Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and spread, and it remains critical to understand the functional consequences of mutations in dominant viral variants. The recombinant JN.1 subvariant XEC recently replaced KP.3.1.1 to become the most prevalent subvariant worldwide. Here, we measure the in vitro neutralization of KP.3.1.1 and XEC by human sera, monoclonal antibodies, and the soluble human ACE2 (hACE2) receptor relative to the parental subvariants KP.3 and JN.1. KP.3.1.1 and XEC are slightly more resistant (1.3- to 1.6-fold) than KP.3 to serum neutralization and antigenically similar. Both also demonstrate greater resistance to neutralization by select monoclonal antibodies and soluble hACE2, all of which target the top of the viral spike. Our findings suggest that the upward motion of the receptor-binding domain in the spike may be partially hindered by the N-terminal domain mutations in KP.3.1.1 and XEC, allowing these subvariants to better evade serum antibodies that target the viral spike in the up position and to have a growth advantage.