A proposal for biologically relevant classification of SARS-CoV-2 variants

The present classification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants plays a central role in shaping public health policies, vaccine strategies, and global risk communication. However, existing designations of variants of concern (VOCs) rely on evolving epidemiological and phenotypic criteria rather than quantitative genetic divergence thresholds. In this study, we evaluated the genetic divergence of SARS-CoV-2 variants relative to human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV), and influenza A virus, and proposed a framework integrating genetic, functional, and epidemiological criteria for variant classification. Comparative phylogenetic analysis assessed the divergence of SARS-CoV-2 (S) relative to HIV-1 (env), HCV (E1), and influenza A virus (HA). Maximum likelihood phylogenies with bootstrap support were constructed using MEGA6, and pairwise genetic distances were calculated through the maximum composite likelihood model. Monte Carlo simulations (n = 1,000) using adjusted SARS-CoV-2 evolutionary rates (0.0006 – 0.003 substitutions/site/year) estimated time to reach divergence thresholds defined by other viruses. SARS-CoV-2 variants showed a maximum divergence of 0.006 substitutions/site – far below thresholds for HIV-1 (0.157), HCV (0.371), and influenza A (1.956). Projections estimate HIV-1-like divergence in 53.7 years, HCV-like in 126.8 years, and influenza A-like in 668.6 years. No present VOC met all proposed functional criteria: transmissibility, immune escape, disease severity, and global dominance. Omicron exhibited partial immune escape but insufficient divergence for lineage reclassification. While present classification supports short-term response, integrating evolutionary benchmarks would enhance their biological relevance as the virus continues to diversify. A new evidence-based framework is needed to reduce public alarm, guide rational policymaking, and prioritize durable countermeasures over variant-specific responses.