Research roadmap for coronavirus vaccine development

Identity of virulence factors

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Identity of virulence factors

Research Question

To identify the key virulence factors in animal coronaviruses that contribute to disease severity, infectivity, and transmissibility. By mapping these factors to various components of the viral genome (RNA sequences/ proteins/ alternative transcripts) and understanding their role in pathogenesis, we hope to develop better vaccines and antiviral strategies to mitigate outbreaks in animals. Understanding virulence determinants is crucial for quick understanding of viral variants if they emerge mid-epidemic

Zoonotic risk: For novel viruses there is the large outstanding question of how to understand zoonotic risk from sequence alone?
Understanding of virulence factors: Broadly we must identify virulence factors that contribute to viral infectivity, transmissibility and immune evasions of severe animal coronavirus diseases and understand their conservation across species/hosts. Coronaviruses have large genomes with multiple non-structural and accessory proteins whose contributions to virulence remain unclear. In addition, virulence factors may behave differently in various host species, affecting disease outcomes and transmissibility
Emergence of new variance: As with SARS2 VOCs, the emergence of new variants with altered virulence necessitates constant monitoring and characterization of these changes in animal populations, especially mid-epidemic

Genomic approaches to understand variant emergence: Study factors and determinants that give rise to emerging variants of interest (pathogenic and/or zoonotic) using the same genomic approaches applied to SARS2 to understand variant emergence. Feasible to, in tandem, use reverse genetics to create mutations in suspected virulence factors (e.g., ORF3, ORF8 and their orthologies) and assess their impact on infectivity, replication etc. Use of predictive animal models: Animal models (preferable in a relevant host – easier for animal coronas?) to predict virulence and transmissibility of variants with different virulence factors would be good.

Understanding which animal coronaviruses we have detailed pathogenesis studies for, and which needs more preliminary work to enable the solutions detailed above. Understanding which viruses have the most detailed genomic screening at the moment (in the field), and which need improving. Identifying orthologues across species – is there the possibility of coronaviruses targeting the same pathways in slightly different ways, or are they all very different?