SARS-CoV-2 virus lacking the envelope and membrane open-reading frames as a vaccine platform

• Published in: Nature communications Vol. 16; no. 1; pp. 4453 - 14
• Main Authors: Kuroda, Makoto, Halfmann, Peter J., Uraki, Ryuta, Yamayoshi, Seiya, Kim, Taksoo, Armbrust, Tammy A., Spyra, Sam, Dahn, Randall, Babujee, Lavanya, Kawaoka, Yoshihiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/1647/334/1874/1535; 631/326/590/1867; 631/326/596/4130; Animals; Antibodies, Viral - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Coronavirus Envelope Proteins; COVID-19; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 - virology; COVID-19 Vaccines - administration & dosage; COVID-19 Vaccines - genetics; COVID-19 Vaccines - immunology; Cricetinae; Female; Hamsters; Humanities and Social Sciences; Humans; Immunization; Immunization, Secondary; Immunoglobulin A; Lymphocytes; Lymphocytes T; Membranes; Mesocricetus; mRNA; multidisciplinary; Nucleocapsids; Open reading frames; Open Reading Frames - genetics; Proteins; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Structural proteins; Vaccination; Vaccines; Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Viral diseases; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-59533-4

To address the need for broadly protective SARS-CoV-2 vaccines, we developed an attenuated a SARS-CoV-2 vaccine virus that lacks the open reading frames of two viral structural proteins: the envelope (E) and membrane (M) proteins. This vaccine virus (ΔEM) replicates in a cell line stably expressing E and M but not in wild-type cells. Vaccination with ΔEM elicits a CD8 T-cell response against the viral spike and nucleocapsid proteins. Two vaccinations with ΔEM provide better protection of the lower respiratory tissues than a single dose against the Delta and Omicron XBB variants in hamsters. Moreover, ΔEM is effective as a booster in hamsters previously vaccinated with an mRNA-based vaccine, providing higher levels of protection in both respiratory tissues compared to the mRNA vaccine booster. Collectively, our data demonstrate the feasibility of a SARS-CoV-2 ΔEM vaccine candidate virus as a vaccine platform. In this study, the authors report a single cycle-replicating SARS-CoV-2 vaccine candidate virus (ΔEM) and show that it induces spike-specific IgA and CD8+ T cells targeting spike and nucleocapsid proteins and provides broad and efficient protection in vaccinated animals.