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

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 and Luka Čičin-Šain ()
Additional contact information
Najat Bdeir: Helmholtz Centre for Infection Research
Tatjana Lüddecke: Helmholtz Centre for Infection Research
Henrike Maaß: Helmholtz Centre for Infection Research
Stefan Schmelz: Helmholtz Centre for Infection Research Braunschweig
Ulfert Rand: DSMZ- German Collection of Microorganisms and Cell Cultures
Henning Jacobsen: Helmholtz Centre for Infection Research
Kristin Metzdorf: Helmholtz Centre for Infection Research
Upasana Kulkarni: Helmholtz Centre for Infection Research
Anne Cossmann: Hannover Medical School
Metodi V. Stankov: Hannover Medical School
Markus Hoffmann: German Primate Center – Leibniz Institute for Primate Research
Stefan Pöhlmann: German Primate Center – Leibniz Institute for Primate Research
Wulf Blankenfeldt: Helmholtz Centre for Infection Research Braunschweig
Alexandra Dopfer-Jablonka: Hannover Medical School
Georg M. N. Behrens: Hannover Medical School
Luka Čičin-Šain: Helmholtz Centre for Infection Research

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55871-5

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