Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants

Qu, Liang; Yi, Zongyi; Shen, Yong; Xu, Yiyuan; Wu, Zeguang; Tang, Huixian; Xiao, Xia; Dong, Xiaojing; Guo, Li; Yisimayi, Ayijiang; Cao, Yunlong; Zhou, Zhuo; Wang, Jianwei; Xie, Xiaoliang Sunney; Wei, Wensheng

SARS-CoV-2 has caused a worldwide pandemic. The emerging variants B.1.1.7 in the UK, B.1.351 in South Africa, and P.1 in Brazil have recently spread rapidly, arousing concerns about the efficacy of the current vaccines and antibody therapies. Therefore, there is still a high demand for alternative vaccines with great efficacy, high design flexibility, and fast manufacturing speed. Here, we reported a circular RNA (circRNA) vaccine that encodes the trimeric RBD of SARS-CoV-2 spike protein. Being a circularized RNA molecule, circRNARBD could be rapidly produced via in vitro transcription and is highly stable without nucleotide modification. Lipid-nanoparticle-encapsulated circRNARBD elicited potent and sustained neutralizing antibodies, as well as Th1-biased T cell responses in mice. Notably, antibodies from mice immunized with circRNA encoding RBD variant (K417N-E484K-501Y) effectively neutralized B.1.351 variant. Moreover, we developed therapeutic circRNAs, encoding SARS-CoV-2 neutralizing nanobodies or hACE2 decoys, which could effectively neutralize SARS-CoV-2 pseudovirus. Our study suggests that circular RNA holds the potential to become a novel vaccine and therapeutic platform.