Generation of coronavirus live-attenuated vaccines
SARS-CoV-2 is responsible for causing upper respiratory disease and pneumonia, threatening countless lives worldwide. SARS-CoV-2 critically relies on the reprogramming of cellular metabolism. We aim to identify vulnerabilities of the virus during its usurpation of the host cell and to use this knowledge to attenuate SARS-CoV-2.
SARS-CoV-2, like all viruses, is dependent on hijacking the host cell translational machinery to achieve successful infection. It is important therefore to identify critical mechanisms that the virus uses to modify and reprogram cellular translation. Based on this knowledge, it will be possible to recode the SARS-CoV-2 genome and develop attenuated viruses for vaccine development. By combining this with established recoding strategies for virus attenuation, we will evaluate the attenuated viruses in cell culture and advanced animal models for different aspects of COVID-19.
We will study SARS-CoV-2 RNA modifications and characterise the translational landscape and levels of cellular tRNA and tRNA modifications during infection in order to generate live-attenuated SARS-CoV-2 vaccine strains. This involves the generation of rationally re-coded SARS-CoV-2 and the assessment of attenuation, safety, and immunogenicity in several animal models.
Expected results and envisaged products
Our project is based on an iterative optimisation process. First, we generate vaccine strains instructed by molecular virus-host interactions in the context of RNA modification and translation. Second, we assess vaccine strain attenuation, pathogenicity and immunogenicity, and third, we refine the re-coded SARS-CoV-2 vaccine strains to optimally adjust virus attenuation to induce protective immune responses. The envisaged products are well characterised SARS-CoV-2 vaccine candidates that are rationally designed and assessed in vivo concerning attenuation, safety, and immunogenicity.
Specific contribution to tackle the current pandemic
Our project will contribute to the global effort in providing SARS-CoV-2 vaccines. We expect that first-generation of RNA-, subunit-, and vector-based vaccines will be swiftly available. However, we also expect that the resulting efficacy and safety data may reveal limitations of the first-generation vaccines. We predict that there will be a continued need to develop and distribute second-generation SARS-CoV-2 vaccines that overcome possible shortcomings of first-generation vaccines as regards, for example, ease of production, storage and cost-efficiency.
Recoding the SARS-CoV-2 genome - A multidisciplinary approach to generate live-attenuated coronavirus vaccines