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Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine

Influenza B virus (IBV) is a major respiratory pathogen of humans, particularly in the elderly and children, and vaccines are the most effective way to control it. In previous work, incorporation of two mutations (E580G, S660A) along with the addition of an HA epitope tag in the PB1 segment of B/Bri...

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Autores principales: Mo, Jongsuk, Cardenas-Garcia, Stivalis, Santos, Jefferson J. S., Ferreri, Lucas M., Cáceres, C. Joaquín, Geiger, Ginger, Perez, Daniel R., Rajao, Daniela S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310045/
https://www.ncbi.nlm.nih.gov/pubmed/34358217
http://dx.doi.org/10.3390/vaccines9070800
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author Mo, Jongsuk
Cardenas-Garcia, Stivalis
Santos, Jefferson J. S.
Ferreri, Lucas M.
Cáceres, C. Joaquín
Geiger, Ginger
Perez, Daniel R.
Rajao, Daniela S.
author_facet Mo, Jongsuk
Cardenas-Garcia, Stivalis
Santos, Jefferson J. S.
Ferreri, Lucas M.
Cáceres, C. Joaquín
Geiger, Ginger
Perez, Daniel R.
Rajao, Daniela S.
author_sort Mo, Jongsuk
collection PubMed
description Influenza B virus (IBV) is a major respiratory pathogen of humans, particularly in the elderly and children, and vaccines are the most effective way to control it. In previous work, incorporation of two mutations (E580G, S660A) along with the addition of an HA epitope tag in the PB1 segment of B/Brisbane/60/2008 (B/Bris) resulted in an attenuated strain that was safe and effective as a live attenuated vaccine. A third attempted mutation (K391E) in PB1 was not always stable. Interestingly, viruses that maintained the K391E mutation were associated with the mutation E48K. To explore the contribution of the E48K mutation to stability of the K391E mutation, a vaccine candidate was generated by inserting both mutations, along with attenuating mutations E580G and S660A, in PB1 of B/Bris (B/Bris PB1att 4M). Serial passages of the B/Bris PB1att 4M vaccine candidate in eggs and MDCK indicated high stability. In silico structural analysis revealed a potential interaction between amino acids at positions 48 and 391. In mice, B/Bris PB1att 4M was safe and provided complete protection against homologous challenge. These results confirm the compensatory effect of mutation E48K to stabilize the K391E mutation, resulting in a safer, yet still protective, IBV LAIV vaccine.
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spelling pubmed-83100452021-07-25 Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine Mo, Jongsuk Cardenas-Garcia, Stivalis Santos, Jefferson J. S. Ferreri, Lucas M. Cáceres, C. Joaquín Geiger, Ginger Perez, Daniel R. Rajao, Daniela S. Vaccines (Basel) Article Influenza B virus (IBV) is a major respiratory pathogen of humans, particularly in the elderly and children, and vaccines are the most effective way to control it. In previous work, incorporation of two mutations (E580G, S660A) along with the addition of an HA epitope tag in the PB1 segment of B/Brisbane/60/2008 (B/Bris) resulted in an attenuated strain that was safe and effective as a live attenuated vaccine. A third attempted mutation (K391E) in PB1 was not always stable. Interestingly, viruses that maintained the K391E mutation were associated with the mutation E48K. To explore the contribution of the E48K mutation to stability of the K391E mutation, a vaccine candidate was generated by inserting both mutations, along with attenuating mutations E580G and S660A, in PB1 of B/Bris (B/Bris PB1att 4M). Serial passages of the B/Bris PB1att 4M vaccine candidate in eggs and MDCK indicated high stability. In silico structural analysis revealed a potential interaction between amino acids at positions 48 and 391. In mice, B/Bris PB1att 4M was safe and provided complete protection against homologous challenge. These results confirm the compensatory effect of mutation E48K to stabilize the K391E mutation, resulting in a safer, yet still protective, IBV LAIV vaccine. MDPI 2021-07-19 /pmc/articles/PMC8310045/ /pubmed/34358217 http://dx.doi.org/10.3390/vaccines9070800 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mo, Jongsuk
Cardenas-Garcia, Stivalis
Santos, Jefferson J. S.
Ferreri, Lucas M.
Cáceres, C. Joaquín
Geiger, Ginger
Perez, Daniel R.
Rajao, Daniela S.
Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine
title Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine
title_full Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine
title_fullStr Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine
title_full_unstemmed Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine
title_short Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine
title_sort mutation e48k in pb1 polymerase subunit improves stability of a candidate live attenuated influenza b virus vaccine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310045/
https://www.ncbi.nlm.nih.gov/pubmed/34358217
http://dx.doi.org/10.3390/vaccines9070800
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