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Microbes & Immunity SARS-CoV-2 complementary classification

like” events – abrupt, mutation-rich transitions following variant at a given time point was often misinterpreted as
prolonged periods of undetected evolution. These contrast increased viral fitness, without sufficient consideration of
with the more gradual, “drift-like” evolution observed immune landscape effects, stochastic founder effects, and
within the Omicron lineage. Complementary CDC shifting population-level immunity in shaping variant
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genomic surveillance during 2023 – 2024 indicated that emergence. By relying on short-term epidemiological
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dominant Omicron sub-lineages (e.g., XBB.1.5, JN.1) observations rather than virological principles, the present
remained genetically close to earlier variants. 146,147 classification system of SARS-CoV-2 VOCs appears to
To further contextualize the slow evolutionary promote an illusion of continuous viral emergence, despite
trajectory of SARS-CoV-2, the time required for the genetic evidence indicating relative evolutionary stability
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virus to reach genetic divergence thresholds observed of SARS-CoV-2, as shown by Lv et al.
in HIV-1, HCV, and influenza A was modeled. Using A more rigorous and biologically grounded framework
the estimated evolutionary rate of SARS-CoV-2 (0.0004 for classifying SARS-CoV-2 variants would complement
– 0.002 s/s per year), the timeframes necessary for the the existing system by providing clearer genetic and
accumulation of genetic distances comparable to those of functional thresholds. This integrative approach could
other RNA viruses were calculated as follows: On average, enhance the present SARS-CoV-2 classification schemes,
HIV-1-like divergence would require 54 years; HCV- offering additional context for long-term surveillance while
like divergence would require 127 years; and influenza preserving their relevance for rapid public health response.
A virus-like divergence would require 669 years. Even This approach would help to ensure that SARS-CoV-2
under accelerated evolutionary scenarios that incorporate variant classifications are based on measurable
recombination events, the time required for SARS-CoV-2 evolutionary changes, rather than transient mutations that
to evolve into a distinct viral lineage is projected to exceed have contributed to public anxiety and misdirected public
the present pandemic timeline. This finding disputes the health responses. 123,124 A robust classification system must
variant-driven narrative that suggests SARS-CoV-2 is first define genetic divergence thresholds aligned with
undergoing rapid evolutionary shifts with each new lineage the established evolutionary dynamics of RNA viruses.
designation. Instead, the data support a preliminary In the case of HIV-1, HCV, and influenza A virus, genetic
conclusion that SARS-CoV-2 remains evolutionarily distances serve as a key determinant of whether a viral
constrained, undergoing relatively slow genetic drift rather strain is classified as a distinct subtype/CRF, genotype/sub-
than true speciation. genotype, or lineage.
As stated earlier, the WHO classification framework for While genetic divergence serves as the foundation of viral
SARS-CoV-2 variants is not entirely based on established classification, the functional consequences of mutations
genetic divergence thresholds but rather on epidemiological must also be considered. A variant should not be designated
trends and qualitative assessments of transmissibility, solely based on genetic alterations, but rather on whether
immune escape, and severity. However, the findings of these changes confer a meaningful impact on transmission,
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this study suggest several contradictory aspects. Variant immune evasion, or disease severity. Functional criteria
designations are applied inconsistently, with transient must also be met in conjunction with genetic divergence
genetic mutations (e.g., D614G, N501Y) serving as the thresholds to ensure that only biologically significant
primary justification for labeling variants, despite similar variants are designated as VOCs. These functional criteria
mutations occurring in other viruses without warranting include: (1) A demonstrable increase in transmissibility
separate classification. 45,148 compared to the previously dominant variant; (2) a
Further supporting the hypothesis that some significant reduction in neutralizing antibody titers,
SARS-CoV-2 variant classifications may lack robust confirmed in real-world immunological studies rather than
biological justification is the consistent observation that isolated in vitro assays, indicating a meaningful immune
functional changes attributed to SARS-CoV-2 variants escape advantage; (3) a significant increase in hospitalization
are quantitatively minor, particularly in comparison rates attributable to increased intrinsic virulence, rather
to antigenic shifts in influenza A virus. 75,149 While than confounding factors such as healthcare system burden
Omicron sub-lineages exhibit a 3 – 4-fold reduction in or case misclassification; and (4) sustained epidemiological
neutralizing antibody titers, this pales in comparison to dominance lasting ≥12 months, ensuring that the emergent
the differences observed between HIV-1 subtypes/CRFs, variant represents a sustained shift in viral evolution rather
highlighting the exaggerated portrayal of SARS-CoV-2 than a transient lineage fluctuation.
mutations as profound evolutionary shifts. 150,151 Thus, To put these criteria into practical aspects, influenza
the epidemiological dominance of a SARS-CoV-2 emerges as a stark example with antigenic shifts between

Volume 2 Issue 3 (2025) 98 doi: 10.36922/MI025190042