Chih‐Jen Lai1,2, Dokyun Kim1,2, Seokmin Kang1,2, Kun Li3, Inho Cha1,4, Akimi Sasaki1,2, Jose Porras3, Tian Xia1,2, Jae U. Jung1,2
1Department of Cancer Biology and Infection Biology, Lerner Research Institute, Clevel and Clinic, Cleveland, Ohio, USA
2Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
3Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, Florida, USA
4Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Chih-Jen Lai and Dokyun Kim contributed equally to this study.
CorrespondenceJae U. Jung
Life-long persistent herpesviruses carry “trans-inducers” to overcome the unusual codon usage of their glycoproteins for efficient expression. Strikingly, this “trans-inducibility” can be achieved by simply changing the codon-usage of acute virus glycoproteins to that of persistent herpesvirus glycoproteins with herpesviral trans-inducer. Here, we apply the “persistent viral codon-usage-trans-inducer” principle to SARS-CoV-2 Spike mRNA vaccine platform, in which the codon-usage of Spike is changed to that of Herpes Simplex Virus-1 (HSV-1) glycoprotein B (gB) with its “trans-inducer” ICP27. The HSVgB-ICP27-codon-optimized Spike mRNA vaccine induced markedly high antigen expression and stability, total IgG, neutralizing antibody, and T cell response, ultimately enhancing protection against lethal SARS-CoV-2 challenge. Moreover, the HSVgB- codon-optimized Delta (B.1.617.2) strain Spike mRNA vaccine provided significant enhancements in antigen expression and long-term protection against SARS-CoV-2 challenge. Thus, we report a novel persistent viral codon-usage-trans-inducer mRNA vaccine platform for enhanced antigen expression and long-term protection against lethal viral infection.