Potent Omicron-neutralizing antibodies isolated from a patient vaccinated 6 months before Omicron emergence

• Published in: Cell reports (Cambridge) Vol. 42; no. 5; p. 112421
• Main Authors: Hastie, Kathryn M., Yu, Xiaoying, Ana-Sosa-Batiz, Fernanda, Zyla, Dawid S., Harkins, Stephanie S., Hariharan, Chitra, Wasserman, Hal, Zandonatti, Michelle A., Miller, Robyn, Maule, Erin, Kim, Kenneth, Valentine, Kristen M., Shresta, Sujan, Saphire, Erica Ollmann
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.05.2023; Elsevier; The Author(s)
• Subjects: Animals; antibodies; Antibodies, Neutralizing; Antibodies, Viral - therapeutic use; bivalent antibody binding; Broadly Neutralizing Antibodies; coronavirus; COVID-19; CP: Immunology; CP: Microbiology; cryo-EM; Mice; neutralization; Omicron; SARS-CoV-2; COVID-19; CP: Immunology; SARS-CoV-2; neutralization; CP: Microbiology; coronavirus; antibodies; Omicron; cryo-EM; bivalent antibody binding
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112421

Therapeutic antibodies are an important tool in the arsenal against coronavirus infection. However, most antibodies developed early in the pandemic have lost most or all efficacy against newly emergent strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly those of the Omicron lineage. Here, we report the identification of a panel of vaccinee-derived antibodies that have broad-spectrum neutralization activity. Structural and biochemical characterization of the three broadest-spectrum antibodies reveal complementary footprints and differing requirements for avidity to overcome variant-associated mutations in their binding footprints. In the K18 mouse model of infection, these three antibodies exhibit protective efficacy against BA.1 and BA.2 infection. This study highlights the resilience and vulnerabilities of SARS-CoV-2 antibodies and provides road maps for further development of broad-spectrum therapeutics. [Display omitted] •Antibodies effective against Omicron lineages can be elicited by vaccination•Structural analysis demonstrates three different spike engagements•Antibodies targeting Omicron have varying requirements for avidity•mAbs show therapeutic efficacy against BA.1 and BA.2 in a mouse model Hastie et al. identify antibodies from a vaccinated subject that show broad activity against multiple Omicron lineages. Structural analysis of these mAbs illustrates different binding modes and differential dependencies on IgG avidity. These mAbs also exhibit protective efficacy in a mouse model of BA.1 and BA.2 infection.