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Detection of SARS-CoV-2 Neutralizing Antibodies using High-Throughput Fluorescent Imaging of Pseudovirus Infection
Published on: June 5, 2021
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Retrospective SARS-CoV-2 human antibody development trajectories are largely sparse and permissive
Monica B Kirby1, Brian M Petersen1, Jonathan G Faris1
1Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO 80305.
Summary
Human antibody development pathways for SARS-CoV-2 Spike antibodies involve few mutations that significantly alter binding affinity. These mutations can occur in any order, with precursors needing only a slight affinity advantage to dominate the immune response.
Area of Science:
- Immunology
- Molecular Biology
- Computational Biology
Background:
- Humoral immune responses, crucial for vaccines, rely on antibody development against novel antigens.
- While broadly neutralizing antibody (bnAb) development is studied, human subtype-specific antibody precursor trajectories remain less understood.
Purpose of the Study:
- To investigate the retrospective development pathways of eight human anti-SARS-CoV-2 Spike antibodies.
- To understand how mutations influence antibody affinity and the order of these changes during maturation.
Main Methods:
- Deep mutational scanning of anti-S1 molecular antibody fragments (Fabs) using yeast display and fluorescence-activated cell sorting.
- Analysis of mutation effects on monovalent binding dissociation constants (kd).
- Adaptation of a coarse-grained affinity maturation model to simulate germinal center (GC) selection dynamics.
Main Results:
- Human antibody development pathways typically involve few mutations that significantly alter binding affinity (kd).
- Mutations conferring affinity changes can occur in nearly any order during maturation.
- Broadly neutralizing antibodies (bnAbs) require more maturation steps on average than subtype-specific antibodies to reach similar affinities.
- Subtype-specific antibodies often possess inherent antigen affinity, a finding robust across inferred precursor sequences.
- Computational modeling demonstrated that antibody precursors with even minimal affinity advantages rapidly outcompete others in GC selection.
Conclusions:
- Antibody affinity maturation is characterized by a limited number of key mutations that can be acquired in flexible orders.
- The initial affinity of antibody precursors plays a critical role in determining the dominant clonotype during germinal center selection.
- These findings provide insights into the development of effective antibody responses, relevant for vaccine design and therapeutic antibody development.
