The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo. Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness. ONE SENTENCE SUMMARY Epitope-focused S2 stem-helix nanoparticle immunogens elicit protective broadly neutralizing antibodies (bnAbs) against diverse betacoronaviruses in non-human primates, establishing a framework for development of pan-betacoronavirus vaccines.
Panpan Zhou, Ziqi Feng, Wan-ting He et al.· bioRxiv· 0 citations
ABSTRACT Rapid antigenic drift of the SARS‐CoV‐2 receptor‐binding domain (RBD) underlies immune escape and continues to challenge the durability of antibody‐mediated protection. Among the major classes of RBD‐directed antibodies, germline‐encoded IGHV3‐53 responses are highly potent against early SARS‐CoV‐2 variants but are generally compromised by Omicron‐associated mutations. Here, we identify an intrinsically cross‐reactive IGHV3‐53 germline antibody that recognizes multiple pre‐Omicron variants, including SARS‐CoV‐2 wild‐type, Alpha, and Delta. Notably, we demonstrate that targeted somatic evolution can further expand this breadth to overcome the immune escape of different Omicron variants. Guided by integrated structural and sequence analyses, we introduce four somatic mutations (G26E, T28I, S53P, and Y58F) into the germline antibody, resulting in markedly enhanced binding and neutralization of Omicron BA.1, and BA.4/5. High‐resolution crystal structures reveal that these mutations re‐establish interactions disrupted by substitutions in the Omicron RBD and improve binding at a remodeled epitope interface. Collectively, our findings define the structural basis by which specific mutations enhance cross‐variant recognition of SARS‐CoV‐2. This work highlights the underappreciated breadth encoded within the naïve B‐cell repertoire and provides a conceptual framework for engineering and eliciting antibody responses resilient to future antigenic drift.
Huibin Lv, Ziqi Feng, Q. Teo et al.· Advancement of science· 0 citations
Broadly neutralizing antibodies (bnAbs) targeting conserved regions of the betacoronavirus spike are important for pan-betacoronavirus protection and pandemic preparedness. Here, we report the isolation of a human monoclonal antibody, CC65.1, from a SARS-CoV-2 convalescent donor that targets the conserved S2 stem helix region. CC65.1 neutralizes various sarbecoviruses, including SARS-CoV-2, and binds to the MERS-CoV spike but lacks MERS-CoV-neutralizing activity due to insufficient binding affinity. We utilized directed evolution to enhance the binding affinity of CC65.1 for the MERS-CoV S2 stem helix, yielding engineered antibody variants with newly acquired MERS-CoV-neutralizing activity. High-resolution structural analysis reveals key paratope mutations that enhance binding and stabilize epitope engagement. Our findings demonstrate the potential of in vitro affinity maturation to expand the neutralization breadth of stem-helix-targeting antibodies across divergent betacoronaviruses. This work supports the development of engineered bnAbs for broadly protective betacoronavirus countermeasures and provides a strategy for achieving cross-lineage neutralization.
Panpan Zhou, M. Yuan, Yue-Xiu Zhang et al.· PLoS Pathogens· 0 citations
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