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Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection

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  • Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection

    Transplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard “2 doses” scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses. One sentence summary The generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04757883 ### Funding Statement XC is supported by a funding from the Societe Francophone de Transplantation. ME is supported by the Hospices civils de Lyon and currently holds a poste accueil position funded by INSERM. OT is supported by the Etablissement Francais du Sang and the Fondation pour la Recherche Medicale (PME20180639518). ### 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: The study protocol complied with the tenets of the Helsinki Declaration and was approved by the Institutional Review Board (approval number: 18/21 03, Comite de Protection de Personnes Ouest IV Nantes) and registered on [clinicaltrial.gov][1] as [NCT04757883][2]. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 not applicable [1]: http://clinicaltrial.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04757883&atom=%2Fmedrxiv%2Fearly%2F2021%2F07%2F24%2F2021.07.22.21260852.atom

    Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection

    Xavier Charmetant, Maxime Espi, Ilies Benotmane, Francoise Heibel, Fanny Buron, Gabriela Gautier-Vargas, Marion Delafosse, Peggy Perrin, Alice Koenig, Noelle Cognard, Charlene Levi, Floriane Gallais, Louis Manière, Paola Rossolillo, Eric Soulier, Florian Pierre, Anne Ovize, Emmanuel Morelon, Thierry Defrance, Samira Fafi-Kremer, Sophie Caillard, Olivier Thaunat
    medRxiv 2021.07.22.21260852; doi: https://doi.org/10.1101/2021.07.22.21260852 This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

    Abstract

    Transplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard “2 doses” scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses.
    One sentence summary The generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells.
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