Is SARS-CoV-2 Spike Evolution Being Retargeted at the N-Terminal Domain?

Since 2020, most of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) evolution has been focused on the receptor-binding domain (RBD) of the Spike protein. Nevertheless, the N-terminal domain (NTD) of Spike has been shown to represent the target for neutralizing antibodies, and accordingly, NTD mutations are relevant for immune escape. In 2024, after the introduction of the BA.2.86 saltation variant (heavily mutated at the NTD antigenic supersite), its descendant JN.1 has further explored NTD evolution in its progeny, largely focused on positions 22, 31, 59 and 60. In this review, we explore such convergent evolution in detail and hypothesize the underlying mechanisms.