Broadly cross-reactive human antibodies that inhibit genogroup I and II noroviruses

Gabriela Alvarado, Wilhelm Salmen, Khalil Ettayebi, Liya Hu, Banumathi Sankaran, Mary K. Estes, B. V. Venkataram Prasad () and James E. Crowe ()
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Gabriela Alvarado: Vanderbilt University Medical Center
Wilhelm Salmen: Baylor College of Medicine
Khalil Ettayebi: Baylor College of Medicine
Liya Hu: The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine
Banumathi Sankaran: Berkeley Center for Structural Biology, Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley Laboratory
Mary K. Estes: Baylor College of Medicine
B. V. Venkataram Prasad: Baylor College of Medicine
James E. Crowe: Vanderbilt University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract The rational development of norovirus vaccine candidates requires a deep understanding of the antigenic diversity and mechanisms of neutralization of the virus. Here, we isolate and characterize a panel of broadly cross-reactive naturally occurring human monoclonal IgMs, IgAs and IgGs reactive with human norovirus (HuNoV) genogroup I or II (GI or GII). We note three binding patterns and identify monoclonal antibodies (mAbs) that neutralize at least one GI or GII HuNoV strain when using a histo-blood group antigen (HBGA) blocking assay. The HBGA blocking assay and a virus neutralization assay using human intestinal enteroids reveal that the GII-specific mAb NORO-320, mediates HBGA blocking and neutralization of multiple GII genotypes. The Fab form of NORO-320 neutralizes GII.4 infection more potently than the mAb, however, does not block HBGA binding. The crystal structure of NORO-320 Fab in complex with GII.4 P-domain shows that the antibody recognizes a highly conserved region in the P-domain distant from the HBGA binding site. Dynamic light scattering analysis of GII.4 virus-like particles with mAb NORO-320 shows severe aggregation, suggesting neutralization is by steric hindrance caused by multivalent cross-linking. Aggregation was not observed with the Fab form of NORO-320, suggesting that this clone also has additional inhibitory features.

Date: 2021
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DOI: 10.1038/s41467-021-24649-w

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