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

Georgia Bullen,Deividas Pazeraitis,Wing-Yiu Jason Lee,Kovilen Sawmynaden,Lien Moreels,Sandra Ergueta-Carballo,Mark D Carr,Edward W Masters,Richard Cowan,Giada Mattiuzzo,Jane Osbourn,Simon E Hufton,Claire Tebbutt,John Mccafferty,David Tang,Ioannis Diamantopoulos,Omodele Ashiru,Lucia Crippa,Sophie Millett,Paul Pfeffer,Line Ledsgaard,Krishna Chaitanya,Matthew W Bowler,Danielle Tongue,Jacob D Galson,Kothai Parthiban,Emma Bentley ,Pedro Caballero Villar ,David J Matthews ,G G Hall ,Jamie I D Campbell ,R H Brown ,Rachael A Leah ,Sachin Surade ,Aneesh Karatt-­Vellatt

doi:10.3389/fimmu.2021.678570

Abstract

Passive immunization using monoclonal antibodies will play a vital role in the fight against COVID-19. The recent emergence of viral variants with reduced sensitivity to some current antibodies and vaccines highlights the importance of broad cross-reactivity. This study describes deep-mining of the antibody repertoires of hospitalized COVID-19 patients using phage display technology and B cell receptor (BCR) repertoire sequencing to isolate neutralizing antibodies and gain insights into the early antibody response. This comprehensive discovery approach has yielded a panel of potent neutralizing antibodies which bind distinct viral epitopes including epitopes conserved in SARS-CoV-1. Structural determination of a non-ACE2 receptor blocking antibody reveals a previously undescribed binding epitope, which is unlikely to be affected by the mutations in any of the recently reported major viral variants including B.1.1.7 (from the UK), B.1.351 (from South Africa) and B.1.1.28 (from Brazil). Finally, by combining sequences of the RBD binding and neutralizing antibodies with the B cell receptor repertoire sequencing, we also describe a highly convergent early antibody response. Similar IgM-derived sequences occur within this study group and also within patient responses described by multiple independent studies published previously.

Highlights

In the past two decades, three major virus outbreaks caused by coronaviruses have emerged
In order to link sequence data to information on binding properties, variable heavy chain (VH) populations from these donors were incorporated into phage display libraries in the form of single chain variable fragments
By one approach we constructed hybrid libraries where the variable heavy (VH) genes from the patient IgG repertoire were combined with a pre-existing library of variable light (VL) genes derived from healthy donors [6]

Summary

Introduction

In the past two decades, three major virus outbreaks caused by coronaviruses have emerged. The latest, COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has resulted in a pandemic with over 153 million people infected and causing over 3.2 million deaths. The majority of drug development efforts have been focused on vaccine development, with 93 and. Despite the accelerated development timeframes and regulatory approval of the leading vaccine candidates, the world is still one or two years away from attaining population immunity due to the manufacturing and logistical challenges of mass vaccinating billions of people. Monoclonal antibodies have potential as a key component in the early fight against COVID-19. Viral neutralizing antibodies can offer a twoin-one approach, being used both to treat symptomatic individuals following acute exposure, and as a prophylactic to protect healthcare workers and at-risk groups, including individuals who respond poorly to vaccines

Methods

Results

Conclusion