus infection. However, the emergence ...[more]

PMID: 28718801

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Project description:RNA viruses demonstrate a vast range of variants, called quasispecies, due to error-prone replication by viral RNA-dependent RNA polymerase. Although live attenuated vaccines are effective in preventing RNA virus infection, there is a risk of reversal to virulence after their administration. To test the hypothesis that high-fidelity viral polymerase reduces the diversity of influenza virus quasispecies, resulting in inhibition of reversal of the attenuated phenotype, we first screened for a high-fidelity viral polymerase using serial virus passages under selection with a guanosine analog ribavirin. Consequently, we identified a Leu66-to-Val single amino acid mutation in polymerase basic protein 1 (PB1). The high-fidelity phenotype of PB1-L66V was confirmed using next-generation sequencing analysis and biochemical assays with the purified influenza viral polymerase. As expected, PB1-L66V showed at least two-times-lower mutation rates and decreased misincorporation rates, compared to the wild type (WT). Therefore, we next generated an attenuated PB1-L66V virus with a temperature-sensitive (ts) phenotype based on FluMist, a live attenuated influenza vaccine (LAIV) that can restrict virus propagation by ts mutations, and examined the genetic stability of the attenuated PB1-L66V virus using serial virus passages. The PB1-L66V mutation prevented reversion of the ts phenotype to the WT phenotype, suggesting that the high-fidelity viral polymerase could contribute to generating an LAIV with high genetic stability, which would not revert to the pathogenic virus.IMPORTANCE The LAIV currently in use is prescribed for actively immunizing individuals aged 2 to 49 years. However, it is not approved for infants and elderly individuals, who actually need it the most, because it might prolong virus propagation and cause an apparent infection in these individuals, due to their weak immune systems. Recently, reversion of the ts phenotype of the LAIV strain currently in use to a pathogenic virus was demonstrated in cultured cells. Thus, the generation of mutations associated with enhanced virulence in LAIV should be considered. In this study, we isolated a novel influenza virus strain with a Leu66-to-Val single amino acid mutation in PB1 that displayed a significantly higher fidelity than the WT. We generated a novel LAIV candidate strain harboring this mutation. This strain showed higher genetic stability and no ts phenotype reversion. Thus, our high-fidelity strain might be useful for the development of a safer LAIV.

Project description:BackgroundAdjuvant formulations are critical components of modern vaccines based on recombinant proteins, which are often poorly immunogenic without additional immune stimulants. Oil-in-water emulsions comprise an advanced class of vaccine adjuvants that are components of approved seasonal and pandemic influenza vaccines. However, few reports have been published that systematically evaluate the in vitro stability and in vivo adjuvant effects of different emulsion components.ObjectivesTo evaluate distinct classes of surfactants, oils, and excipients, for their effects on emulsion particle size stability, antigen structural interactions, and in vivo activity when formulated with a recombinant H5N1 antigen.MethodsEmulsions were manufactured by high pressure homogenization and characterized alone or in the presence of vaccine antigen by dynamic light scattering, zeta potential, viscosity, pH, hemolytic activity, electron microscopy, fluorescence spectroscopy, and SDS-PAGE. In vivo vaccine activity in the murine model was characterized by measuring antibody titers, antibody-secreting plasma cells, hemagglutination inhibition titers, and cytokine production.ResultsWe demonstrate that surfactant class and presence of additional excipients are not critical for biological activity, whereas oil structure is crucial. Moreover, we report that simplified two-component emulsions appear more stable by particle size than more complex formulations.Finally, differences in antigen structural interactions with the various emulsions do not appear to correlate with in vivo activity.ConclusionsOil-in-water emulsions can significantly enhance antibody and cellular immune responses to a pandemic influenza antigen. The dramatic differences in adjuvant activity between squalene-based emulsion and medium chain triglyceride-based emulsion are due principally to the biological activity of the oil composition rather than physical interactions of the antigen with the emulsion.

Dataset Information

From Variation of Influenza Viral Proteins to Vaccine Development.

Publications

From Variation of Influenza Viral Proteins to Vaccine Development.

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