@article{Richardson2021,
abstract = {SARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with decreased disease severity and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement W.A.B. is supported by the EDCTP2 programme of the European Unions Horizon 2020 programme (TMA2016SF-1535-CaTCH-22) and Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust (203135/Z/16/Z). N.A.B.N acknowledges funding from the SA-MRC, MRC UK, NRF and the Lily and Ernst Hausmann Trust. PLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa, the SA Medical Research Council SHIP program, the Centre for the AIDS Program of Research (CAPRISA). SIR is a LOreal/UNESCO Women in Science South Africa Young Talents awardee. Related research by the authors is conducted as part of the DST-NRF Centre of Excellence in HIV Prevention, which is supported by the Department of Science and Technology and the National Research Foundation. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was received from the University of Pretoria, Human Research Ethics Committee (Medical) (247/2020), the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town (R021/2020). The study was also approved by the University of Cape Town Human Research Ethics Committee (HREC 190/2020 and 209/2020) and the University of the Witwatersrand Human Research Ethics Committee (Medical) (no M210429). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors},
author = {Richardson, Simone I and Manamela, Nelia P and Motsoeneng, Boitumelo M and Kaldine, Haajira and Ayres, Frances and Makhado, Zanele and Mennen, Mathilda and Skelem, Sango and Williams, Noleen and Sullivan, Nancy J and Misasi, John and Gray, Glenda G and Bekker, Linda-Gail and Ueckermann, Veronica and Rossouw, Theresa M and Boswell, Michael T and Ntusi, Ntobeko A B and Burgers, Wendy A and Moore, Penny L},
doi = {10.1101/2021.11.05.21265853},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Richardson et al. - 2021 - A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {nov},
pages = {2021.11.05.21265853},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity}},
url = {https://www.medrxiv.org/content/10.1101/2021.11.05.21265853v1 https://www.medrxiv.org/content/10.1101/2021.11.05.21265853v1.abstract},
year = {2021}
}

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Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement W.A.B. is supported by the EDCTP2 programme of the European Unions Horizon 2020 programme (TMA2016SF-1535-CaTCH-22) and Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust (203135/Z/16/Z). N.A.B.N acknowledges funding from the SA-MRC, MRC UK, NRF and the Lily and Ernst Hausmann Trust. PLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa, the SA Medical Research Council SHIP program, the Centre for the AIDS Program of Research (CAPRISA). SIR is a LOreal/UNESCO Women in Science South Africa Young Talents awardee. Related research by the authors is conducted as part of the DST-NRF Centre of Excellence in HIV Prevention, which is supported by the Department of Science and Technology and the National Research Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was received from the University of Pretoria, Human Research Ethics Committee (Medical) (247/2020), the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town (R021/2020). The study was also approved by the University of Cape Town Human Research Ethics Committee (HREC 190/2020 and 209/2020) and the University of the Witwatersrand Human Research Ethics Committee (Medical) (no M210429). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors","author":[{"propositions":[],"lastnames":["Richardson"],"firstnames":["Simone","I"],"suffixes":[]},{"propositions":[],"lastnames":["Manamela"],"firstnames":["Nelia","P"],"suffixes":[]},{"propositions":[],"lastnames":["Motsoeneng"],"firstnames":["Boitumelo","M"],"suffixes":[]},{"propositions":[],"lastnames":["Kaldine"],"firstnames":["Haajira"],"suffixes":[]},{"propositions":[],"lastnames":["Ayres"],"firstnames":["Frances"],"suffixes":[]},{"propositions":[],"lastnames":["Makhado"],"firstnames":["Zanele"],"suffixes":[]},{"propositions":[],"lastnames":["Mennen"],"firstnames":["Mathilda"],"suffixes":[]},{"propositions":[],"lastnames":["Skelem"],"firstnames":["Sango"],"suffixes":[]},{"propositions":[],"lastnames":["Williams"],"firstnames":["Noleen"],"suffixes":[]},{"propositions":[],"lastnames":["Sullivan"],"firstnames":["Nancy","J"],"suffixes":[]},{"propositions":[],"lastnames":["Misasi"],"firstnames":["John"],"suffixes":[]},{"propositions":[],"lastnames":["Gray"],"firstnames":["Glenda","G"],"suffixes":[]},{"propositions":[],"lastnames":["Bekker"],"firstnames":["Linda-Gail"],"suffixes":[]},{"propositions":[],"lastnames":["Ueckermann"],"firstnames":["Veronica"],"suffixes":[]},{"propositions":[],"lastnames":["Rossouw"],"firstnames":["Theresa","M"],"suffixes":[]},{"propositions":[],"lastnames":["Boswell"],"firstnames":["Michael","T"],"suffixes":[]},{"propositions":[],"lastnames":["Ntusi"],"firstnames":["Ntobeko","A","B"],"suffixes":[]},{"propositions":[],"lastnames":["Burgers"],"firstnames":["Wendy","A"],"suffixes":[]},{"propositions":[],"lastnames":["Moore"],"firstnames":["Penny","L"],"suffixes":[]}],"doi":"10.1101/2021.11.05.21265853","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Richardson et al. - 2021 - A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity.pdf:pdf","journal":"medRxiv","keywords":"OA,fund_ack,original","mendeley-tags":"OA,fund_ack,original","month":"nov","pages":"2021.11.05.21265853","publisher":"Cold Spring Harbor Laboratory Press","title":"A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity","url":"https://www.medrxiv.org/content/10.1101/2021.11.05.21265853v1 https://www.medrxiv.org/content/10.1101/2021.11.05.21265853v1.abstract","year":"2021","bibtex":"@article{Richardson2021,\r\nabstract = {SARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with decreased disease severity and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses. {\\#}{\\#}{\\#} Competing Interest Statement The authors have declared no competing interest. {\\#}{\\#}{\\#} Funding Statement W.A.B. is supported by the EDCTP2 programme of the European Unions Horizon 2020 programme (TMA2016SF-1535-CaTCH-22) and Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust (203135/Z/16/Z). N.A.B.N acknowledges funding from the SA-MRC, MRC UK, NRF and the Lily and Ernst Hausmann Trust. PLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa, the SA Medical Research Council SHIP program, the Centre for the AIDS Program of Research (CAPRISA). SIR is a LOreal/UNESCO Women in Science South Africa Young Talents awardee. Related research by the authors is conducted as part of the DST-NRF Centre of Excellence in HIV Prevention, which is supported by the Department of Science and Technology and the National Research Foundation. {\\#}{\\#}{\\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was received from the University of Pretoria, Human Research Ethics Committee (Medical) (247/2020), the Human Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town (R021/2020). The study was also approved by the University of Cape Town Human Research Ethics Committee (HREC 190/2020 and 209/2020) and the University of the Witwatersrand Human Research Ethics Committee (Medical) (no M210429). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). 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