Shared IGHV1-69-encoded neutralizing antibodies contribute to the emergence of L452R substitution in SARS-CoV-2 variants

Abstract

SARS-CoV-2 variants continue to emerge facing established herd immunity. L452R, previously featured in the Delta variant, quickly emerged in Omicron subvariants, including BA.4/BA.5, implying a continued selection pressure on this residue. The underlying links between spike mutations and their selective pressures remain incompletely understood. Here, by analyzing 221 structurally characterized antibodies, we found that IGHV1-69-encoded antibodies preferentially contact L452 using germline-encoded hydrophobic residues at the tip of HCDR2 loop. Whereas somatic hypermutations or VDJ rearrangements are required to acquire L452-contacting hydrophobic residues for non-IGHV1-69 encoded antibodies. Antibody repertoire analysis revealed that IGHV1-69 L452-contacting antibody lineages are commonly induced among COVID-19 convalescents but non-IGHV1-69 encoded antibodies exhibit limited prevalence. In addition, we experimentally demonstrated that L452R renders most published IGHV1-69 antibodies ineffective. Furthermore, we found that IGHV1-69 L452-contacting antibodies are enriched in convalescents experienced Omicron BA.1 (without L452R) breakthrough infections but rarely found in Delta (with L452R) breakthrough infections. Taken together, these findings support that IGHV1-69 population antibodies contribute to selection pressure for L452 substitution. This study thus provides a better understanding of SARS-CoV-2 variant genesis and immune evasion.

Somatically hypermutated antibodies isolated from SARS-CoV-2 Delta infected patients cross-neutralize heterologous variants

“…7). In particular, we note that the VH1-69 "HCDR2 epitope", a hydrophobic patch in RBD formed by L452, F490 and L492 previously noted by us 10,36 , is contacted by SHM introduced "up" RBD "up" RBD "up" RBD "down" RBD "down" RBD "down" RBD "down" RBD "down" RBD "down" RBD "down" RBD "down" RBD "down" RBD "up" RBD "up" RBD "up" RBD "up" RBD "up" RBD "up" RBD "up" RBD "up" RBD "up" RBD S30G S30G S30G S30I of HCDR1, 55I ins and 56L ins of HCDR2 (Fig. 4b).…”

“…Among these, Sheward et al reported a VH3-53 antibody with different CDRs from YB9-258 likely to withstand Omicron variants by a different molecular mechanism 54 . It has been reported that Omicron BA.1 resistant VH3-53/ VH3-66 and VH1-69 antibodies are recalled in Omicron BA.1 breakthrough infections 12,16,36 . Isolation of Omicron resistant VH3-53 and related VH3-66 antibodies YB12-197 and YB9-258 in this study shown in colors and 47D1 is shown in gray.…”

“…4c). In humans, germline IGHV1-69 genes are the only genes with a hydrophobic HCDR2 tip 36 . Hydrophobic HCDR2 loops have been shown to be probably the most important feature for VH1-69 antibodies, implicated in immunity against diverse viral pathogens 38 .…”

“…10). Both RBD residues 452 and 490 are known mutation hot spots 10,21,36 , suggesting that antibodies recognizing this epitope pose strong immune pressure towards SARS-CoV-2. L452R featured in the Delta variant was shown to escape VH1-69 antibody LY-CoV555 targeting a similar epitope as YB13-292 39 .…”

Transcriptional Profiles Analysis of COVID-19 and Malaria Patients Reveals Potential Biomarkers in Children

“…Among the top highly expressed genes, we found some small nuclear and long noncoding RNAs such as RN7SKP255, RN7SK, that are known to play a role in macrophage differentiation, polarization, and innate immune functions [32, 33]. IGHV1-69-2 gene encoding the Immunoglobulin heavy variable was also found among the top expressed genes alongside H2BP2, an extrachromosomal histone that stimulates innate and acquired immune defenses in different cells upon detection of double-stranded DNA (dsDNA) fragments derived from infectious agents or damaged cells [34, 35].…”