High Titers of Low Affinity Antibodies in COVID-19 Patients Are Associated With Disease Severity

Abstract

BackgroundAlmost 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 MethodsWe 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.ResultsA 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.ConclusionIn 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.

The quantity and quality of anti-SARS-CoV-2 antibodies show contrariwise association with COVID-19 severity: lessons learned from IgG avidity

“…Our results are in line with the findings of Hendriks et al's study that reported a correlation between high levels of antibodies with low affinity and disease severity in COVID-19 patients [3]. Similar to our study, they found a significantly higher antibody titers against SARS-CoV-2 antigens (RBD, N, S1 and S1S2) in hospitalized or critically ill patients compared to mild patients.…”

“…Based on the literature, COVID-19 reinfection cases are not so infrequent that according to a study on healthcare workers in Chicago, up to 2.5% of subjects, within a 6-month follow-up, presented a probable SARS-CoV-2 reinfection [2]. Even after more than 2.5 years of SARS-CoV-2 global spread and intensive scientific efforts, many questions on specific patient factors determining disease severity, underlying pathology and the protective/damaging roles of humoral immune responses have remained to be fully addressed [3]. As a notable feature of COVID-19, affected patients exhibit a large heterogeneity in Edited by Matthias J. Reddehase.…”

“…As a notable feature of COVID-19, affected patients exhibit a large heterogeneity in Edited by Matthias J. Reddehase. their responses to this viral infection [4] ranging from mild or even an asymptomatic disease course (in a larger group of patients) to disease progression and escalation, leading to hospitalization and potential death (in a smaller group of patients) [3]. In this regard, how the associated immune response characteristics contribute to this vulnerability have remained, for the most part, elusive.…”

Antibody affinity and cross-variant neutralization of SARS-CoV-2 Omicron BA.1, BA.2 and BA.3 following third mRNA vaccination

“…The protective efficacy by vaccine-induced antibodies against emerging variants may be impacted by both specific amino acid mutations in the spike and the affinity of the polyclonal antibodies against the SARS-CoV-2 variants. An association was observed between high titers of low-affinity antibodies against RBD with the disease severity of COVID-19 patients 35 . In previous studies, we had demonstrated a strong correlation between antibody affinity and protection from highly pathogenic avian influenza viruses 36 , 37 and a correlation with clinical benefit in patients infected with Zika virus 38 , Ebola virus 10 , influenza virus 39 and COVID-19 8 , 14 .…”

Evidence for deleterious effects of immunological history in SARS-CoV-2

“…Similar levels of Ab binding to both Ep9 and EpNeu in the subset of hospitalized and ICU-admitted patients could suggest impaired affinity maturation in patients with more severe outcomes. Impaired Ab affinity maturation have been previously shown to correlate with COVID-19 severity [ 23 , 24 ]. While multiple factors may lead to disease severity during COVID-19, our results suggest that a reliance on high levels of imprinted influenza Abs by a subset of COVID-19 patients could be indicative of a less effective immune response and consequently more severe disease outcomes.…”