Pillar 3

Evolution is a complex process driven by many factors, including time. Given sufficient time, replicating viruses like SARS-CoV-2 can rapidly acquire genetic changes (mutations) that benefit their ability to infect its host. The pandemic has taught us that the virus adapts rapidly with new variants that are more virulent and transmissible. When new, virus-specific therapies are released (such as antiviral drugs or vaccines), evolution is affected and those mutations that favor greater resistance to treatments or evasion of vaccine-induced immunity become dominant.

Because evolution is difficult to predict in cells in a dish, we infected mice with unaltered Beta and Delta SARS-CoV-2 variants in order to study how disease severity and resistance to antibodies changed after the virus was passed across mice up to twenty times. This mimicked the evolution of SARS-CoV-2 in unexposed, unvaccinated humans, permitting us to witness its evolution in the absence of selective pressures like vaccination.

Our results indicate that some mutations were rapidly acquired and maintained – those that advantaged the virus – while others, which were disadvantageous, were lost. One striking observation was the acquisition of the Spike protein mutation S371F, which confers immune evasion properties, when no evolution-driving pressures were present. The S317F mutation is a signature mutation of Omicron variants.

Our results also indicate that passing Beta and Delta viruses in mice, emulating virus passed between unvaccinated humans, resulted in a virus that caused more severe disease. The Delta virus passed 20 times in mice could better resist neutralization from antibodies elicited by vaccination. Overall, our model can rapidly emulate pandemic progression in mammals and enable the development of more evolution-resistant treatments.

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Sunday Willett JD, Gravel A, Dubuc I, Gudimard L, FortinP, Liu JL, Galvez JH, Zwaig M, Roy AM, Lee S, Chen SH, Ragoussis J, Flamand L. Natural evolution of SARS-CoV-2 variants in K18-ACE2 mice gives rise to more virulent virus and variant alleles associated with treatment resistance. bioRxiv. January 17, 2023. doi: https://doi.org/10.1101/2023.01.16.523994