Multivalent circular RNA vaccines that are broadly protective against zoonotic betacoronaviruses

In the past 20 years, three betacoronaviruses thought to have originated in bats have caused devastating diseases in humans. The global pandemic caused by the latest such virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlights the need to protect against other strains that could threaten humans to protect against future outbreaks and pandemics. During the COVID-19 pandemic, mRNA vaccines from Moderna and Pfizer/BioNTech provide powerful protection against SARS-CoV-2 and have saved countless lives; however, they are unable to prevent infection and viral transmission due to their ineffectiveness in eliciting robust mucosal immunity. Moreover, these vaccines delivering a single soluble immunogen, i.e., Spike protein, have been shown to only elicit weak or no cross-reactive immune responses, limiting their ability to combat other strains of zoonotic coronaviruses. This proposal seeks to develop a novel multivalent-coronavirus vaccine by leveraging a self-adjuvanted lipid nanoparticle to intranasally deliver circular RNAs encoding multivalent antigens from the SARS-CoV-2 and MERS-CoV that pose a threat to humans. We hypothesize that the proposed technology promises to elicit a broadly protective mucosal immune response against zoonotic betacoronaviruses, which can not only protect the individual but also prevent infection as well as virus transmission. This project will not only help fight the ongoing pandemic but also prevent the re-emergence of these previously existent dangerous pathogens, as well as shed insights to prepare for future zoonotic pathogenic coronavirus outbreaks. Moreover, the knowledge gained from achieving the outlined aims will provide a strong foundation for numerous mucosal vaccine strategies for many pathogens and cancers. The deliverables of this project grant will further encourage the industrial development of RNA vaccines in Canada and help Canadians to respond better to future health emergencies.