Unbiased spectral cytometry immunome characterization predicts COVID-19 mRNA vaccine failure in older adults and patients with lymphoid malignancies

COVID-19 affects the population unequally with a higher impact on aged and immunosuppressed people. Hence, we assessed the effect of SARS-CoV-2 vaccination in immune compromised patients (older adults and oncohematologic patients), compared with healthy counterparts. While the acquired humoral and cellular memory did not predict subsequent infection 18 months after full immunization, spectral and computational cytometry revealed several subsets within the CD8+ T-cells, B-cells, NK cells, monocytes and CD45RA+CCR7- Tγδ cells differentially expressed in further infected and non-infected individuals not just following immunization, but also prior to that. Of note, up to 7 subsets were found within the CD45RA+CCR7- Tγδ population with some of them being expanded and other decreased in subsequently infected individuals. Moreover, some of these subsets also predicted COVID-induced hospitalization in oncohematologic patients. Therefore, we hereby have identified several cellular subsets that, even before vaccination, strongly related to COVID-19 vulnerability as opposed to the acquisition of cellular and/or humoral memory following vaccination with SARS-CoV- 2 mRNA vaccines. SUMMARY An in depth and unbiased spectral cytometry characterization of the immune system before and after COVID-19 vaccination can predict not just subsequent PCR-confirmed infection, but also COVID-induced hospitalization in immune compromised patients. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study has been funded through Programa Estrategico Instituto de Biologia y Genetica Molecular (IBGM Junta de Castilla y Leon. Ref. CCVC8485), Junta de Castilla y Leon (Proyectos COVID 07.04.467B04.74011.0) and the European Commission NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global; SGL21 03 026 and SGL2021 03 038) ### 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 committee of VALLADOLID HEALTH AREA gave ethical approval for this work (code PI 21-2098) 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors