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<p>Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 receptor-binding domain are used to treat and prevent COVID-19. However, the rapid evolution of SARS-CoV-2 drives continuous escape from therapeutic mAbs. Therefore, the ability to identify broadly neutralizing antibodies (bnAbs) to future variants is needed. Here we use deep mutational scanning to predict viral receptor-binding domain evolution and to select for mAbs neutralizing both existing and prospective variants. A retrospective analysis of 1,103 SARS-CoV-2 wild-type-elicited mAbs shows that this method can increase the probability of identifying effective bnAbs to the XBB.1.5 strain from 1% to 40% in an early pandemic set-up. Among these bnAbs, BD55-1205 showed potent activity to all tested variants. Cryogenic electron microscopy structural analyses revealed the receptor mimicry of BD55-1205, explaining its broad reactivity. Delivery of mRNA–lipid nanoparticles encoding BD55-1205-IgG in mice resulted in serum half-maximal neutralizing antibody titre values of ~5,000 to XBB.1.5, HK.3.1 and JN.1 variants. Combining bnAb identification using viral evolution prediction with the versatility of mRNA delivery technology can enable rapid development of next-generation antibody-based countermeasures against SARS-CoV-2 and potentially other pathogens with pandemic potential.</p>

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Viral evolution prediction identifies broadly neutralizing antibodies to existing and prospective SARS-CoV-2 variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月10日

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  • Fanchong Jian,
  • Anna Z. Wec,
  • Leilei Feng,
  • Yuanling Yu,
  • Lei Wang,
  • Peng Wang,
  • Lingling Yu,
  • Jing Wang,
  • Jacob Hou,
  • Daniela Montes Berrueta,
  • Diana Lee,
  • Tessa Speidel,
  • LingZhi Ma,
  • Thu Kim,
  • Ayijiang Yisimayi,
  • Weiliang Song,
  • Jing Wang,
  • Lu Liu,
  • Sijie Yang,
  • Xiao Niu,
  • Tianhe Xiao,
  • Ran An,
  • Yao Wang,
  • Fei Shao,
  • Youchun Wang,
  • Simone Pecetta,
  • Xiangxi Wang,
  • Laura M. Walker,
  • Yunlong Cao

摘要

Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 receptor-binding domain are used to treat and prevent COVID-19. However, the rapid evolution of SARS-CoV-2 drives continuous escape from therapeutic mAbs. Therefore, the ability to identify broadly neutralizing antibodies (bnAbs) to future variants is needed. Here we use deep mutational scanning to predict viral receptor-binding domain evolution and to select for mAbs neutralizing both existing and prospective variants. A retrospective analysis of 1,103 SARS-CoV-2 wild-type-elicited mAbs shows that this method can increase the probability of identifying effective bnAbs to the XBB.1.5 strain from 1% to 40% in an early pandemic set-up. Among these bnAbs, BD55-1205 showed potent activity to all tested variants. Cryogenic electron microscopy structural analyses revealed the receptor mimicry of BD55-1205, explaining its broad reactivity. Delivery of mRNA–lipid nanoparticles encoding BD55-1205-IgG in mice resulted in serum half-maximal neutralizing antibody titre values of ~5,000 to XBB.1.5, HK.3.1 and JN.1 variants. Combining bnAb identification using viral evolution prediction with the versatility of mRNA delivery technology can enable rapid development of next-generation antibody-based countermeasures against SARS-CoV-2 and potentially other pathogens with pandemic potential.