Abstract
Influenza A virus leads to yearly epidemics and sporadic pandemics. Present prophylactic strategies focus on egg-grown, live, attenuated influenza vaccines (LAIVs), in which attenuation is generated by conferring temperature sensitivity onto the virus. Here we describe an alternative approach to attenuating influenza A virus based on microRNA-mediated gene silencing. By incorporating nonavian microRNA response elements (MREs) into the open-reading frame of the viral nucleoprotein, we generate reassortant LAIVs for H1N1 and H5N1 that are attenuated in mice but not in eggs. MRE-based LAIVs show a greater than two-log reduction in mortality compared with control viruses lacking MREs and elicit a diverse antibody response. This approach might be combined with existing LAIVs to increase attenuation and improve vaccine safety.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Body Weight
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Cell Line
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Humans
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Influenza A Virus, H1N1 Subtype / genetics*
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Influenza A Virus, H1N1 Subtype / immunology
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Influenza A Virus, H1N1 Subtype / pathogenicity
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Influenza A Virus, H5N1 Subtype / genetics*
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Influenza A Virus, H5N1 Subtype / immunology
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Influenza A Virus, H5N1 Subtype / pathogenicity
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Influenza Vaccines* / genetics
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Influenza Vaccines* / immunology
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Influenza, Human / immunology
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Influenza, Human / prevention & control
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Mice
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MicroRNAs* / genetics
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Orthomyxoviridae Infections / immunology
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Orthomyxoviridae Infections / prevention & control
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RNA Interference*
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RNA, Viral / genetics
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Response Elements / genetics
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Species Specificity
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Vaccines, Attenuated* / genetics
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Vaccines, Attenuated* / immunology
Substances
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Influenza Vaccines
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MicroRNAs
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RNA, Viral
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Vaccines, Attenuated