In Silico Assessment of SARS-CoV-2 Mutations with Relevancy to Prophylactic and Monoclonal-Based Treatment Strategies

Abstract

Abstract The ongoing pandemic caused by SARS-CoV-2 has inflicted significant disease burden worldwide. Several vaccines are now in use that are based on the virus’s highly immunogenic spike “S” protein, which mediates infection of host cells. However, since the emergence of the reference strain in 2019, the virus has underdone >40,000 nucleotide mutations, many of which have resulted in deletions or amino acid substitutions in the S protein. Most mutations appear to be random, while others deviate from expected outcomes. Indeed, some non-random mutations appear to confer resistance to either innate or adaptive immune functions while other enhance transmissibility. Although the consequences of these mutations are largely unknown, there is concern for the ability of select mutations to detract from the protection conferred by prophylaxis strategies and interventional therapies. We have therefore selected >50 whole genome-length mutant strain from 3 relatively closed populations to compare against widely circulating strains of concern and the reference strain so that we could assess differences in mutation events within the context of distinct population immunogenetics. For each strain we have biochemically characterized potentially critical mutations, assessed the randomness of each mutation, and assessed key mutations occurring in the S, M, E and N proteins for their ability to influence innate or adaptive immune recognition using bioinformatic platforms. The results of this study further our understanding for how these mutations influence population-based immunity to the virus, including biomedical interventions, as well as help explain the selection pressures and external events that are driving this genetic diversification.