Decoding omicron: Genetic insight into its transmission dynamics, severity spectrum and ever-evolving strategies of immune escape in comparison with other SARS-CoV-2 variants

•In-depth study of SARS-CoV-2 BA.2.86, JN.1, KP.1, KP.2, showing mutations for transmissibility.•Unique spike mutations in NTD/RBD enhance receptor binding, immune evasion, especially for KP.1.•KP.1 in BA.2.86 shows high fitness, stability, ACE2 binding, nAb resistance, aiding spread.•Fitness assessment shows KP.1 has higher stability, immune evasion, warranting close monitoring.•Impact on the public healthcare with emphasis on genomic surveillance and adaptive vaccinations. The coronavirus disease 2019 (COVID-19) pandemic, driven by the rapid evolution of the SARS-CoV-2 virus, has led to the emergence of multiple variants with significant impacts on global health. This study aims to analyze the evolutionary trends and mutational landscape of SARS-CoV-2 variants circulating in Pune, Maharashtra, India, from August 2022 to April 2024. Using comprehensive genomic surveillance data, we identified the predominance of variants such as BA.2.75, XBB.x, and the newly emerged subvariants JN.1, KP.1, and KP.2. These subvariants, belonging to the BA.2.86 lineage, have raised concerns owing to their potential for increased transmissibility and immune evasion. Phylogenetic analysis of 84 sequenced samples from Pune revealed 18 distinct lineages, with JN.1 and KP.2 forming a novel branch compared with their ancestral lineage, BA.2. Detailed mutational analysis highlighted key mutations in the N-terminal domain (NTD) and receptor-binding domain (RBD) of the spike protein, affecting viral stability, ACE2 binding affinity, and neutralizing antibody escape. Our findings, along with the predictions of SpikePro, suggest that the combination of these mutations enhances the viral fitness of JN.1 and KP.2, contributing to their rapid emergence and spread. This study underscores the importance of continuous genomic surveillance and advanced computational modeling to track and predict the evolutionary trajectories of SARS-CoV-2 variants. The insights gained from this research are crucial for informing public health strategies, vaccine updates, and therapeutic interventions to mitigate the impact of current and future SARS-CoV-2 variants.