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However, their antibody\u2010dependent cellular cytotoxicity (ADCC) functionality is still poorly characterized. Here, we investigated ADCC activity in convalescent sera from infected patients with wild\u2010type (WT) severe acute respiratory syndrome coronavirus\u20102 (SARS\u2010CoV\u20102) or omicron variant compared with three coronavirus disease 2019 (COVID\u201019) vaccine platforms and postvaccination breakthrough infection (BTI). We analyzed ADCC activity targeting SARS\u2010CoV\u20102 spike (S) and nucleocapsid (N) proteins in convalescent sera following WT SARS\u2010CoV\u20102\u2010infection (<jats:italic>n<\/jats:italic>\u2009=\u200991), including symptomatic and asymptomatic infections, omicron\u2010infection (<jats:italic>n<\/jats:italic>\u2009=\u20098), COVID\u201019 vaccination with messenger RNA\u2010 (mRNA)\u2010 (BNT162b2 or mRNA\u20101273, <jats:italic>n<\/jats:italic>\u2009=\u200977), adenovirus vector\u2010 (<jats:italic>n<\/jats:italic>\u2009=\u200941), and inactivated virus\u2010 (<jats:italic>n<\/jats:italic>\u2009=\u200946) based vaccines, as well as post\u2010mRNA vaccination BTI caused by omicron (<jats:italic>n<\/jats:italic>\u2009=\u200928). Correlations between ADCC, binding, and NAb titers were reported. ADCC was elicited within the first month postinfection and \u2010vaccination and remained detectable for \u22653 months. WT\u2010infected symptomatic patients had higher S\u2010specific ADCC levels than asymptomatic and vaccinated individuals. Also, no difference in N\u2010specific ADCC activity was seen between symptomatic and asymptomatic patients, but the levels were higher than the inactivated vaccine. Notably, omicron infection showed reduced overall ADCC activity compared to WT SARS\u2010CoV\u20102 infection. Although post\u2010mRNA vaccination BTI elicited high levels of binding and NAbs, ADCC activity was significantly reduced. Also, there was no difference in ADCC levels across the four vaccines, although NAbs and binding antibody titers were significantly higher in mRNA\u2010vaccinated individuals. All evaluated vaccine platforms are inferior in inducing ADCC compared to natural infection with WT SARS\u2010CoV\u20102. The inactivated virus\u2010based vaccine can induce N\u2010specific ADCC activity, but its relevance to clinical outcomes requires further investigation. Our data suggest that ADCC could be used to estimate the extra\u2010neutralization level against COVID\u201019 and provides evidence that vaccination should focus on other Fc\u2010effector functions besides NAbs. Also, the decreased susceptibility of the omicron variant to ADCC offers valuable guidance for forthcoming efforts to identify the specific targets of antibodies facilitating ADCC.<\/jats:p>","DOI":"10.1002\/jmv.29527","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T06:20:07Z","timestamp":1711002007000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["SARS\u2010CoV\u20102 infection triggers more potent antibody\u2010dependent cellular cytotoxicity (ADCC) responses than mRNA\u2010, vector\u2010, and inactivated virus\u2010based COVID\u201019 vaccines"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9484-7290","authenticated-orcid":false,"given":"Hadeel T.","family":"Zedan","sequence":"first","affiliation":[{"name":"Infectious Diseases Department, Biomedical Research Center, Research Complex Qatar University Doha Qatar"},{"name":"Department 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