Antibody-dependent cellular cytotoxicity against SARS-CoV-2 Omicron sub-lineages is reduced in convalescent sera regardless of infecting variant

Cell Rep Med. 2023 Jan 17;4(1):100910. doi: 10.1016/j.xcrm.2022.100910. Epub 2022 Dec 22.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4 and BA.5 variants caused major waves of infections. Here, we assess the sensitivity of BA.4 to binding, neutralization, and antibody-dependent cellular cytotoxicity (ADCC) potential, measured by FcγRIIIa signaling, in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high-level neutralization resistance regardless of the infecting variant. However, BTIs retain activity against BA.4, albeit at reduced titers. BA.4 sensitivity to ADCC is reduced compared with other variants but with smaller fold losses compared with neutralization and similar patterns of cross-reactivity. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infection, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC potential against BA.4 is reduced, residual activity may contribute to observed protection from severe disease.

Keywords: COVID-19; Fc effector function; Omicron BA.4; SARS-CoV-2; VOC; antibody-dependent cellular cytotoxicity; breakthrough infection; neutralization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies
  • Antibody-Dependent Cell Cytotoxicity*
  • Breakthrough Infections
  • COVID-19 / immunology
  • COVID-19 / therapy
  • COVID-19 Serotherapy*
  • Humans
  • SARS-CoV-2* / immunology


  • Antibodies