Combined anti-S1 and anti-S2 antibodies from hybrid immunity elicit potent cross-variant ADCC against SARS-CoV-2
Michael D. Grant, Kirsten Bentley, Ceri A. Fielding, Keeley M. Hatfield, Danielle P. Ings, Debbie Harnum, Eddie C.Y. Wang, Richard J. Stanton, Kayla A. Holder
Michael D. Grant, Kirsten Bentley, Ceri A. Fielding, Keeley M. Hatfield, Danielle P. Ings, Debbie Harnum, Eddie C.Y. Wang, Richard J. Stanton, Kayla A. Holder
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Research Article Immunology Vaccines

Combined anti-S1 and anti-S2 antibodies from hybrid immunity elicit potent cross-variant ADCC against SARS-CoV-2

Abstract

Antibodies capable of neutralizing SARS-CoV-2 are well studied, but Fc receptor–dependent antibody activities that can also significantly impact the course of infection have not been studied in such depth. Since most SARS-CoV-2 vaccines induce only anti-spike antibodies, here we investigated spike-specific antibody-dependent cellular cytotoxicity (ADCC). Vaccination produced antibodies that weakly induced ADCC; however, antibodies from individuals who were infected prior to vaccination (hybrid immunity) elicited strong anti-spike ADCC. Quantitative and qualitative aspects of humoral immunity contributed to this capability, with infection skewing IgG antibody production toward S2, vaccination skewing toward S1, and hybrid immunity evoking strong responses against both domains. A combination of antibodies targeting both spike domains support strong antibody-dependent NK cell activation, with 3 regions of antibody reactivity outside the receptor-binding domain (RBD) corresponding with potent anti-spike ADCC. Consequently, ADCC induced by hybrid immunity with ancestral antigen was conserved against variants containing neutralization escape mutations in the RBD. Induction of antibodies recognizing a broad range of spike epitopes and eliciting strong and durable ADCC may partially explain why hybrid immunity provides superior protection against infection and disease compared with vaccination alone, and it demonstrates that spike-only subunit vaccines would benefit from strategies that induce combined anti-S1 and anti-S2 antibody responses.

Authors

Michael D. Grant, Kirsten Bentley, Ceri A. Fielding, Keeley M. Hatfield, Danielle P. Ings, Debbie Harnum, Eddie C.Y. Wang, Richard J. Stanton, Kayla A. Holder

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Figure 6

Peptide scanning to identify distinct linear regions associated with robust ADCC.

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Peptide scanning to identify distinct linear regions associated with rob...
Linear FLS Ab epitope reactivity was determined by ELISA-based peptide scanning. (A) A representative depiction of anti-IgG Ab reactive to linear segments is illustrated by an overlaid line graph. The blue line represents OD results of the full S peptide scan of a sample collected from 1 participant recovered from moderate COVID-19 infection, and the orange overlay represents a sample from the same participant collected 1 month after their first vaccination. (B) Compiled peptide scan data from samples collected from 7 participants postinfection (PI) and after hybrid immunity (H) were illustrated using a heatmap and aligned with known mutations in Delta and Omicron sequences. Three determinants associated with ADCC are identified by asterisks. (C) The left axis depicts anti–S1 CDT1/2 (triangle), –S1 CTD2 (circle), and anti–S2 CD (square) IgG Ab OD and compares these levels with ADCC (right axis) for 2 participants after infection (open black bar) and after subsequent vaccination (open red bar). (D and E) Participant IgG Ab OD collected from peptide scanning (n = 30) were scored for number of distinct regions or tallied, and associations between Ab reactivity and levels of ADCC were assessed by Spearman’s correlation.