Circular RNA vaccines against SARS-CoV-2 and emerging variants

As the emerging variants of SARS-CoV-2 continue to drive the worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in both mice and rhesus macaques. Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine and elicited a higher proportion of neutralizing antibodies and distinct Th1-skewed immune responses. Importantly, we found that the circRNARBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant. In contrast, the circRNARBD-Delta vaccine protected against both Delta and Omicron or functioned as a booster after two doses of either native- or Delta-specific vaccination, making it a favorable choice against the current variants of concern (VOCs) of SARS-CoV-2. [Display omitted] •Highly stable circRNA vaccines induce potent humoral and cellular immune responses•CircRNA vaccines elicit a high proportion of neutralizing antibodies•CircRNA vaccines enable effective protection against SARS-CoV-2 in mice and monkeys•CircRNARBD-Delta vaccine provides broad-spectrum protection against SARS-CoV-2 VOCs A circular RNA (circRNA) vaccine that encodes the trimeric RBD antigens of SARS-CoV-2 spike provides protection and memory boosting against SARS-CoV-2 variants of concern, in mice and rhesus macaques.