Grant: Project Grant - PA: Pandemic Preparedness and Health Emergencies Research

Messenger RNA (mRNA) technology has revolutionized our ability to develop safe, effective vaccines in a short time frame and at a large scale. Although the mRNA vaccines have had an incredible impact on the COVID-19 pandemic, there is still room for improvement. For example, we now know that the side effects are directly proportional to the dose of RNA, which motivates minimizing the required dose. Furthermore, the duration of immunity of the current mRNA vaccines is relatively short lived, requiring boosters approximately every six months. Finally, a certain proportion of the population has anaphylactic reactions to certain vaccine components, including polyethylene glycol (PEG). In this research program, we aim to develop RNA vaccines that improve upon the current mRNA vaccines and would be rapidly deployable in the event of an outbreak or pandemic. Self-amplifying RNA (saRNA) is the next generation of mRNA and the focus of my research program; it is a special type of mRNA that is able to replicate once it gets into a cell and requires a much lower dose. Like mRNA, saRNA requires a formulation that protects it from degrading and delivers it safely and consistently into cells. We hypothesize that by optimizing lipid nanoparticle formulations, which are the current state of the art technology for administering mRNA, and the dosing interval, we can identify lead clinical candidates for more potent and safer RNA vaccines. First, we will optimize LNP formulations that more efficiently the target immune cells that make a robust vaccine response. We will also optimize the dosing regimen to enable creation of a stronger immune 'memory' and longer lasting protection. Finally, we will engineer new LNP formulations that do not contain PEG so that more of the population is eligible to receive RNA vaccines. These vaccines can be applied to outbreaks, including COVID, seasonal viruses such as influenza, and future pandemics and will improve the health of millions of Canadians.