The SARS-CoV-2 pandemic is constantly changing with new variants appearing that are more contagious (Alpha and Delta), evade the neutralising antibody (NAb) response (Beta), or both (Omicron). This is a challenge for vaccine development. We generated a novel universal SARS-CoV-2 DNA vaccine containing the receptor binding domain (RBD) loops from the original huCoV-19/WH01, the Alpha, and the Beta variants, combined with the membrane and nucleoproteins from the huCoV-19/WH01 strain. This vaccine induced high levels of spike antibodies that crossreacted between the huCoV-19/WH01, Beta, and Delta spike proteins, and neutralized the huCoV-19/WH01, Beta, Delta and Omicron virus in vitro. The vaccine induced T cells to all vaccine proteins in mice and rabbits that recognized Bat-CoV N sequences. Finally, the vaccine protected K18 mice against lethal SARS-CoV-2 Beta variant infection, whereas only priming N-specific T cells was 60% protective. This universal SARS-CoV vaccine candidate induces a uniquely broad functional immunity.
