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

Cox, Andrew; Schmierer, Jordana; D’Angelo, Josephine; Smith, Andrew; Levenson, Dustyn; Treanor, John; Kim, Baek; Dewhurst, Stephen

doi:10.3390/v12111246

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

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Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, NY 14642, USA

Medical Scientist Training Program, University of Rochester School of Medicine and Dentistry, Rochester, New York, NY 14642, USA

Department of Pediatrics, Pediatric Residency Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA

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Upstate Medical School, State University of New York, Syracuse, NY 13210, USA

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M.D./Ph.D. Training Program, Wayne State University, Detroit, MI 48202, USA

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Division of Infectious Diseases, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, NY 14642, USA

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Biomedical Advanced Research and Development Authority (BARDA)/HHS/ASPR, Influenza and Emerging Diseases Division 21J14, 200 C St SW, Washington, DC 20515, USA

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Department of Pediatrics, Emory University, Atlanta, GA 30322, USA

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Center for Drug Discovery, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA

Author to whom correspondence should be addressed.

Viruses 2020, 12(11), 1246; https://doi.org/10.3390/v12111246

Received: 4 October 2020 / Revised: 20 October 2020 / Accepted: 24 October 2020 / Published: 31 October 2020

(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)

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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. View Full-Text

Keywords: Influenza A Virus; LAIV; temperature sensitivity; vaccine; polymerase

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Cox, A.; Schmierer, J.; D’Angelo, J.; Smith, A.; Levenson, D.; Treanor, J.; Kim, B.; Dewhurst, S. A Mutated PB1 Residue 319 Synergizes with the PB2 N265S Mutation of the Live Attenuated Influenza Vaccine to Convey Temperature Sensitivity. Viruses 2020, 12, 1246. https://doi.org/10.3390/v12111246

AMA Style

Cox A, Schmierer J, D’Angelo J, Smith A, Levenson D, Treanor J, Kim B, Dewhurst S. A Mutated PB1 Residue 319 Synergizes with the PB2 N265S Mutation of the Live Attenuated Influenza Vaccine to Convey Temperature Sensitivity. Viruses. 2020; 12(11):1246. https://doi.org/10.3390/v12111246

Chicago/Turabian Style

Cox, Andrew, Jordana Schmierer, Josephine D’Angelo, Andrew Smith, Dustyn Levenson, John Treanor, Baek Kim, and Stephen Dewhurst. 2020. "A Mutated PB1 Residue 319 Synergizes with the PB2 N265S Mutation of the Live Attenuated Influenza Vaccine to Convey Temperature Sensitivity" Viruses 12, no. 11: 1246. https://doi.org/10.3390/v12111246

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

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