Exploring cross-neutralizing anti-SARS-CoV-2 antibody responses among the general population

In a recent study posted to the bioRxiv* preprint server, researchers performed a molecular analysis of cross-reactive antibodies targeted against the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains among the general population.

Study: Molecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2. Image Credit: Corona Borealis Studio/Shutterstock
Study: Molecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2. Image Credit: Corona Borealis Studio/Shutterstock

Background

As SARS-CoV-2 strains continue to emerge, cross-neutralizing antibody responses are essential for the development of a universal SARS-CoV-2 vaccine that would neutralize the antigenically distinct SARS-CoV-2 strains with high potency.

Studies have reported that IGHV2-5/IGLV2-14 (immunoglobulin heavy chain variable region 2-5/ immunoglobulin lambda variable cluster 2-14)-encoded RBD antibodies have a wide breadth of SARS-CoV-2 neutralization and can even neutralize Omicron and its sublineages. The antibodies are a general population antibody clonotype and therefore, they underpin the rationale and scheme for the development of a more universal coronavirus disease 2019 (COVID-19) vaccine.

The representative monoclonal antibody of the authors for the present study was the IGHV2-5/IGLV2-14 -encoded LY-CoV1404 (Bebtelovimab) which has demonstrated cross-neutralization potency against all SARS-CoV-2 strains including Omicron and its sublineages.

About the study

In the present study, researchers elucidated the molecular basis for the development of heterogeneous cross-reactive RBD antibodies against SARS-CoV-2 and the mechanistic basis for their allelic preferences among the general population.

The titers of 11 IGHV2-5/IGLV2-14-encoded-RBD antibodies from a minimum of seven donor individuals were assessed. A structural analysis was performed to uncover the sequence determinants of IGHV2- 75 5/IGLV2-14-encoded antibodies for engagement of RBD. The team also assessed the somatic hypermutations (SHMs) in the IGHV2-5/IGLV2-14-encoded antibodies.

In addition, sequence analysis was performed to determine the allelic preferences of the antibodies and the mechanistic basis for the allelic preferences was elucidated. Further, the complementarity-determining region (CDR) H3 sequences of the IGHV2-5/IGLV2-14-encoded antibodies were analyzed and further subjected to an IgBlast analysis. The B lymphocyte repertoires among the healthy donor individuals were also assessed.  

Results

The structural analysis showed that all the IGHV2-5/IGLV2-14-encoded antibodies demonstrated the same RBD binding mode. The majority of the paratope’s amino acid side chains were germline-encoded and formed the key RBD interactions. For e.g., the germline-encoded VH S32 of the CDR H1 was inserted into a polar pocket within the RBD.

The germline-encoded VH Y52, R58, D54, and D56 of the CDR H2 assembled into an elaborate network of hydrogen (H)-bonds with electrostatic RBD interactions. Further, two main paratope residues of the light chain VL viz. Y91 and Y32 also demonstrated germline-encoding. This indicated that the determinants of RBD-binding were encoded within the germline sequences of IGLV2-14 and IGHV2-5.

Many IGHV2-5/IGLV2-14-encoded antibodies possessed only a few SHMs, for e.g., S24-223 had one SHM only, whereas COV2-2268 had only four SHMs. Notably, the SHMs did not demonstrate overlapping.

The sequence analysis showed that IGHV2-5/IGLV2-14-encoded antibodies preferred the IGHV2-5*02 allele. Out of 11 IGHV2-5/IGLV2-14-encoded antibodies, eight were assigned to IGHV2-5*02, while the allelic preference of the remaining three antibodies was not clear. The IGHV2-5*02 allele preference of the antibodies was due to an allelic polymorphism at the amino-acid residue 54 of IGHV2-5, which was located at the paratope.

B lymphocyte repertoire analysis among 13 healthy donor individuals showed high frequencies of use of the IGHV2-5*01 and IGHV2-5*02 allele usage, which were 33% and 64%, respectively, by the IGHV2-5 RBD antibodies. Out of nine IGHV2-5/IGLV2-14-encoded antibodies, eight demonstrated aspartic acid (Asp) at VH residue 54, while the remaining one demonstrated glutamic acid (Glu) at VH residue 54. The observations provide a mechanistic explanation for the IGHV2-5*01 allele preference, despite its prevalence among the general population. As a coincidence, a similar finding was noted for the IGHV2-5-encoded human immunodeficiency virus (HIV) antibody, in which VH D54 demonstrated a more robust binding than VH N54.

In the CH3 sequence analysis, out of 10, eight IGHV2-5/IGLV2-14-encoded antibodies preferred a CDR H3 length of 11 amino acids and shared the HxIxxI motif or its HxVxxI and HxIxxL variants. The HxIxxI motif comprised VH I100, H95, and I97, and was not commonly observed in the CDR H3 sequences of IGHV2-5-encoded RBD antibodies among the B lymphocyte repertoires. VH I100, H95, and I97 of the HxIxxI motif were necessary to stabilize the RBD binding and loop-type conformations.

The IgBlast analysis showed that the conserved HxIxxI motif was mainly encoded by the addition of N-nucleotide, although VH I97 was also encoded by the immunoglobulin heavy constant delta (IGHD) gene. Notably, although the CDR H3 of XG005 comprised 12 amino acids, it adopted an 11-amino-acid conformation. The findings indicate that IGHV2-5/IGLV2-14-encoded antibodies with an 11-amino acid-CDR H3 length possessed converging CDR H3 sequences, and therefore, could be categorized as a clonotype of the general population.

The healthy donor 112 was most probably IGHV2-5*01 homozygous as 94% of the donor’s IGHV2-5-encoded RBD antibodies had been assigned to IGHV2-5*01. Furthermore, the conserved HxIxxI motif within the CDR H3 of the IGHV2-5/IGLV2-14-encoded antibodies was largely encoded by the addition of N-nucleotide, which explains the comparative rarity of the IGHV2-5/IGLV2-14-encoded antibody producing-B lymphocyte germline clones. The findings justify the genetic heterogenicity of the neutralizing antibody responses against SARS-CoV-2 strains among different individuals.

Overall, the study findings showed that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes all SARS-COV-2 strains to date, including Omicron and its sublineages.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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