https://orcid.org/0000-0002-3964-1740
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ABSTRACT
Neutralizing antibodies are a key component in protective humoral immunity against SARS-CoV-2. Currently, available technologies cannot track epitope-specific antibodies in global antibody repertoires. Thus, the comprehensive repertoire of spike-specific neutralizing antibodies elicited by SARS-CoV-2 infection is not fully understood. We therefore combined high-throughput immunoglobulin heavy chain (IgH) repertoire sequencing, and structural and bioinformatics analysis to establish an antibodyomics pipeline, which enables tracking spike-specific antibody lineages that target certain neutralizing epitopes. We mapped the neutralizing epitopes on the spike and determined the epitope-preferential antibody lineages. This analysis also revealed numerous overlaps between immunodominant neutralizing antibody-binding sites and mutation hotspots on spikes as observed so far in SARS-CoV-2 variants. By clustering 2677 spike-specific antibodies with 360 million IgH sequences that we sequenced, a total of 329 shared spike-specific antibody clonotypes were identified from 33 COVID-19 convalescents and 24 SARS-CoV-2-naïve individuals. Epitope mapping showed that the shared antibody responses target not only neutralizing epitopes on RBD and NTD but also non-neutralizing epitopes on S2. The immunodominance of neutralizing antibody response is determined by the occurrence of specific precursors in human naïve B-cell repertoires. We identified that only 28 out of the 329 shared spike-specific antibody clonotypes persisted for at least 12 months. Among them, long-lived IGHV3-53 antibodies are likely to evolve cross-reactivity to Omicron variants through accumulating somatic hypermutations. Altogether, we created a comprehensive atlas of spike-targeting antibody lineages in COVID-19 convalescents and antibody precursors in human naïve B cell repertoires, providing a valuable reference for future vaccine design and evaluation.
Acknowledgments
This work supported by grants from National Natural Science Foundation of China (82201932, 92269201, 61971187, 32170941). China Postdoctoral Science Foundation (2022M710891), State Key Laboratory of Respiratory Disease (SKLRD-Z-202324). Guangzhou Science and Technology Bureau (Jointly funded by Municipal Schools and Colleges, 2060206-202201020428).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Competing interests
Author Wenjing Pan and Congli Tang are employed by Nanjing ARP Biotechnology Co. Ltd, Nanjing, China. Author Jian Han is employed by iRepertoire Inc., Huntsville, USA. The other authors declare no competing interests.
Data availability
The data that support this study are available from the corresponding authors upon reasonable request. Raw IgH sequences generated in this study have been deposited at the National Genomics Data Center (https://bigd.big.ac.cn/) under accession number PRJCA003775.