Abstract
The evolution of SARS-CoV-2 has led to the emergence of numerous variants of concern (VOCs), marked by changes in the viral spike glycoprotein, the primary target for neutralising antibody (nAb) responses. Emerging VOCs, particularly omicron sub-lineages, show resistance to nAbs induced by prior infection or vaccination. The precise spike protein changes contributing to this resistance remain unclear in infectious cell culture systems. In the present study, a large panel of infectious SARS-CoV-2 mutant viruses, each with spike protein changes found in VOCs, including omicron JN.1 and its derivatives KP.2 and KP.3, was generated using a reverse genetic system. The susceptibility of these viruses to antibody neutralisation was measured using plasma from convalescent and vaccinated individuals. Synergistic roles of combined substitutions in the spike receptor binding domain (RBD) were observed in neutralisation resistance. However, recombinant viruses with the entire spike protein from a specific VOC showed enhanced resistance, indicating that changes outside the RBD are also significant. In silico analyses of spike antibody epitopes suggested that changes in neutralisation could be due to altered antibody binding affinities. Assessing ACE2 usage for entry through anti-ACE2 antibody blocking and ACE2 siRNA revealed that omicron BA.2.86 and JN.1 mutant viruses were less dependent on ACE2 for entry. However, surface plasmon resonance analysis showed increased affinity for ACE2 for both BA.2.86 and JN.1 compared to the ancestral spike. This detailed analysis of specific changes in the SARS-CoV-2 spike enhances understanding of coronavirus evolution, particularly regarding neutralising antibody evasion and ACE2 entry receptor dependence.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 2412643 |
| Tidsskrift | Emerging Microbes and Infections |
| Vol/bind | 13 |
| Udgave nummer | 1 |
| Antal sider | 20 |
| ISSN | 2222-1751 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:The study received grant support from The Region H Foundation (L.P., C.S., S.R., J.B.), The Novo Nordisk Foundation (A.U., N.W., J.B.), Independent Research Fund Denmark (DFF), Medical Sciences (J.B.), the Candys Foundation (L.P., C.F-A., J.B.), The Danish Cancer Society (J.B.), The Weimann Foundation (U.F.), The Mauritzen La Fontaine Foundation (J.B.), The Mauritzen La Fontaine Family Foundation (J.B.), and the Danish Agency for Science and Higher Education (S.R., J.B.). A.U. was supported by a Postdoctoral BRIDGE Fellowship at the University of Copenhagen. BLM is part of the Novo Nordisk Foundation Center for Protein Research (NNF-CPR), which is supported financially by the Novo Nordisk Foundation [grant number NNF14CC0001]. J.B. is the 2015 recipient of the Novo Nordisk Prize, the 2019 and 2023 recipient of Distinguished Investigator grants from the Novo Nordisk Foundation, the 2022 recipient of the Hagedorn Prize, and the 2024 recipient of the KFJ Prize. We thank Anna-Louise S\u00F8rensen and Lotte Mikkelsen (Copenhagen University Hospital, Hvidovre) for laboratory assistance, and Bjarne \u00D8rskov Lindhardt (Copenhagen University Hospital, Hvidovre) and Charlotte Menne Bonefeld (University of Copenhagen) for valuable support. We thank Signe Lysemose Villadsen (Copenhagen University Hospital, Hvidovre) for collecting the blood samples from COVID-19 and vaccinated individuals.
Publisher Copyright:
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd.