Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines

Journal Article · · Journal of Virology
DOI:https://doi.org/10.1128/JVI.00710-18· OSTI ID:1503566
; ; ; ; ; ; ; ; ; ;

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.

IMPORTANCEEmergent 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.

Research Organization:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE
DOE Contract Number:
AC05-76RL01830
OSTI ID:
1503566
Report Number(s):
PNNL-SA-134212
Journal Information:
Journal of Virology, Vol. 92, Issue 17; ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English

References (36)

Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia November 2012
Coronavirus virulence genes with main focus on SARS-CoV envelope gene December 2014
Infidelity of SARS-CoV Nsp14-Exonuclease Mutant Virus Replication Is Revealed by Complete Genome Sequencing May 2010
SAS-6 turns a cartwheel trick February 2011
A decade after SARS: strategies for controlling emerging coronaviruses November 2013
A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge September 2011
Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus September 2013
SARS: Systematic Review of Treatment Effects September 2006
Successful Vaccination Strategies That Protect Aged Mice from Lethal Challenge from Influenza Virus and Heterologous Severe Acute Respiratory Syndrome Coronavirus October 2010
Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury August 2013
Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants December 2006
Complete Protection against Severe Acute Respiratory Syndrome Coronavirus-Mediated Lethal Respiratory Disease in Aged Mice by Immunization with a Mouse-Adapted Virus Lacking E Protein April 2013
Reverse genetics with a full-length infectious cDNA of severe acute respiratory syndrome coronavirus October 2003
A mouse model for MERS coronavirus-induced acute respiratory distress syndrome November 2016
One Health, emerging infectious diseases and wildlife: two decades of progress? June 2017
SARS-like WIV1-CoV poised for human emergence March 2016
Release of Severe Acute Respiratory Syndrome Coronavirus Nuclear Import Block Enhances Host Transcription in Human Lung Cells January 2013
Coronaviruses post-SARS: update on replication and pathogenesis May 2009
Cell-based antiviral screening against coronaviruses: Developing virus-specific and broad-spectrum inhibitors January 2014
Jumping species—a mechanism for coronavirus persistence and survival April 2017
Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses June 2017
Coronavirus non-structural protein 16: Evasion, attenuation, and possible treatments December 2014
Identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine October 2015
Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis November 2017
MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis August 2017
Attenuation and Restoration of Severe Acute Respiratory Syndrome Coronavirus Mutant Lacking 2'-O-Methyltransferase Activity January 2014
Coronaviruses — drug discovery and therapeutic options February 2016
Aged BALB/c Mice as a Model for Increased Severity of Severe Acute Respiratory Syndrome in Elderly Humans April 2005
A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence November 2015
A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease November 2012
A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice January 2007
Immunization with an attenuated severe acute respiratory syndrome coronavirus deleted in E protein protects against lethal respiratory disease March 2010
Engineering a Replication-Competent, Propagation-Defective Middle East Respiratory Syndrome Coronavirus as a Vaccine Candidate September 2013
Severe Acute Respiratory Syndrome Coronaviruses with Mutations in the E Protein Are Attenuated and Promising Vaccine Candidates January 2015
MERS-CoV vaccine candidates in development: The current landscape June 2016
Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus January 2017

Similar Records

Related Subjects

Evolview
evolgenius
SARS-CoV
NSP14 exonuclease