A Mutated PB1 Residue 319 Synergizes with the PB2 N265S Mutation of the Live Attenuated Influenza Vaccine to Convey Temperature Sensitivity

• Type of Material: Article
• Authors: Andrew Cox, University of Rochester; Jordana Schmierer, University of Rochester; Josephine D'Angelo, University of Rochester; Andrew Smith, University of Rochester; Dustyn Levenson, University of Rochester; John Treanor, University of Rochester; Baek Kim, Emory University; Stephen Dewhurst, University of Rochester
• Language: English
• Date: 2020-11-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/v12111246
• Title of Journal or Parent Work: VIRUSES-BASEL
• Volume: 12
• Issue: 11
• Grant/Funding Information: This study was funded in part by grants from the National Institutes of Health (HHSN266200700008C to BK, and SD, R21AI112717 to SD, T32GM068411 to AC, and T32GM07356 to AC). Additional support was provided to AC by the University of Rochester’s Technology Development Fund.
• Keywords: TRIVALENT; vaccine; LAIV; GENETIC STABILITY; HEALTHY-ADULTS; Influenza A Virus; temperature sensitivity; IN-VITRO; NEURAMINIDASE; Science & Technology; Virology; Life Sciences & Biomedicine; A VIRUS; SAFETY; COLD-ADAPTED VIRUS; PHASE-III; H1N1; polymerase
• Research Categories: Health Sciences, Public Health; Biology, Virology; Biology, Genetics

Abstract

Current influenza vaccines have modest efficacy. This is especially true for current live attenuated influenza vaccines (LAIV), which have been inferior to the inactivated versions in recent years. Therefore, a new generation of live vaccines may be needed. We previously showed that a mutation at PB1 residue 319 confers enhanced temperature sensitivity and attenuation in an LAIV constructed in the genetic background of the mouse-adapted Influenza A Virus (IAV) strain A/PR/8/34 (PR8). Here, we describe the origin/discovery of this unique mutation and demonstrate that, when combined with the PB2 N265S mutation of LAIV, it conveys an even greater level of temperature sensitivity and attenuation on PR8 than the complete set of attenuating mutations from LAIV. Furthermore, we show that the combined PB1 L319Q and PB2 N265S mutations confer temperature sensitivity on IAV polymerase activity in two different genetic backgrounds, PR8 and A/Cal/04/09. Collectively, these findings show that the PB2 LAIV mutation synergizes with a mutation in PB1 and may have potential utility for improving LAIVs.