Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus

• Published in: eLife Vol. 12
• Main Authors: Ketaren, Natalia E, Mast, Fred D, Fridy, Peter C, Olivier, Jean Paul, Sanyal, Tanmoy, Sali, Andrej, Chait, Brian T, Rout, Michael P, Aitchison, John D
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 07-05-2024; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antibodies, Viral - therapeutic use; betacoronavirus; Biochemistry and Chemical Biology; COVID-19; COVID-19 - immunology; COVID-19 - virology; Enzymes; FDA approval; Health aspects; Humans; Immune response; Immunotherapy; Infections; Infectious diseases; Microbiology and Infectious Disease; Monoclonal antibodies; Mutation; Nanobodies; neutralization; Proteins; Research Advance; SARS-CoV-2 - immunology; SARS-CoV-2 variants; Severe acute respiratory syndrome coronavirus 2; single-domain antibodies; Single-Domain Antibodies - immunology; spike; Spike Glycoprotein, Coronavirus - immunology; Spike protein; Vaccination; China; viruses; nanobodies; chemical biology; infectious disease; neutralization; betacoronavirus; biochemistry; SARS-CoV-2 variants; microbiology; single-domain antibodies; human; spike
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.89423

To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune responses generated by vaccination or exposure to previous variants poses a significant challenge. A compelling new therapeutic strategy against SARS-CoV-2 is that of single-domain antibodies, termed nanobodies, which address certain limitations of monoclonal antibodies. Here, we demonstrate that our high-affinity nanobody repertoire, generated against wild-type SARS-CoV-2 spike protein (Mast et al., 2021), remains effective against variants of concern, including omicron BA.4/BA.5; a subset is predicted to counter resistance in emerging XBB and BQ.1.1 sublineages. Furthermore, we reveal the synergistic potential of nanobody cocktails in neutralizing emerging variants. Our study highlights the power of nanobody technology as a versatile therapeutic and diagnostic tool to combat rapidly evolving infectious diseases such as SARS-CoV-2.