Comparative analysis of replication and immune evasion among SARS-CoV-2 subvariants BA.2.86, JN.1, KP.2, and KP.3.

Summary

Head-to-head testing of recombinant SARS-CoV-2 with BA.2.86-descendant spikes in primary human airway epithelium shows that recurrent RBD mutations (L455S, F456L, Q493E, R346T) tune the balance between immune escape and replication, explaining the succession from BA.2.86 to JN.1, KP.2, and KP.3. Notably, L455S favors immune evasion, while Q493E enhances replication, and RBD mutations can modulate spike cleavage.

Key Findings

• JN.1 (with L455S) replicated slower than BA.2.86 but showed greater resistance to XBB.1.5-infection sera, implicating immune escape as driver of BA.2.86→JN.1.
• KP.2 (R346T+L455S+F456L) had enhanced replication and increased resistance compared with JN.1, supporting dual selection on fitness and escape.
• KP.3 (L455S+F456L+Q493E) replicated more than KP.2 without increased neutralization resistance, indicating Q493E boosts replication.
• RBD mutations L455S and Q493E affected spike cleavage despite being distal to the furin site.

Clinical Implications

Surveillance should prioritize recurrent RBD mutations (L455S, F456L, Q493E, R346T) as early markers of fitness/escape changes. Vaccine strain selection and monoclonal cocktails may need updating to maintain breadth against these changes.

Limitations

• In vitro/ex vivo systems may not fully capture in vivo transmission dynamics
• Neutralization panels were limited to certain infection sera (e.g., XBB.1.5/JN.1)

Future Directions

Integrate antigenic cartography and animal transmission models to quantify fitness-escape trade-offs and pre-emptively evaluate vaccine candidates against emergent RBD constellations.