Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera
Abstract The recently detected Omicron BA.2.86 lineage contains more than 30 amino acid mutations relative to BA.2. BA.2.86 and its JN.1 derivative evade neutralization by serum antibodies of fully vaccinated individuals. In this study, we elucidate epitopes driving the immune escape of BA.2.86 and...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55871-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594541848297472 |
|---|---|
| author | Najat Bdeir Tatjana Lüddecke Henrike Maaß Stefan Schmelz Ulfert Rand Henning Jacobsen Kristin Metzdorf Upasana Kulkarni Anne Cossmann Metodi V. Stankov Markus Hoffmann Stefan Pöhlmann Wulf Blankenfeldt Alexandra Dopfer-Jablonka Georg M. N. Behrens Luka Čičin-Šain |
| author_facet | Najat Bdeir Tatjana Lüddecke Henrike Maaß Stefan Schmelz Ulfert Rand Henning Jacobsen Kristin Metzdorf Upasana Kulkarni Anne Cossmann Metodi V. Stankov Markus Hoffmann Stefan Pöhlmann Wulf Blankenfeldt Alexandra Dopfer-Jablonka Georg M. N. Behrens Luka Čičin-Šain |
| author_sort | Najat Bdeir |
| collection | DOAJ |
| description | Abstract The recently detected Omicron BA.2.86 lineage contains more than 30 amino acid mutations relative to BA.2. BA.2.86 and its JN.1 derivative evade neutralization by serum antibodies of fully vaccinated individuals. In this study, we elucidate epitopes driving the immune escape of BA.2.86 and JN.1 via pseudovirus neutralization. Here we generate 33 BA.2.86 mutants, each reverting a single mutation back to BA.2. We use this library in an approach that we call reverse mutational scanning to define distinct neutralization titers against each epitope. Mutations within the receptor binding domain at K356T, V483Δ, and to a lesser extent N460K, A484K, and F486P enhance immune escape. Interestingly, 16insMPLF within the spike N-terminal domain and P621S within S1/S2 also significantly contribute to antibody escape of BA.2.86. Upon XBB.1.5 booster vaccination, neutralization titers against JN.1 and BA.2.86 improve considerably, and residual immune escape is driven by 16insMPLF, N460K, E554K, and to a lesser extent P621S, and A484K. |
| format | Article |
| id | doaj-art-3d3104dd41e146c385b0310f75f97917 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3d3104dd41e146c385b0310f75f979172025-01-19T12:30:45ZengNature PortfolioNature Communications2041-17232025-01-0116111310.1038/s41467-025-55871-5Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal seraNajat Bdeir0Tatjana Lüddecke1Henrike Maaß2Stefan Schmelz3Ulfert Rand4Henning Jacobsen5Kristin Metzdorf6Upasana Kulkarni7Anne Cossmann8Metodi V. Stankov9Markus Hoffmann10Stefan Pöhlmann11Wulf Blankenfeldt12Alexandra Dopfer-Jablonka13Georg M. N. Behrens14Luka Čičin-Šain15Department of Viral Immunology, Helmholtz Centre for Infection ResearchDepartment of Viral Immunology, Helmholtz Centre for Infection ResearchDepartment of Viral Immunology, Helmholtz Centre for Infection ResearchDepartment Structure and Function of Proteins, Helmholtz Centre for Infection Research BraunschweigDSMZ- German Collection of Microorganisms and Cell CulturesDepartment of Viral Immunology, Helmholtz Centre for Infection ResearchDepartment of Viral Immunology, Helmholtz Centre for Infection ResearchDepartment of Viral Immunology, Helmholtz Centre for Infection ResearchDepartment of Rheumatology and Immunology, Hannover Medical SchoolDepartment of Rheumatology and Immunology, Hannover Medical SchoolInfection Biology Unit, German Primate Center – Leibniz Institute for Primate ResearchInfection Biology Unit, German Primate Center – Leibniz Institute for Primate ResearchDepartment Structure and Function of Proteins, Helmholtz Centre for Infection Research BraunschweigDepartment of Rheumatology and Immunology, Hannover Medical SchoolDepartment of Rheumatology and Immunology, Hannover Medical SchoolDepartment of Viral Immunology, Helmholtz Centre for Infection ResearchAbstract The recently detected Omicron BA.2.86 lineage contains more than 30 amino acid mutations relative to BA.2. BA.2.86 and its JN.1 derivative evade neutralization by serum antibodies of fully vaccinated individuals. In this study, we elucidate epitopes driving the immune escape of BA.2.86 and JN.1 via pseudovirus neutralization. Here we generate 33 BA.2.86 mutants, each reverting a single mutation back to BA.2. We use this library in an approach that we call reverse mutational scanning to define distinct neutralization titers against each epitope. Mutations within the receptor binding domain at K356T, V483Δ, and to a lesser extent N460K, A484K, and F486P enhance immune escape. Interestingly, 16insMPLF within the spike N-terminal domain and P621S within S1/S2 also significantly contribute to antibody escape of BA.2.86. Upon XBB.1.5 booster vaccination, neutralization titers against JN.1 and BA.2.86 improve considerably, and residual immune escape is driven by 16insMPLF, N460K, E554K, and to a lesser extent P621S, and A484K.https://doi.org/10.1038/s41467-025-55871-5 |
| spellingShingle | Najat Bdeir Tatjana Lüddecke Henrike Maaß Stefan Schmelz Ulfert Rand Henning Jacobsen Kristin Metzdorf Upasana Kulkarni Anne Cossmann Metodi V. Stankov Markus Hoffmann Stefan Pöhlmann Wulf Blankenfeldt Alexandra Dopfer-Jablonka Georg M. N. Behrens Luka Čičin-Šain Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera Nature Communications |
| title | Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera |
| title_full | Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera |
| title_fullStr | Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera |
| title_full_unstemmed | Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera |
| title_short | Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera |
| title_sort | reverse mutational scanning of sars cov 2 spike ba 2 86 identifies epitopes contributing to immune escape from polyclonal sera |
| url | https://doi.org/10.1038/s41467-025-55871-5 |
| work_keys_str_mv | AT najatbdeir reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT tatjanaluddecke reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT henrikemaaß reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT stefanschmelz reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT ulfertrand reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT henningjacobsen reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT kristinmetzdorf reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT upasanakulkarni reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT annecossmann reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT metodivstankov reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT markushoffmann reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT stefanpohlmann reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT wulfblankenfeldt reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT alexandradopferjablonka reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT georgmnbehrens reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera AT lukacicinsain reversemutationalscanningofsarscov2spikeba286identifiesepitopescontributingtoimmuneescapefrompolyclonalsera |