No patient is the same; lessons learned from antibody repertoire profiling in hospitalized severe COVID-19 patients

Here, by using mass spectrometry-based methods IgG1 and IgA1 clonal repertoires were monitored quantitatively and longitudinally in more than 50 individual serum samples obtained from 17 COVID-19 patients admitted to intensive care units because of acute respiratory distress syndrome. These serological clonal profiles were used to examine how each patient reacted to a severe SARS-CoV-2 infection. All 17 donors revealed unique polyclonal repertoires and changes after infection. Substantial changes over time in the IgG1 and/or IgA1 clonal repertoires were observed in individual patients, with several new clones appearing following the infection, in a few cases leading to a few very high abundant IgG1 and/or IgA1 clones dominating the repertoire. Several of these clones were de novo sequenced through combinations of top-down, middle-down and bottom-up proteomics approaches. This revealed several sequence features in line with sequences deposited in the SARS-CoV-specific database of antibodies. In other patients, the serological Ig profiles revealed the treatment with tocilizumab, as after treatment, this IgG1-mAb dominated the serological IgG1 repertoire. Tocilizumab clearance could be monitored and a half-life of approximately 6 days was established in these patients. Overall, our longitudinal monitoring of IgG1 and IgA1 repertoires of individual donors reveals that antibody responses are highly personalized traits of each patient, affected by the disease and the chosen clinical treatment. The impact of these observations argues for a more personalized and longitudinal approach in patients’ diagnostics, both in serum proteomics as well as in monitoring immune responses. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study received support from the Dutch Research Council (NWO) through the X-omics Road Map program (project 184.034.019) and the EU Horizon 2020 program INFRAIA project Epic-XS (Project 823839). This research was funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009), and the Utrecht Molecular Immunology Hub. ### 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 ethics committee Comitato Etico di Area Vasta Emilia Centro, Bologna, Italy gave ethical approval for this work. The study is registered at www.clinicaltrials.gov with the identifier [NCT04343053][1], as also described in the manuscript 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 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04343053&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F26%2F2022.12.23.22283896.atom