A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene

ABSTRACT Lassa virus (LASV) is endemic in Western Africa and is estimated to infect hundreds of thousands of individuals annually. A considerable number of these infections result in Lassa fever (LF), which is associated with significant morbidity and a case-fatality rate as high as 69% among hospit...

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Autores principales:	Yingyun Cai, Chengjin Ye, Benson Cheng, Aitor Nogales, Masaharu Iwasaki, Shuiqing Yu, Kurt Cooper, David X. Liu, Randy Hart, Ricky Adams, Tyler Brady, Elena N. Postnikova, Jonathan Kurtz, Marisa St Claire, Jens H. Kuhn, Juan Carlos de la Torre, Luis Martínez-Sobrido
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Arenaviridae arenavirid arenavirus Bunyavirales bunyavirus guinea pig Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8cc7b2d7a47643b695aca684103bc6c5
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spelling	oai:doaj.org-article:8cc7b2d7a47643b695aca684103bc6c52021-11-15T15:56:58ZA Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene10.1128/mBio.00039-202150-7511https://doaj.org/article/8cc7b2d7a47643b695aca684103bc6c52020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00039-20https://doaj.org/toc/2150-7511ABSTRACT Lassa virus (LASV) is endemic in Western Africa and is estimated to infect hundreds of thousands of individuals annually. A considerable number of these infections result in Lassa fever (LF), which is associated with significant morbidity and a case-fatality rate as high as 69% among hospitalized confirmed patients. U.S. Food and Drug Administration-approved LF vaccines are not available. Current antiviral treatment is limited to off-label use of a nucleoside analogue, ribavirin, that is only partially effective and associated with significant side effects. We generated and characterized a recombinant LASV expressing a codon-deoptimized (CD) glycoprotein precursor gene (GPC), rLASV-GPC/CD. Comparison of growth kinetics and peak titers showed that rLASV-GPC/CD is slightly attenuated in cell culture compared to wild-type (WT) recombinant LASV (rLASV-WT). However, rLASV-GPC/CD is highly attenuated in strain 13 and Hartley guinea pigs, as reflected by the absence of detectable clinical signs in animals inoculated with rLASV-GPC/CD. Importantly, a single subcutaneous dose of rLASV-GPC/CD provides complete protection against an otherwise lethal exposure to LASV. Our results demonstrate the feasibility of implementing a CD approach for developing a safe and effective LASV live-attenuated vaccine candidate. Moreover, rLASV-GPC/CD might provide investigators with a tool to safely study LASV outside maximum (biosafety level 4) containment, which could accelerate the elucidation of basic aspects of the molecular and cell biology of LASV and the development of novel LASV medical countermeasures. IMPORTANCE Lassa virus (LASV) infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever (LF) cases. Licensed LF vaccines are not available, and anti-LF therapy is limited to off-label use of the nucleoside analog ribavirin with uncertain efficacy. We describe the generation of a novel live-attenuated LASV vaccine candidate. This vaccine candidate is based on mutating wild-type (WT) LASV in a key region of the viral genome, the glycoprotein precursor (GPC) gene. These mutations do not change the encoded GPC but interfere with its production in host cells. This mutated LASV (rLASV-GPC/CD) behaves like WT LASV (rLASV-WT) in cell culture, but in contrast to rLASV-WT, does not cause disease in inoculated guinea pigs. Guinea pigs immunized with rLASV-GPC/CD were protected against an otherwise lethal exposure to WT LASV. Our results support the testing of this candidate vaccine in nonhuman primate models ofLF.Yingyun CaiChengjin YeBenson ChengAitor NogalesMasaharu IwasakiShuiqing YuKurt CooperDavid X. LiuRandy HartRicky AdamsTyler BradyElena N. PostnikovaJonathan KurtzMarisa St ClaireJens H. KuhnJuan Carlos de la TorreLuis Martínez-SobridoAmerican Society for MicrobiologyarticleArenaviridaearenaviridarenavirusBunyaviralesbunyavirusguinea pigMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arenaviridae arenavirid arenavirus Bunyavirales bunyavirus guinea pig Microbiology QR1-502
spellingShingle	Arenaviridae arenavirid arenavirus Bunyavirales bunyavirus guinea pig Microbiology QR1-502 Yingyun Cai Chengjin Ye Benson Cheng Aitor Nogales Masaharu Iwasaki Shuiqing Yu Kurt Cooper David X. Liu Randy Hart Ricky Adams Tyler Brady Elena N. Postnikova Jonathan Kurtz Marisa St Claire Jens H. Kuhn Juan Carlos de la Torre Luis Martínez-Sobrido A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene
description	ABSTRACT Lassa virus (LASV) is endemic in Western Africa and is estimated to infect hundreds of thousands of individuals annually. A considerable number of these infections result in Lassa fever (LF), which is associated with significant morbidity and a case-fatality rate as high as 69% among hospitalized confirmed patients. U.S. Food and Drug Administration-approved LF vaccines are not available. Current antiviral treatment is limited to off-label use of a nucleoside analogue, ribavirin, that is only partially effective and associated with significant side effects. We generated and characterized a recombinant LASV expressing a codon-deoptimized (CD) glycoprotein precursor gene (GPC), rLASV-GPC/CD. Comparison of growth kinetics and peak titers showed that rLASV-GPC/CD is slightly attenuated in cell culture compared to wild-type (WT) recombinant LASV (rLASV-WT). However, rLASV-GPC/CD is highly attenuated in strain 13 and Hartley guinea pigs, as reflected by the absence of detectable clinical signs in animals inoculated with rLASV-GPC/CD. Importantly, a single subcutaneous dose of rLASV-GPC/CD provides complete protection against an otherwise lethal exposure to LASV. Our results demonstrate the feasibility of implementing a CD approach for developing a safe and effective LASV live-attenuated vaccine candidate. Moreover, rLASV-GPC/CD might provide investigators with a tool to safely study LASV outside maximum (biosafety level 4) containment, which could accelerate the elucidation of basic aspects of the molecular and cell biology of LASV and the development of novel LASV medical countermeasures. IMPORTANCE Lassa virus (LASV) infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever (LF) cases. Licensed LF vaccines are not available, and anti-LF therapy is limited to off-label use of the nucleoside analog ribavirin with uncertain efficacy. We describe the generation of a novel live-attenuated LASV vaccine candidate. This vaccine candidate is based on mutating wild-type (WT) LASV in a key region of the viral genome, the glycoprotein precursor (GPC) gene. These mutations do not change the encoded GPC but interfere with its production in host cells. This mutated LASV (rLASV-GPC/CD) behaves like WT LASV (rLASV-WT) in cell culture, but in contrast to rLASV-WT, does not cause disease in inoculated guinea pigs. Guinea pigs immunized with rLASV-GPC/CD were protected against an otherwise lethal exposure to WT LASV. Our results support the testing of this candidate vaccine in nonhuman primate models ofLF.
format	article
author	Yingyun Cai Chengjin Ye Benson Cheng Aitor Nogales Masaharu Iwasaki Shuiqing Yu Kurt Cooper David X. Liu Randy Hart Ricky Adams Tyler Brady Elena N. Postnikova Jonathan Kurtz Marisa St Claire Jens H. Kuhn Juan Carlos de la Torre Luis Martínez-Sobrido
author_facet	Yingyun Cai Chengjin Ye Benson Cheng Aitor Nogales Masaharu Iwasaki Shuiqing Yu Kurt Cooper David X. Liu Randy Hart Ricky Adams Tyler Brady Elena N. Postnikova Jonathan Kurtz Marisa St Claire Jens H. Kuhn Juan Carlos de la Torre Luis Martínez-Sobrido
author_sort	Yingyun Cai
title	A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene
title_short	A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene
title_full	A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene
title_fullStr	A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene
title_full_unstemmed	A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene
title_sort	lassa fever live-attenuated vaccine based on codon deoptimization of the viral glycoprotein gene
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/8cc7b2d7a47643b695aca684103bc6c5
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A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene

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