Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines.
Identifieur interne : 001E90 ( Ncbi/Checkpoint ); précédent : 001E89; suivant : 001E91Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines.
Auteurs : Vineet D. Menachery [États-Unis] ; Lisa E. Gralinski [États-Unis] ; Hugh D. Mitchell [États-Unis] ; Kenneth H. Dinnon [États-Unis] ; Sarah R. Leist [États-Unis] ; Boyd L. Yount [États-Unis] ; Eileen T. Mcanarney [États-Unis] ; Rachel L. Graham [États-Unis] ; Katrina M. Waters [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- Journal of virology [ 1098-5514 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux, Cellules Vero, Coronavirus (immunologie), Infections à coronavirus (), Infections à coronavirus (immunologie), Infections à coronavirus (virologie), Methyltransferases (génétique), Methyltransferases (immunologie), Modèles animaux de maladie humaine, Mutation, Méthylation, Protéines d'archée (génétique), Protéines virales non structurales (génétique), Protéines virales non structurales (immunologie), Réplication virale, Souris, Souris de lignée BALB C, Sujet immunodéprimé, Vaccins antiviraux (génétique), Vaccins antiviraux (immunologie), Vaccins atténués (génétique), Vaccins atténués (immunologie), Vieillissement (immunologie), Virus du SRAS (génétique), Virus du SRAS (immunologie).
- MESH :
- génétique : Methyltransferases, Protéines d'archée, Protéines virales non structurales, Vaccins antiviraux, Vaccins atténués, Virus du SRAS.
- immunologie : Coronavirus, Infections à coronavirus, Methyltransferases, Protéines virales non structurales, Vaccins antiviraux, Vaccins atténués, Vieillissement, Virus du SRAS.
- virologie : Infections à coronavirus.
- Animaux, Cellules Vero, Infections à coronavirus, Modèles animaux de maladie humaine, Mutation, Méthylation, Réplication virale, Souris, Souris de lignée BALB C, Sujet immunodéprimé.
English descriptors
- KwdEn :
- Aging (immunology), Animals, Archaeal Proteins (genetics), Chlorocebus aethiops, Coronavirus (immunology), Coronavirus Infections (immunology), Coronavirus Infections (prevention & control), Coronavirus Infections (virology), Disease Models, Animal, Immunocompromised Host, Methylation, Methyltransferases (genetics), Methyltransferases (immunology), Mice, Mice, Inbred BALB C, Mutation, SARS Virus (genetics), SARS Virus (immunology), Vaccines, Attenuated (genetics), Vaccines, Attenuated (immunology), Vero Cells, Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (immunology), Viral Vaccines (genetics), Viral Vaccines (immunology), Virus Replication.
- MESH :
- chemical , genetics : Archaeal Proteins, Methyltransferases, Vaccines, Attenuated, Viral Nonstructural Proteins, Viral Vaccines.
- genetics : SARS Virus.
- immunology : Aging, Coronavirus, Coronavirus Infections, Methyltransferases, SARS Virus, Vaccines, Attenuated, Viral Nonstructural Proteins, Viral Vaccines.
- prevention & control : Coronavirus Infections.
- virology : Coronavirus Infections.
- Animals, Chlorocebus aethiops, Disease Models, Animal, Immunocompromised Host, Methylation, Mice, Mice, Inbred BALB C, Mutation, Vero Cells, Virus Replication.
Abstract
With an ongoing threat posed by circulating zoonotic strains, new strategies are required to prepare for the next emergent coronavirus (CoV). Previously, groups had targeted conserved coronavirus proteins as a strategy to generate live attenuated vaccine strains against current and future CoVs. With this in mind, we explored whether manipulation of CoV NSP16, a conserved 2'O methyltransferase (MTase), could provide a broad attenuation platform against future emergent strains. Using the severe acute respiratory syndrome-CoV mouse model, an NSP16 mutant vaccine was evaluated for protection from heterologous challenge, efficacy in the aging host, and potential for reversion to pathogenesis. Despite some success, concerns for virulence in the aged and potential for reversion makes targeting NSP16 alone an untenable approach. However, combining a 2'O MTase mutation with a previously described CoV fidelity mutant produced a vaccine strain capable of protection from heterologous virus challenge, efficacy in aged mice, and no evidence for reversion. Together, the results indicate that targeting the CoV 2'O MTase in parallel with other conserved attenuating mutations may provide a platform strategy for rapidly generating live attenuated coronavirus vaccines.IMPORTANCE Emergent coronaviruses remain a significant threat to global public health and rapid response vaccine platforms are needed to stem future outbreaks. However, failure of many previous CoV vaccine formulations has clearly highlighted the need to test efficacy under different conditions and especially in vulnerable populations such as the aged and immunocompromised. This study illustrates that despite success in young models, the 2'O methyltransferase mutant carries too much risk for pathogenesis and reversion in vulnerable models to be used as a stand-alone vaccine strategy. Importantly, the 2'O methyltransferase mutation can be paired with other attenuating approaches to provide robust protection from heterologous challenge and in vulnerable populations. Coupled with increased safety and reduced pathogenesis, the study highlights the potential for 2'O methyltransferase attenuation as a major component of future live attenuated coronavirus vaccines.
DOI: 10.1128/JVI.00710-18
PubMed: 29976657
Affiliations:
- États-Unis
- Caroline du Nord, Texas, Washington (État)
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
Links toward previous steps (curation, corpus...)
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- to stream PubMed, to step Curation: 000845
- to stream PubMed, to step Checkpoint: 000985
- to stream Ncbi, to step Merge: 001E90
- to stream Ncbi, to step Curation: 001E90
Links to Exploration step
pubmed:29976657Le document en format XML
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<front><div type="abstract" xml:lang="en">With an ongoing threat posed by circulating zoonotic strains, new strategies are required to prepare for the next emergent coronavirus (CoV). Previously, groups had targeted conserved coronavirus proteins as a strategy to generate live attenuated vaccine strains against current and future CoVs. With this in mind, we explored whether manipulation of CoV NSP16, a conserved 2'O methyltransferase (MTase), could provide a broad attenuation platform against future emergent strains. Using the severe acute respiratory syndrome-CoV mouse model, an NSP16 mutant vaccine was evaluated for protection from heterologous challenge, efficacy in the aging host, and potential for reversion to pathogenesis. Despite some success, concerns for virulence in the aged and potential for reversion makes targeting NSP16 alone an untenable approach. However, combining a 2'O MTase mutation with a previously described CoV fidelity mutant produced a vaccine strain capable of protection from heterologous virus challenge, efficacy in aged mice, and no evidence for reversion. Together, the results indicate that targeting the CoV 2'O MTase in parallel with other conserved attenuating mutations may provide a platform strategy for rapidly generating live attenuated coronavirus vaccines.<b>IMPORTANCE</b>
Emergent coronaviruses remain a significant threat to global public health and rapid response vaccine platforms are needed to stem future outbreaks. However, failure of many previous CoV vaccine formulations has clearly highlighted the need to test efficacy under different conditions and especially in vulnerable populations such as the aged and immunocompromised. This study illustrates that despite success in young models, the 2'O methyltransferase mutant carries too much risk for pathogenesis and reversion in vulnerable models to be used as a stand-alone vaccine strategy. Importantly, the 2'O methyltransferase mutation can be paired with other attenuating approaches to provide robust protection from heterologous challenge and in vulnerable populations. Coupled with increased safety and reduced pathogenesis, the study highlights the potential for 2'O methyltransferase attenuation as a major component of future live attenuated coronavirus vaccines.</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Caroline du Nord</li>
<li>Texas</li>
<li>Washington (État)</li>
</region>
<settlement><li>Chapel Hill (Caroline du Nord)</li>
</settlement>
<orgName><li>Université de Caroline du Nord à Chapel Hill</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Texas"><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</name>
</region>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name>
<name sortKey="Dinnon, Kenneth H" sort="Dinnon, Kenneth H" uniqKey="Dinnon K" first="Kenneth H" last="Dinnon">Kenneth H. Dinnon</name>
<name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L" last="Graham">Rachel L. Graham</name>
<name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name>
<name sortKey="Leist, Sarah R" sort="Leist, Sarah R" uniqKey="Leist S" first="Sarah R" last="Leist">Sarah R. Leist</name>
<name sortKey="Mcanarney, Eileen T" sort="Mcanarney, Eileen T" uniqKey="Mcanarney E" first="Eileen T" last="Mcanarney">Eileen T. Mcanarney</name>
<name sortKey="Mitchell, Hugh D" sort="Mitchell, Hugh D" uniqKey="Mitchell H" first="Hugh D" last="Mitchell">Hugh D. Mitchell</name>
<name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M" last="Waters">Katrina M. Waters</name>
<name sortKey="Yount, Boyd L" sort="Yount, Boyd L" uniqKey="Yount B" first="Boyd L" last="Yount">Boyd L. Yount</name>
</country>
</tree>
</affiliations>
</record>
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