Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the most recent coronavirus disease 2019 (COVID-19) pandemic, is a positive-sense, single-stranded RNA virus with a genome size of around 30 kb. Many variants of SARS-CoV-2 with distinct mutational signatures have emerged throughout the pandemic. Depending on their spike protein mutational landscape, some variants have shown higher transmissibility, infectivity, and virulence.

The BA.2.86 lineage of SARS-CoV-2, which was first identified in August 2023, is phylogenetically distinct from the currently circulating Omicron XBB lineages, including EG.5.1 and HK.3. The BA.2.86 lineage contains more than 30 mutations in the spike protein, indicating that this lineage is highly capable of evading the pre-existing anti-SARS-CoV-2 immunity.

The JN.1 (BA.2.86.1.1) is the most recently emerged variant of SARS-CoV-2 that descended from the BA.2.86 lineage. The JN.1 contains a hallmark mutation L455S in the spike protein and three other mutations in the non-spike proteins. Studies investigating HK.3 and other “FLip” variants have shown that acquiring L455F mutation in the spike protein is associated with increased viral transmissibility and immune evasion ability. The L455F and F456L mutations are nicknamed ”Flip” mutations because they switch the positions of two amino acids, labeled F and L, on the spike protein.

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