Since emerging in Wuhan in December 2019, SARS-CoV-2 has caused a global pandemic. Its large RNA genome, replicated by RNA-dependent RNA polymerase (RdRP) with an exoribonuclease (ExoN) proofreading enzyme, allows for high rates of recombination, insertions, deletions, and point mutations—though lower than other RNA viruses due to the proofreading. Early SARS-CoV-2 evolution showed limited adaptation; however, a single spike substitution (D614G) conferred a growth advantage and quickly became dominant. From October 2020, more heavily mutated variants emerged, exhibiting altered transmissibility and antigenicity. The World Health Organization has declared five variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron. Each VOC demonstrated a transmission advantage over its predecessor, rapidly becoming dominant regionally or globally. The spike protein's interaction with human ACE2 and the polybasic furin cleavage site (FCS) are crucial for efficient human-to-human transmission. SARS-CoV-2's ability to infect various mammalian species, including mink and white-tailed deer, highlights its generalist nature. Understanding the drivers of SARS-CoV-2 fitness, which determines its reproductive success, is crucial for public health.

The review extensively examines existing literature on SARS-CoV-2 variants. It synthesizes data on transmissibility and antigenicity, the role of mutations in the furin spike cleavage site and non-spike proteins, the impact of recombination, and the virus's evolution in relation to T cell responses, innate immunity, and population-level immunity. The review also explores the complexities of the relationship between viral antigenicity, transmission, and virulence, highlighting its implications for the future course of the COVID-19 pandemic. Previous work on spike-mediated humoral immunity is referenced.

This is a review article; therefore, there is no original methodology. The authors synthesized and analyzed data from published literature on SARS-CoV-2 variants. This involved examining peer-reviewed studies focusing on various aspects of viral evolution, including transmissibility, immune escape mechanisms, mutations within different viral proteins (spike, nucleocapsid, membrane, envelope), the role of recombination, and the interplay between the virus and the innate and adaptive immune systems. The analysis included both in vitro and in vivo studies, as well as epidemiological data on variant prevalence and disease severity. The authors integrated data from studies using diverse methodologies such as: deep mutational scanning of the spike protein's receptor-binding domain; in vitro assays using virus-like particles or live viruses; studies of viral replication and entry mechanisms; experiments analyzing T cell and antibody responses; studies of innate immune evasion; and epidemiological investigations of transmission rates and clinical outcomes in different populations and time periods. This systematic review approach ensured the broad consideration of relevant findings from multiple research areas related to SARS-CoV-2 variants.

The review highlights several key findings concerning SARS-CoV-2 variant evolution and fitness. Mutations optimizing furin cleavage contributed to the enhanced transmissibility of Alpha and Delta variants. However, Omicron's success was primarily driven by immune escape rather than furin cleavage optimization. Omicron's ability to use alternative cell entry pathways (via endosomal proteases) is linked to reduced disease severity. Mutations in non-spike proteins (N, M, E) also affect infectivity. The 106-108 deletion in NSP6 enhances replication organelle formation. T cell responses are important in protection against severe COVID-19; however, some mutations in spike, nucleocapsid, and M proteins cause T cell escape. The overall T cell response is fairly preserved against VOCs despite some epitope loss. Innate immune evasion plays a role in VOC transmission. Alpha and Omicron show reduced sensitivity to interferons. The increasing population immunity from infection and vaccination creates a dynamic fitness landscape where antigenic novelty is increasingly important for variant success. Omicron showed an unprecedented degree of antigenic novelty, potentially comparable to an influenza antigenic shift. The review notes inconsistencies in the relationship between virulence and transmissibility among different variants, with Omicron showing reduced severity compared to Delta, potentially due to reduced fusogenicity and altered tropism. Recombination between variants can generate new viruses with properties from both parent viruses; however, recombinants haven't had a substantial impact on the pandemic course until recently. Animal models largely recapitulate human severity data but have limitations.

The findings emphasize the complex interplay between viral biology, immune escape, and population immunity in shaping the evolution and fitness of SARS-CoV-2 variants. The initial success of VOCs was driven by enhancements in intrinsic biological features such as furin cleavage and ACE2 binding. However, as population immunity increased due to prior infection and vaccination, immune escape became the primary driver of variant success, as seen with Omicron. The review highlights the importance of considering both intrinsic viral properties and the dynamic immune landscape when predicting the future trajectory of SARS-CoV-2 evolution. The unpredictable nature of the virus's evolution, particularly in the context of chronic infections in immunocompromised hosts and the potential for recombination events, underscores the necessity for ongoing genomic surveillance and the development of broadly protective countermeasures.

SARS-CoV-2 continues to evolve, with antigenic novelty and immune evasion as major drivers of variant success. While Omicron currently dominates, the emergence of new, antigenically distinct VOCs remains a possibility. Genomic surveillance remains crucial for early detection of new variants. Further research should focus on understanding the mechanisms of immune evasion, the contribution of non-spike protein mutations, the role of recombination, and the development of broadly protective vaccines and therapeutics.

The review is limited by the inherent limitations of the studies it synthesizes. In vivo studies often rely on animal models that may not perfectly represent human responses. The dynamic nature of the pandemic and the continuous emergence of new variants create challenges for drawing definitive conclusions. In some cases, data on specific aspects of viral biology and immunity are still limited, requiring further research to clarify inconsistencies.