Ling Chen ^1,2* Linbing QU ^1* Liqiang Feng ^1* Weiqi Deng ^1,3 Xuefeng Niu ⁴ Ping He ² Qihong Yan ^1,4 Huan Liang ⁴ Yongping Wang ¹ Lishan Ning ¹ Zihan Lin ¹ Yudi Zhang ¹ Xinwei Zhao ^1,2

• ¹ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, China
• ² Guangzhou National Laboratory, Guangzhou, China
• ³ University of Chinese Academy of Sciences, Beijing, Beijing, China
• ⁴ State Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

Although immunoglobulin (Ig) alleles play a pivotal role in the antibody response to pathogens, research to understand their role in the humoral immune response is still limited. We present an allelic atlas of immunoglobulin heavy chain (IgH) variable regions, illustrating the diversity of allelic variants across 33 IGHV family germline sequences by sequencing the IgH repertoire of 130 SARS-CoV-2 infected and healthy individuals. Our comprehensive analysis of 10,643 SARS-CoV-2 spike-specific antibodies revealed the preferential use of specific Ig alleles among these antibodies.We observed an association between Ig alleles and antibody binding epitopes. Different allelic genotypes binding to the same RBD epitope on the spike show different neutralizing potency and breadth. To elucidate the effect of Ig allelic polymorphisms on the binding and neutralization of SARS-CoV-2 variants, we selected two IgH families, IGHV1-69 and IGHV2-5 antibodies, for in-depth study. We found that antibodies carrying the IGHV1-69*02 allele tended to bind to the RBD E2.2 epitope.The antibodies carrying G50 and L55 amino acid residues exhibit potential enhancements in binding affinity and neutralizing potency to SARS-CoV-2 variants containing the L452R mutation on RBD, whereas R50 and F55 amino acid residues tend to have reduced binding affinity and neutralizing potency. IGHV2-5*02 antibodies using the D56 allele bind to the RBD D2 epitope with greater binding and neutralizing potency due to the interaction between D56 on HCDR2 and K444 on RBD of most Omicron subvariants. In contrast, IGHV2-5*01 antibodies using the N56 allele show increased binding resistance to the K444T mutation on RBD. This study provides valuable insights into humoral immune responses from the perspective of Ig alleles and population genetics.