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Publications

Journal Article Epublish 1 citation

PubMed: 39827186 DOI: 10.1038/s41467-025-55871-5

Reverse mutational scanning of SARS-CoV-2 spike BA.2.86 identifies epitopes contributing to immune escape from polyclonal sera.

Nat Commun 16(1):809

Authors: 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

Affiliations

  • Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • Department Structure and Function of Proteins, Helmholtz Centre for Infection Research Braunschweig, Braunschweig, Germany.
  • DSMZ- German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
  • Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.
  • Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany. Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany.
  • Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany.
  • Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany.
  • Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany.
  • German Center for Infection Research, partner site Hannover-Braunschweig, Hannover, Germany.
  • Centre for Individualized Infection Medicine, a joint venture of HZI and Hannover Medical School, Hannover, Germany.
  • Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • German Center for Infection Research, partner site Hannover-Braunschweig, Hannover, Germany.
  • Centre for Individualized Infection Medicine, a joint venture of HZI and Hannover Medical School, Hannover, Germany.

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.

MeSH

Sars-Cov-2, Epitopes, Vaccines, Biological Science Disciplines, Severe Acute Respiratory Syndrome-Related Coronavirus, Mutation

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