Abstract
Abstract New strategies are urgently needed for developing vaccines and/or anti-viral drugs against influenza viruses, because antigenic shift and drift inevitably occurs in circulating strains each year, and new strains resistant to anti-viral drugs have recently emerged. In our study, we designed and incorporated artificial microRNAs (amiRNAs) into the NA segment of rescued influenza viruses to separately target two host genes, CLK1 and SON, which were found to play an essential role in virus replication. Mouse epithelial fibroblast (MEF) or A549 cells infected with engineered influenza PR8 based viruses containing amiR-30CLK1 (PR8-amiR-30CLK1) or amiR-93SON (PR8-amiR-93SON) had reduced expression of host proteins CLK1 and SON, respectively. All engineered influenza viruses functioned as attenuated vaccines, induced significantly higher antibody responses, and provided significantly greater protective efficacy. In addition, they were found to be safe, based on the mouse weight changes and clinical signs observed. In contrast to the engineered viruses targeting SON, mice treated with engineered viruses targeting CLK1 by 6 hours after lethal-dose PR8 infection, recovered from weight loss and survived lethal infection, suggesting that our PR8-amiR-30CLK1-engineered influenza virus could be used as a new post exposure therapeutic influenza vaccine.
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