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In Vivo Evolution of Antibody CR3022 Expands Cross-Neutralization of SARS-CoV-2 Variants and Informs Pan-sarbecovirus Immunity

ABSTRACT: Monoclonal antibody CR3022, isolated from a patient infected during the 2003 SARS-CoV outbreak, shows cross-reactive binding and, with targeted mutagenesis, neutralization of SARS-CoV-2. These findings suggest that targeting the CR3022 epitope may be a promising candidate for broadly protecting against a wide range of coronavirus variants and zoonotic strains that may pose future pandemic threats. However, it is unclear how readily and broadly this epitope can be adapted against variant coronavirus strains in vivo. To address this issue, we generated immunoglobulin (Ig)-humanized mice expressing the predicted germline heavy chain of CR3022 for a direct evaluation of the epitopes’ in vivo adaptation potential. Following a SARS-CoV/SARS-CoV-2 sequential immunization regimen, we observed the convergent evolution of the germline CR3022 variable gene through somatic hypermutation to resemble that of the mutated WT counterpart. Most CR3022-like clones acquired cross-neutralizing activity against SARS-CoV-2, plus adaptation against key variants and more divergent Sarbecovirus strains. Notably, while simple prime-boost strategies drove CR3022-epitope targeting, an intensive vaccination protocol drove dominant responses to other epitopes even with a predominance of CR3022-like precursors. X-ray crystallography revealed that SARS-CoV-2-neutralizing CR3022 antibodies readily exhibited enhanced affinity due to varied adaptive changes, resulting in significantly increased electrostatic interactions with the receptor-binding domain (RBD). Overall, these findings show ready adaptation of CR3022-like clones by minor shifts in affinity with appropriate vaccination strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE304367 | GEO | 2026/02/18

REPOSITORIES: GEO

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Project description:Next-generation T-cell-directed vaccines for COVID-19 aim to induce durable T-cell immunity against circulating and future hypermutated SARS-CoV-2 variants. Mass Spectrometry (MS)based immunopeptidomics holds promise for guiding vaccine design, but computational challenges impede the precise and unbiased identification of conserved T-cell epitopes crucial for vaccines against rapidly mutating viruses. We introduce a computational framework and analysis platform integrating a novel machine learning algorithm, immunopeptidomics, intra-host data, epitope immunogenicity, and geo-temporal CD8+ T-cell epitope conservation analyses. Central to our approach is MHCvalidator, a novel artificial neural network algorithm enhancing MS-based immunopeptidomics sensitivity by modeling antigen presentation and sequence features. MHCvalidator identified a novel nonconventional SARS-CoV-2 T-cell epitope presented by B7 supertype molecules, originating from a +1-frameshift in a truncated Spike (S) antigen, supported by ribo-seq data. Intra-host analysis of SARS-CoV-2 proteomes from ~100,000 COVID-19 patients revealed a prevalent S antigen truncation in ~51% of cases, exposing a rich source of frameshifted viral antigens. Our framework includes EpiTrack, a new computational pipeline tracking global mutational dynamics of MHCvalidator-identified SARS-CoV-2 CD8+ epitopes from vaccine BNT162b4. While most vaccine-encoded CD8+ epitopes exhibit global conservation from January 2020 to October 2023, a highly immunodominant A*01-associated epitope, especially in hospitalized patients, undergoes substantial mutations in Delta and Omicron variants. Our approach unveils unprecedented SARS-CoV-2 T-cell epitopes, elucidates novel antigenic features, and underscores mutational dynamics of vaccine-relevant epitopes. The analysis platform is applicable to any viruses, and underscores the need for continual vigilance in T-cell vaccine development against the evolving landscape of hypermutating SARS-CoV-2 variants.

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In Vivo Evolution of Antibody CR3022 Expands Cross-Neutralization of SARS-CoV-2 Variants and Informs Pan-sarbecovirus Immunity

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