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Functional and structural basis of Omicron BA.3.2.1 spike
Yan Wang1, Yanping Hu1, Zhenhang Chen2
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
Cell Reports
|August 9, 2026
Summary
SARS-CoV-2 BA.3.2.1 shows increased immune evasion but reduced replication fitness. Its unique spike structure enhances stability, limiting receptor engagement and antibody accessibility, explaining its limited prevalence.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- SARS-CoV-2 BA.3.2 sublineages exhibit significant spike protein divergence, raising concerns about viral fitness and antigenicity.
- BA.3.2.1 was identified as a representative strain for studying these altered characteristics.
Purpose of the Study:
- To engineer live-attenuated SARS-CoV-2 encoding spike proteins from BA.3.2.1, LP.8.1, or XEC.
- To compare the fitness and antigenicity of BA.3.2.1 against other SARS-CoV-2 variants like BA.3 and KP.3.
Main Methods:
- Engineered live-attenuated SARS-CoV-2 strains.
- In vitro replication assays in primary human airway epithelium.
- Neutralization assays using convalescent sera.
- Cryo-electron microscopy for structural analysis.
Main Results:
- BA.3.2.1 outcompeted BA.3 in human airway epithelium but replicated less efficiently than JN.1 descendants.
- BA.3.2.1 displayed significant resistance to neutralization by KP.2/KP.3 convalescent sera.
- Cryo-EM revealed a stabilized, closed conformation of the BA.3.2.1 spike, limiting receptor binding and antibody epitope accessibility.
Conclusions:
- The BA.3.2.1 spike's architecture enhances immune evasion at the expense of replication fitness.
- Structural adaptations explain the limited prevalence of BA.3.2 sublineages.
- Continuous SARS-CoV-2 variant surveillance is crucial.
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