The recent COVID-19 pandemic has posed major health challenges. To expand our molecular understanding beyond those seeking medical care, we conducted a cross-sectional survey targeting random residents from Sweden's two largest cities. Two thousand participants were invited during 2021 to self-sample dried blood spots (DBS) and provide health information. DBS samples were analysed for multiple anti-SARS-CoV-2 antibodies (Abs), auto-reactive antibodies (AAbs) against 23 interferons (IFNs), and for 502 circulating immune-related proteins. Data-driven methodologies characterised the DBS phenotypes in response to infections and vaccination. We received DBS samples from 437 (22%) volunteers aged 18-69, 60% females, and 50% per city. Multi-analyte serology distinguished self-reported infections (26%) and vaccination (40%), revealing a time-dependent discrepancy between reported and measured immunity. Anti-IFN Abs were detected in 21% of the donors and more frequent for type 1 IFNs alongside a natural infection. Integrating proteomics with antibody data provided additional insights into processes of cell-mediated immunity. Proteomics-centric analysis identified 24% of the participants to deviate in their phenotypes due to infection, immunity, respiratory distress, and age-related traits. Multi-molecular analysis of layperson samples uncovered heterogeneity and diversity of immunity and health phenotypes, complementing clinical investigations.

OB is a co-founder and shareholder of Capitainer AB. NR is a co-founder and shareholder of the microsampling companies Capitainer AB and Samplimy Medical AB, and an inventor of several patents on microsampling solutions. JMS is a Scientific Advisor for ABC Development AB and has, unrelated to this work, received travel support from Olink AB and Luminex Corp, and via the institution conducted contract research for Capitainer AB and Luminex Corp. All other authors declare they have no competing interests.

This study was funded by SciLifeLab National COVID-19 Research Program, financed by the Knut and Alice Wallenberg Foundation (2020.0182, 2020.0241); Sweden's innovation agency Vinnova (2020-04451); SciLifeLab's Pandemic Laboratory Preparedness program (VC-2022-0028); The Erling Persson Foundation (20210125); Swedish Research Council (2022-06340); We acknowledge support from the Knut and Alice Wallenberg Foundation for funding the Human Protein Atlas. This work was partially supported by the Wallenberg AI, Autonomous Systems and Software Program (WASP) funded by the Knut and Alice Wallenberg Foundation.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the regional ethical board (EPN Stockholm, Dnr 2015/867-31/1) and the Swedish Ethical Authority (EPM, Dnr 2021-01106 and Dnr 2023-03016-02).

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Data supporting the findings of this study will be deposited under the manuscript's title at SciLifeLab Data Repository (https://scilifelab.figshare.com). The datasets are under restricted access since they represent individual-level human data. As described in the repository, access can be granted for non-commercial validation purposes upon reasonable request to the corresponding authors. Any unique or newly developed analysis code will be available upon publication at https://github.com/Schwenk-Lab.