Broadly neutralizing antibodies to SARS-CoV-2 in Long COVID are associated with viral persistence and clinical outcome
Chenyu Liu, Daniel Sanson, Serhan Soylu, Leen Moens, Isabelle Meyts, Marc Jamoulle, Johan Van Weyenbergh
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Abstract
Long COVID (also known as post-acute sequelae of SARS-CoV-2, PASC) is a chronic condition in which symptoms persist months or years after the acute infection. Neutralizing antibody responses induced by infection and/or vaccination are a surrogate marker for protection against COVID-19. However, their potential role in Long COVID patients is currently unclear.
Herein, we performed pseudoneutralization assays (MSD) of 10 different SARS-CoV-2 variants and whole blood digital transcriptomics (nCounter, Nanostring) in a real-world, perspective Long Covid cohort (n=49 paired samples), examining possible correlations with clinical (brain imaging (SPECT-CT), severity, COOP chart scores) and demographic data.
Across all variants, the number of vaccine doses was significantly correlated with broad neutralization activity (P<0.001, R>0.4 for WT, Alpha, Beta, Gamma, Delta), indicating vaccine response is not defective in Long COVID patients. Moreover, broad neutralization activity was positively correlated with SARS-CoV-2 ORF3a RNA (P= 0.0085, R = 0.37), consistent with previous findings of viral persistence in Long COVID, while inflammatory chemokines CCL2 and CXCL10 (P=0.016, R=-0.346) were negatively correlated with broad neutralizing antibodies.
Interestingly, for the Delta variant, a unique transcriptomic profile was observed compared to all other variants, with negative correlations to IgE heavy chain RNA (IGHE P=0.00085, R=-0.37) and cell cycle-related transcript CDC20 (P=0.00085, R=-0.37). This points at an IgE-dominated humoral response to the Delta variant, which may help explain both its higher virulence and immune escape from neutralizing antibodies.
Although middle-aged women are more frequently affected by Long COVID, age and sex were not significantly associated with neutralizing antibodies to any variant. From a clinical standpoint, broadly neutralizating antibodies were unexpectedly associated with worse clinical outcome, quantified by COOP score changes from baseline (higher values indicate worsening, P= 0.0048, p = 0.42).
In conclusion, our data suggest the presence of a viral reservoir in Long COVID that continuously stimulates neutralizing antibody production, which is however associated with worse clinical outcome. Humoral immune response to the Delta variant is skewed to IgE dominance in Long COVID patients, in keeping with its higher virulence.
PDF | Abstract: BELVIR 2025
Chenyu Liu, Daniel Sanson, Serhan Soylu, Leen Moens, Isabelle Meyts, Marc Jamoulle, Johan Van Weyenbergh
[Line breaks added]
Abstract
Long COVID (also known as post-acute sequelae of SARS-CoV-2, PASC) is a chronic condition in which symptoms persist months or years after the acute infection. Neutralizing antibody responses induced by infection and/or vaccination are a surrogate marker for protection against COVID-19. However, their potential role in Long COVID patients is currently unclear.
Herein, we performed pseudoneutralization assays (MSD) of 10 different SARS-CoV-2 variants and whole blood digital transcriptomics (nCounter, Nanostring) in a real-world, perspective Long Covid cohort (n=49 paired samples), examining possible correlations with clinical (brain imaging (SPECT-CT), severity, COOP chart scores) and demographic data.
Across all variants, the number of vaccine doses was significantly correlated with broad neutralization activity (P<0.001, R>0.4 for WT, Alpha, Beta, Gamma, Delta), indicating vaccine response is not defective in Long COVID patients. Moreover, broad neutralization activity was positively correlated with SARS-CoV-2 ORF3a RNA (P= 0.0085, R = 0.37), consistent with previous findings of viral persistence in Long COVID, while inflammatory chemokines CCL2 and CXCL10 (P=0.016, R=-0.346) were negatively correlated with broad neutralizing antibodies.
Interestingly, for the Delta variant, a unique transcriptomic profile was observed compared to all other variants, with negative correlations to IgE heavy chain RNA (IGHE P=0.00085, R=-0.37) and cell cycle-related transcript CDC20 (P=0.00085, R=-0.37). This points at an IgE-dominated humoral response to the Delta variant, which may help explain both its higher virulence and immune escape from neutralizing antibodies.
Although middle-aged women are more frequently affected by Long COVID, age and sex were not significantly associated with neutralizing antibodies to any variant. From a clinical standpoint, broadly neutralizating antibodies were unexpectedly associated with worse clinical outcome, quantified by COOP score changes from baseline (higher values indicate worsening, P= 0.0048, p = 0.42).
In conclusion, our data suggest the presence of a viral reservoir in Long COVID that continuously stimulates neutralizing antibody production, which is however associated with worse clinical outcome. Humoral immune response to the Delta variant is skewed to IgE dominance in Long COVID patients, in keeping with its higher virulence.
PDF | Abstract: BELVIR 2025
