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

TLDR

Emerging SARS‑CoV‑2 variants drive a need for vaccines that provide broader and more effective protection. A circular RNA vaccine encoding the trimeric RBD elicited potent neutralizing antibodies and Th1‑skewed T‑cell responses, protected mice and macaques, outperformed 1mΨ‑modified mRNA in antigen durability, and variant‑specific formulations (Omicron or Delta) neutralized their target variants, with the Delta version protecting against both Delta and Omicron and serving as an effective booster.

Abstract

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.