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

PLoS One. 2022 Aug 24;17(8):e0272163. doi: 10.1371/journal.pone.0272163. eCollection 2022.


A previous report demonstrated the strong association between the presence of antibodies binding to an epitope region from SARS-CoV-2 nucleocapsid, termed Ep9, and COVID-19 disease severity. Patients with anti-Ep9 antibodies (Abs) had hallmarks of antigenic interference (AIN), including early IgG upregulation and cytokine-associated injury. Thus, the immunological memory of a prior infection was hypothesized to drive formation of suboptimal anti-Ep9 Abs in severe COVID-19 infections. This study identifies a putative primary antigen capable of stimulating production of cross-reactive, anti-Ep9 Abs. Binding assays with patient blood samples directly show cross-reactivity between Abs binding to Ep9 and only one bioinformatics-derived, homologous putative antigen, a sequence derived from the neuraminidase protein of H3N2 influenza A virus. This cross-reactive binding is highly influenza strain specific and sensitive to even single amino acid changes in epitope sequence. The neuraminidase protein is not present in the influenza vaccine, and the anti-Ep9 Abs likely resulted from the widespread influenza infection in 2014. Therefore, AIN from a previous infection could underlie some cases of COVID-19 disease severity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Viral
  • COVID-19*
  • Epitopes
  • Humans
  • Influenza A Virus, H3N2 Subtype
  • Influenza Vaccines*
  • Influenza, Human* / prevention & control
  • Neuraminidase
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus


  • Antibodies, Viral
  • Epitopes
  • Influenza Vaccines
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Neuraminidase

Grant support

This study was funded by the UCI COVID-19 Basic, Translational and Clinical Research Fund (CRAFT), the Allergan Foundation, and the UCOP Emergency COVID-19 Research Seed Fund. The National Institute of General Medical Sciences also supported this paper through fellowship support to AMS (GM69337), the National Center for Advancing Translational Sciences supported JLR (TR001414), and the National Human Genome Research Institute awarded a grant to GAW (1R01HG009188-01).