Natural infection and vaccination interact to shape Fc-mediated immunity against SARS-CoV-2

Natural infection and vaccination interact to shape Fc-mediated immunity against SARS-CoV-2 | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 8 September 2025 V1 Latest version Share on Natural infection and vaccination interact to shape Fc-mediated immunity against SARS-CoV-2 Authors : Matteo Ferrari 0000-0002-4224-8835 , Luis Ohlendorf , Angalee Nadesalingam , Andrew Chan , Ernest Aguinam T , Charlotte George , George William Carnell 0000-0001-8875-0989 , … Show All … , Diego Cantoni , Nigel J. Temperton , Ralf Wagner , Wilhelm Schwaeble , Javier Castillo-Olivares , Helen Baxendale , and Jonathan Heeney L [email protected] Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.175731694.42201476/v1 256 views 132 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objectives: Hybrid immunity, resulting from both SARS-CoV-2 infection and COVID-19 vaccination, is well documented to provide broader antibody-mediated protection compared to infection or vaccination alone. While neutralizing antibodies are recognized correlates of protection, the role of Fc-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) remains poorly defined. This study investigated ADCC responses in UK healthcare workers (HCWs) with varying SARS-CoV-2 exposure histories. Methods: ADCC activity was measured using a Jurkat NFAT reporter cell line expressing CD16, which emits luciferase upon Fc receptor activation by plasma antibodies bound to Spike antigen. Spike-specific IgG1 and IgG3 responses were analysed via automated immunoblotting, and neutralizing capacity was assessed by pseudovirus microneutralization. HCWs were categorized as previously infected before vaccination, naïve-vaccinated (no prior infection), or those with breakthrough infection post-vaccination. Results: Individuals with natural infection prior to immunization showed significantly elevated ADCC compared to naïve-vaccinated individuals. Vaccine-breakthrough infection did not enhance ADCC activity further. In the infection-before-vaccination group, ADCC responses were not significantly influenced by vaccine type, infection severity, age, or gender. Enhanced ADCC correlated with higher levels of Spike-specific IgG1 and IgG3. Principal Component Analysis indicated that IgG1 responses were broadly distributed across all Spike regions, whereas IgG3 responses, especially those targeting the S2 region, contributed distinctively to the observed Fc-mediated activity. Conclusion: These findings highlight that natural infection followed by vaccination drives the most robust ADCC responses in HCWs. IgG1 and IgG3 contribute complementarily to this effect, highlighting the importance of subclass-specific Fc-effector functions in optimizing vaccine-induced immunity. Supplementary Material File (adcc_paper_mf_jlh_v2 for cti journal 150425 hb.docx) Download 96.14 KB File (figures_and_legends_03_04_2025.docx) Download 517.30 KB Information & Authors Information Version history V1 Version 1 08 September 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords adcc fc-effector functions hybrid immunity igg1 igg3 sars-cov-2 vaccine Authors Affiliations Matteo Ferrari 0000-0002-4224-8835 University of Cambridge View all articles by this author Luis Ohlendorf University of Cambridge View all articles by this author Angalee Nadesalingam University of Cambridge View all articles by this author Andrew Chan University of Cambridge View all articles by this author Ernest Aguinam T University of Cambridge View all articles by this author Charlotte George University of Cambridge View all articles by this author George William Carnell 0000-0001-8875-0989 University of Cambridge View all articles by this author Diego Cantoni Medway School of Pharmacy View all articles by this author Nigel J. Temperton Medway School of Pharmacy View all articles by this author Ralf Wagner Universitat Regensburg Institut fur Medizinische Mikrobiologie und Hygiene View all articles by this author Wilhelm Schwaeble University of Cambridge Department of Veterinary Medicine View all articles by this author Javier Castillo-Olivares University of Cambridge View all articles by this author Helen Baxendale Royal Papworth Hospital NHS Foundation Trust View all articles by this author Jonathan Heeney L [email protected] University of Cambridge View all articles by this author Metrics & Citations Metrics Article Usage 256 views 132 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Matteo Ferrari, Luis Ohlendorf, Angalee Nadesalingam, et al. Natural infection and vaccination interact to shape Fc-mediated immunity against SARS-CoV-2. Authorea . 08 September 2025. 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