Spike conformational and glycan heterogeneity associated with furin cleavage causes incomplete neutralization of SARS-CoV-2

Sahil Kumar, Rathina Delipan, Chanchal Sharma, Jyoti Jadoun, Kawkab Kanjo, Randhir Singh, Raju Rajmani, Suprit Deshpande, Rajesh Pandey, Krishan G. Thakur, Jayanta Bhattacharya, Rogier W. Sanders, Marit J. van Gils, Raghavan Varadarajan and Rajesh P. Ringe ()
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Sahil Kumar: CSIR-Institute of Microbial Technology (CSIR-IMTECH)
Rathina Delipan: CSIR-Institute of Microbial Technology (CSIR-IMTECH)
Chanchal Sharma: CSIR-Institute of Microbial Technology (CSIR-IMTECH)
Jyoti Jadoun: CSIR-Institute of Microbial Technology (CSIR-IMTECH)
Kawkab Kanjo: Indian Institute of Science, Molecular Biophysics Unit (MBU)
Randhir Singh: Basavanagudi, Mynvax Pvt. Ltd., 3rd Floor, Brigade MLR Centre, No.50, Vani Vilas Road
Raju Rajmani: Indian Institute of Science, Molecular Biophysics Unit (MBU)
Suprit Deshpande: NCR Biotech Science Cluster, Center for Virus Research, Vaccines and Therapeutics, BRIC-Translational Health Science & Technology Institute
Rajesh Pandey: Mall Road, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB)
Krishan G. Thakur: CSIR-Institute of Microbial Technology (CSIR-IMTECH)
Jayanta Bhattacharya: NCR Biotech Science Cluster, Center for Virus Research, Vaccines and Therapeutics, BRIC-Translational Health Science & Technology Institute
Rogier W. Sanders: New York, Department of Microbiology and Immunology, Weill Medical College of Cornell University
Marit J. van Gils: Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, Location University of Amsterdam
Raghavan Varadarajan: Indian Institute of Science, Molecular Biophysics Unit (MBU)
Rajesh P. Ringe: National Institute of Pharmaceutical Education and Research (NIPER)

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract SARS-CoV-2 Spike - the sole neutralization target, is highly resilient to the immune pressure driving genetic evolution. While potency and breadth of neutralization are widely studied, the incomplete neutralization - the mechanism of resistance without needing genetic change - remains unexplored. Several monoclonal antibodies, although potent, showed incomplete neutralization of genetically homogeneous pseudovirus suggesting the existence of distinct spike conformations. The residual infectivity at high antibody concentration indicates a viral fraction with intrinsic resistance to the antibody. Although the published studies on spike glycosylation, structure, and conformations provide evidence of spike heterogeneity the precise mechanism for the incomplete neutralization has not been established. In this study, we devise a method to separate the un-neutralized virion population, called as persistent fraction of infectivity (PF), and characterize the viral spike protein. The neutralization resistance of PF is stable and unrelated to the conformational equilibrium that exists in the pseudovirus stock. The spike on the PF is highly cleaved between S1 and S2, adopts the closed conformation, and express more mannosidic glycans on RBD than the total virus population. Our study provides possible explanations for the incomplete neutralization by antibodies and delineates the association between furin cleavage of spike, its conformation and glycosylation.

Date: 2025
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DOI: 10.1038/s41467-025-65099-y

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