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Innate Inhibiting Proteins Enhance Expression and Immunogenicity of Self-Amplifying RNA.
Blakney, Anna K; McKay, Paul F; Bouton, Clément R; Hu, Kai; Samnuan, Karnyart; Shattock, Robin J.
  • Blakney AK; Department of Infectious Disease, Imperial College London, London W21PG, UK. Electronic address: a.blakney@imperial.ac.uk.
  • McKay PF; Department of Infectious Disease, Imperial College London, London W21PG, UK.
  • Bouton CR; Department of Infectious Disease, Imperial College London, London W21PG, UK.
  • Hu K; Department of Infectious Disease, Imperial College London, London W21PG, UK.
  • Samnuan K; Department of Infectious Disease, Imperial College London, London W21PG, UK.
  • Shattock RJ; Department of Infectious Disease, Imperial College London, London W21PG, UK. Electronic address: r.shattock@imperial.ac.uk.
Mol Ther ; 29(3): 1174-1185, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-985497
Semantic information from SemMedBD (by NLM)
1. Janus kinase inhibitor AUGMENTS protein expression
Subject
Janus kinase inhibitor
Predicate
AUGMENTS
Object
protein expression
2. Janus kinase inhibitor AUGMENTS protein expression
Subject
Janus kinase inhibitor
Predicate
AUGMENTS
Object
protein expression
ABSTRACT
Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC50) by ∼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Biosynthesis / Vaccines, Synthetic / Viral Envelope Proteins / Immunogenicity, Vaccine / Immunity, Innate Topics: Vaccines Language: English Journal: Mol Ther Journal subject: Molecular Biology / Therapeutics Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Biosynthesis / Vaccines, Synthetic / Viral Envelope Proteins / Immunogenicity, Vaccine / Immunity, Innate Topics: Vaccines Language: English Journal: Mol Ther Journal subject: Molecular Biology / Therapeutics Year: 2021 Document Type: Article