A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region

Lassa virus (LASV), the causative agent of Lassa fever, infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever cases. No U.S. Food and Drug Administration-licensed countermeasures are available to prevent or treat LASV infection. We describe the generation of...

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Main Authors: Yingyun Cai, Masaharu Iwasaki, Daisuke Motooka, David X. Liu, Shuiqing Yu, Kurt Cooper, Randy Hart, Ricky Adams, Tracey Burdette, Elena N. Postnikova, Jonathan Kurtz, Marisa St. Claire, Chengjin Ye, Jens H. Kuhn, Luis Martínez-Sobrido, Juan Carlos de la Torre
Format: Article
Language:English
Published: American Society for Microbiology 2020-03-01
Series:mBio
Subjects:
lav
vhf
igr
Online Access:https://doi.org/10.1128/mBio.00186-20
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spelling doaj-a9e34fe8d2384c668ec32801d6e9df1f2021-07-02T13:13:45ZengAmerican Society for MicrobiologymBio2150-75112020-03-01112e00186-2010.1128/mBio.00186-20A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic RegionYingyun CaiMasaharu IwasakiDaisuke MotookaDavid X. LiuShuiqing YuKurt CooperRandy HartRicky AdamsTracey BurdetteElena N. PostnikovaJonathan KurtzMarisa St. ClaireChengjin YeJens H. KuhnLuis Martínez-SobridoJuan Carlos de la TorreLassa virus (LASV), the causative agent of Lassa fever, infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever cases. No U.S. Food and Drug Administration-licensed countermeasures are available to prevent or treat LASV infection. We describe the generation of a novel LASV live-attenuated vaccine candidate rLASV(IGR/S-S), which is based on the replacement of the large genomic segment noncoding intergenic region (IGR) with that of the small genome segment. rLASV(IGR/S-S) is less fit in cell culture than wild-type virus and does not cause clinical signs in inoculated guinea pigs. Importantly, rLASV(IGR/S-S) protects immunized guinea pigs against an otherwise lethal exposure to LASV.Lassa virus (LASV) poses a significant public health problem within the regions of Lassa fever endemicity in Western Africa. LASV infects several hundred thousand individuals yearly, and a considerable number of Lassa fever cases are associated with high morbidity and lethality. No approved LASV vaccine is available, and current therapy is limited to an off-label usage of ribavirin that is only partially effective and associated with significant side effects. The impact of Lassa fever on human health, together with the limited existing countermeasures, highlights the importance of developing effective vaccines against LASV. Here, we present the development and characterization of a recombinant LASV (rLASV) vaccine candidate [rLASV(IGR/S-S)], which is based on the presence of the noncoding intergenic region (IGR) of the small (S) genome segment (S-IGR) in both large (L) and S LASV segments. In cultured cells, rLASV(IGR/S-S) was modestly less fit than wild-type rLASV (rLASV-WT). rLASV(IGR/S-S) was highly attenuated in guinea pigs, and a single subcutaneous low dose of the virus completely protected against otherwise lethal infection with LASV-WT. Moreover, rLASV(IGR/S-S) was genetically stable during serial passages in cultured cells. These findings indicate that rLASV(IGR/S-S) can be developed into a LASV live-attenuated vaccine (LAV) that has the same antigenic composition as LASV-WT and a well-defined mechanism of attenuation that overcomes concerns about increased virulence that could be caused by genetic changes in the LAV during multiple rounds of multiplication.https://doi.org/10.1128/mBio.00186-20arenaviridaearenaviridarenavirusbunyaviralesbunyavirusguinea piglassalassa feverlassa viruslasvlavlive-attenuated vaccinemammarenavirusstrain 13vaccinevhfviral hemorrhagic feverintergenic regionigrreverse genetics
collection DOAJ
language English
format Article
sources DOAJ
author Yingyun Cai
Masaharu Iwasaki
Daisuke Motooka
David X. Liu
Shuiqing Yu
Kurt Cooper
Randy Hart
Ricky Adams
Tracey Burdette
Elena N. Postnikova
Jonathan Kurtz
Marisa St. Claire
Chengjin Ye
Jens H. Kuhn
Luis Martínez-Sobrido
Juan Carlos de la Torre
spellingShingle Yingyun Cai
Masaharu Iwasaki
Daisuke Motooka
David X. Liu
Shuiqing Yu
Kurt Cooper
Randy Hart
Ricky Adams
Tracey Burdette
Elena N. Postnikova
Jonathan Kurtz
Marisa St. Claire
Chengjin Ye
Jens H. Kuhn
Luis Martínez-Sobrido
Juan Carlos de la Torre
A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
mBio
arenaviridae
arenavirid
arenavirus
bunyavirales
bunyavirus
guinea pig
lassa
lassa fever
lassa virus
lasv
lav
live-attenuated vaccine
mammarenavirus
strain 13
vaccine
vhf
viral hemorrhagic fever
intergenic region
igr
reverse genetics
author_facet Yingyun Cai
Masaharu Iwasaki
Daisuke Motooka
David X. Liu
Shuiqing Yu
Kurt Cooper
Randy Hart
Ricky Adams
Tracey Burdette
Elena N. Postnikova
Jonathan Kurtz
Marisa St. Claire
Chengjin Ye
Jens H. Kuhn
Luis Martínez-Sobrido
Juan Carlos de la Torre
author_sort Yingyun Cai
title A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
title_short A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
title_full A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
title_fullStr A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
title_full_unstemmed A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
title_sort lassa virus live-attenuated vaccine candidate based on rearrangement of the intergenic region
publisher American Society for Microbiology
series mBio
issn 2150-7511
publishDate 2020-03-01
description Lassa virus (LASV), the causative agent of Lassa fever, infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever cases. No U.S. Food and Drug Administration-licensed countermeasures are available to prevent or treat LASV infection. We describe the generation of a novel LASV live-attenuated vaccine candidate rLASV(IGR/S-S), which is based on the replacement of the large genomic segment noncoding intergenic region (IGR) with that of the small genome segment. rLASV(IGR/S-S) is less fit in cell culture than wild-type virus and does not cause clinical signs in inoculated guinea pigs. Importantly, rLASV(IGR/S-S) protects immunized guinea pigs against an otherwise lethal exposure to LASV.Lassa virus (LASV) poses a significant public health problem within the regions of Lassa fever endemicity in Western Africa. LASV infects several hundred thousand individuals yearly, and a considerable number of Lassa fever cases are associated with high morbidity and lethality. No approved LASV vaccine is available, and current therapy is limited to an off-label usage of ribavirin that is only partially effective and associated with significant side effects. The impact of Lassa fever on human health, together with the limited existing countermeasures, highlights the importance of developing effective vaccines against LASV. Here, we present the development and characterization of a recombinant LASV (rLASV) vaccine candidate [rLASV(IGR/S-S)], which is based on the presence of the noncoding intergenic region (IGR) of the small (S) genome segment (S-IGR) in both large (L) and S LASV segments. In cultured cells, rLASV(IGR/S-S) was modestly less fit than wild-type rLASV (rLASV-WT). rLASV(IGR/S-S) was highly attenuated in guinea pigs, and a single subcutaneous low dose of the virus completely protected against otherwise lethal infection with LASV-WT. Moreover, rLASV(IGR/S-S) was genetically stable during serial passages in cultured cells. These findings indicate that rLASV(IGR/S-S) can be developed into a LASV live-attenuated vaccine (LAV) that has the same antigenic composition as LASV-WT and a well-defined mechanism of attenuation that overcomes concerns about increased virulence that could be caused by genetic changes in the LAV during multiple rounds of multiplication.
topic arenaviridae
arenavirid
arenavirus
bunyavirales
bunyavirus
guinea pig
lassa
lassa fever
lassa virus
lasv
lav
live-attenuated vaccine
mammarenavirus
strain 13
vaccine
vhf
viral hemorrhagic fever
intergenic region
igr
reverse genetics
url https://doi.org/10.1128/mBio.00186-20
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