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Background: Almost 2 years from the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there is still a lot unknown how the humoral response affects disease progression. In this study, we investigated humoral antibody responses against specific SARS-CoV2 proteins, their strength of binding, and their relationship with COVID severity and clinical information. Furthermore, we studied the interactions of the specific receptor-binding domain (RBD) in more depth by characterizing specific antibody response to a peptide library., Materials and Methods: We measured specific antibodies of isotypes IgM, IgG, and IgA, as well as their binding strength against the SARS-CoV2 antigens RBD, NCP, S1, and S1S2 in sera of 76 COVID-19 patients using surface plasmon resonance imaging. In addition, these samples were analyzed using a peptide epitope mapping assay, which consists of a library of peptides originating from the RBD., Results: A positive association was observed between disease severity and IgG antibody titers against all SARS-CoV2 proteins and additionally for IgM and IgA antibodies directed against RBD. Interestingly, in contrast to the titer of antibodies, the binding strength went down with increasing disease severity. Within the critically ill patient group, a positive association with pulmonary embolism, d-dimer, and antibody titers was observed., Conclusion: In critically ill patients, antibody production is high, but affinity is low, and maturation is impaired. This may play a role in disease exacerbation and could be valuable as a prognostic marker for predicting severity., Competing Interests: Patents: Provisional patent is filed based on the data generated from this work. Provisional title: Strength of Binding of Antibodies Against Infectious Diseases Measured With Evanescent Field Based Biosensors. COVID-19 Patients With High Titers of Low Affinity Antibodies Are Associated With Disease Severity. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hendriks, Schasfoort, Koerselman, Dannenberg, Cornet, Beishuizen, van der Palen, Krabbe, Mulder and Karperien.)