Cross-Reactive SARS-CoV-2 Neutralizing Antibodies From Deep Mining of Early Patient Responses

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• Passive immunization with monoclonal antibodies is crucial for COVID-19 treatment.
• Emerging SARS-CoV-2 variants exhibit reduced sensitivity to existing antibodies and vaccines, necessitating broad cross-reactivity.
• Understanding the early antibody response is key to developing effective countermeasures.

Purpose of the Study:

• To identify potent neutralizing antibodies against SARS-CoV-2 with broad cross-reactivity.
• To investigate the early antibody response in hospitalized COVID-19 patients.
• To characterize novel antibody binding epitopes, including those conserved across SARS-CoV and SARS-CoV-2 variants.

Main Methods:

• Deep-mining of antibody repertoires using phage display technology.
• B cell receptor (BCR) repertoire sequencing for comprehensive immune profiling.
• Structural determination of isolated neutralizing antibodies to identify binding epitopes.

Main Results:

• A panel of potent neutralizing antibodies was isolated, binding distinct viral epitopes.
• One antibody targets a novel epitope, conserved across SARS-CoV-1 and resistant to mutations in major SARS-CoV-2 variants (B.1.1.7, B.1.351, B.1.1.28).
• Analysis revealed a highly convergent early antibody response, with similar IgM-derived sequences observed across multiple studies.

Conclusions:

• The identified neutralizing antibodies offer a promising therapeutic strategy against current and future SARS-CoV-2 variants.
• The study provides critical insights into the early humoral immune response to SARS-CoV-2 infection.
• Characterization of conserved epitopes facilitates the design of broadly protective antibody-based interventions.