With funding of up to $3.8 million from the Coalition for Epidemic Preparedness Innovations (CEPI), the Houston Methodist vaccinology team aims to advance its ‘circRNA’ platform, a high-impact innovation offering significant potential beyond mRNA vaccines in defending populations against future epidemic and pandemic disease threats.
The project is focused on the design and preclinical evaluation of ‘circRNA’ vaccine candidates, initially against Chikungunya, and aims to generate the data necessary to establish preclinical proof of concept for the vaccine platform.
RNA vaccine technology, which uses the body’s own machinery to make antigenic protein rather than injecting an antigen into the recipient, has made significant progress in recent years. The most ground-breaking advance came with its validation for the first time during the COVID-19 pandemic, when it was used to develop new vaccines in less than a year that went on to save millions of lives and reduce the number of severe cases of COVID-19.
While mRNA vaccines are now expected to play a crucial role in preventing and controlling future outbreaks and pandemics, they have some limitations – including the potential to provoke local reactions or short-term fever in people who receive them. Relative to other types of vaccine, they are currently expensive to manufacture and require costly and complex cold-chain storage and transportation infrastructure.
Circular RNA vaccine technology uses a closed-loop RNA, which could enable vaccine candidates based on it to be more stable and durable than current linear-based mRNA candidates. The technology could also deliver improved efficacy in smaller doses. HMRI’s circRNA platform is still in the early-stages of development, but, if successful, it has the potential to be effective in single-dose regimens, to reduce the amount of RNA needed per dose and to lower the cost of RNA-based vaccines, which could altogether contribute to the accessibility of mRNA vaccines.
“If effective, these circRNA vaccines could progress this new scientific era of mRNA vaccinology even further, leveraging not only the speed at which the technology can be designed and tested in response to infectious disease outbreaks but also the potential to create more durable and accessible mRNA vaccines for greater global protection when faced with a deadly disease threat.”Dr In-Kyu-Yoon, Acting Executive Director of Vaccine R&D at CEPI
CEPI’s investment in HMRI is the latest in its programme to advance novel RNA vaccine platform technologies for emerging and select endemic infectious diseases. The programme aims to evaluate whether the next-generation of RNA technologies could offer substantial advantages over existing mRNA platforms, for example improved immunogenicity, storage, stability, productivity, response time, and cost-of-goods.
circRNAs have unique characteristics that enable their use as vaccines. Because circRNAs have a covalently closed structure and no termini, circRNAs are immune to degradation mediated by exonucleases, conserving a higher stability than their linear mRNA isoforms. In mammalian cells, the intermediate half-life of circRNAs is at least 2.5 times more than that of their linear counterparts. The safe antigen production of circRNA-based vaccines can be ensured by circRNAs’ ability to be expressed endogenously. Recently, several circRNA vaccines have been synthesized and tested in vitro and in vivo. This review introduces the current understanding of the biology and function of translatable circRNAs, molecular biology, synthetic methods, delivery of circRNA, and current circRNA vaccines. Journal of Translational Internal Medicine (Dec 2023)
Based on the current findings, there are a few suggestions that may serve as directions for future research: nucleotide modifications may synergistically enhance circRNA vaccine stability and reduce immunogenicity and more research is needed; circularization methods need to be further investigated as the circularization efficiency of linear precursors decreases with their length, which is one of the limitations of circRNA vaccines; and new purification methods to obtain high-purity circRNA are urgently needed. Signal Transduction and Targeted Therapy (Sep 2023)
Several recent attempts to improve the stability and immunogenicity of messenger RNA (mRNA) vaccines include the use of circular RNA (circRNA), targeted delivery, and lyophilization. However, these research directions have often been pursued independently, ignoring the impact of the modification of lipid nanoparticle-encapsulated mRNA vaccines on their targeted delivery after lyophilization and on their subsequent immunogenicity. this study provides a general platform for the design of lyophilized vaccines with targeted stability, demonstrating the potential of lymph node-targeting circRNAs as next-generation vaccines. mBio (Dec 2023)