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2025BIOMED002
Public access from
03/07/2027
Doctoral thesis

Human antibodies to conserved regions in the S2 subunit of the SARS-CoV-2 spike

  • 2025

PhD: Università della Svizzera italiana

SARS-CoV-2
Coronavirus
Spike
Coldspots
Monoclonal antibodies
English The recent SARS-CoV-2 pandemic highlighted the need for therapeutics that can keep pace with the virus rapid evolution, particularly as emerging variants of concern (VOCs) challenge the effectiveness of available vaccines and monoclonal antibodies (mAbs). Unlike the S1 subunit of the Spike (S) protein, which is the main target of neutralizing mAbs, the S2 subunit exhibits a high degree of conservation across SARS-CoV-2 variants and related coronaviruses. S2 plays a crucial role in viral entry by mediating fusion with the host cell membrane. Thus, the discovery of broadly cross-reactive and neutralizing antibodies targeting conserved regions in S2 may lead to treatments that remain effective in spite of changes brought by VOC. This work aims at discovering antibodies that are resilient to virus evolution because they target highly conserved regions of S, with a particular focus on the S2 subunit. To identify highly conserved regions, bioinformatic tools were applied to analyze millions of sequences of S collected globally during the pandemic, revealing 16 evolution-resistant coldspots. A peptide-based strategy was developed to isolate naturally occurring antibodies against these coldspots from COVID-19 convalescent individuals. The resulting mAbs were characterized through biochemical and functional assays, structural analyses, and in vivo protection experiments to evaluate their binding and neutralizing capabilities against SARS-CoV-2 and its VOCs. Despite their rarity, antibodies were isolated for all 7 coldspots in S2. Notably, neutralizing mAbs targeting the fusion peptide (FP) cross-reacted with Orthocoronavirinae of all four genera, whereas mAbs to the stem helix preceding the heptad repeat 2 (HR2) region demonstrated neutralizing capacity across all SARS-CoV-2 variants described to date.
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  • English
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Medicine
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green
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https://n2t.net/ark:/12658/srd1332274
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