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Background <p>The ongoing emergence of evolving SARS-CoV-2 variants poses great threaten to the efficacy of authorized monoclonal antibody-based passive immunization or treatments. Developing potent broadly neutralizing antibodies (bNabs) against SARS-CoV-2 and elucidating their potential evolutionary pathways are essential for battling the coronavirus disease 2019 (COVID-19) pandemic.</p> Methods <p>Broadly neutralizing antibodies were isolated using single cell sorting from three COVID-19 convalescents infected with prototype SARS-CoV-2 strain. Their neutralizing activity against diverse SARS-CoV-2 strains were tested in vitro and in vivo<i>,</i> respectively. The structures of antibody-antigen complexes were resolved using crystallization or Cryo-EM method. Antibodyomics analyses were performed using the non-bias deep sequencing results of BCR repertoires.</p> Results <p>We obtained a series of RBD-specific monoclonal antibodies with highly neutralizing potency against a variety of pseudotyped and live SARS-CoV-2 variants, including five global VOCs and some Omicron subtypes such as BA.1, BA.2, BA.4/5, BF.7, and XBB. 2YYQH9 and LQLD6HL antibody cocktail also displayed good therapeutic and prophylactic efficacy in an XBB.1.16 infected hamster animal model. Cryo-EM and crystal structural analyses revealed that broadly neutralizing antibodies directly blocked the binding of ACE2 by almost covering the entire receptor binding motif (RBM) and largely avoided mutated RBD residues in the VOCs, demonstrating their broad and potent neutralizing activity. In addition, antibodyomics assays indicate that the germline frequencies of RBD-specific antibodies increase after an inactivated vaccine immunization. Moreover, the CDR3 frequencies of V<sub>κ/λ</sub> presenting high amino acid identity with the broadly neutralizing antibodies were higher than those of V<sub>H</sub>.</p> Conclusions <p>These data suggest that current identified broadly neutralizing antibodies could serve as promising drug candidates for COVID-19 and can be used for reverse vaccine design against future pandemics.</p>

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Function and structure of broadly neutralizing antibodies against SARS-CoV-2 Omicron variants isolated from prototype strain infected convalescents

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月21日

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  • Dan Li,
  • Caiqin Hu,
  • Junwei Su,
  • Shuo Du,
  • Ying Zhang,
  • Wanqi Ni,
  • Li Ren,
  • Yanling Hao,
  • Yi Feng,
  • Changzhong Jin,
  • Shuo Wang,
  • Xinxian Dai,
  • Zheng Wang,
  • Biao Zhu,
  • Junyu Xiao,
  • Yiming Shao

摘要

Background

The ongoing emergence of evolving SARS-CoV-2 variants poses great threaten to the efficacy of authorized monoclonal antibody-based passive immunization or treatments. Developing potent broadly neutralizing antibodies (bNabs) against SARS-CoV-2 and elucidating their potential evolutionary pathways are essential for battling the coronavirus disease 2019 (COVID-19) pandemic.

Methods

Broadly neutralizing antibodies were isolated using single cell sorting from three COVID-19 convalescents infected with prototype SARS-CoV-2 strain. Their neutralizing activity against diverse SARS-CoV-2 strains were tested in vitro and in vivo, respectively. The structures of antibody-antigen complexes were resolved using crystallization or Cryo-EM method. Antibodyomics analyses were performed using the non-bias deep sequencing results of BCR repertoires.

Results

We obtained a series of RBD-specific monoclonal antibodies with highly neutralizing potency against a variety of pseudotyped and live SARS-CoV-2 variants, including five global VOCs and some Omicron subtypes such as BA.1, BA.2, BA.4/5, BF.7, and XBB. 2YYQH9 and LQLD6HL antibody cocktail also displayed good therapeutic and prophylactic efficacy in an XBB.1.16 infected hamster animal model. Cryo-EM and crystal structural analyses revealed that broadly neutralizing antibodies directly blocked the binding of ACE2 by almost covering the entire receptor binding motif (RBM) and largely avoided mutated RBD residues in the VOCs, demonstrating their broad and potent neutralizing activity. In addition, antibodyomics assays indicate that the germline frequencies of RBD-specific antibodies increase after an inactivated vaccine immunization. Moreover, the CDR3 frequencies of Vκ/λ presenting high amino acid identity with the broadly neutralizing antibodies were higher than those of VH.

Conclusions

These data suggest that current identified broadly neutralizing antibodies could serve as promising drug candidates for COVID-19 and can be used for reverse vaccine design against future pandemics.