Evidence for Deleterious Antigenic Imprinting in SARS-CoV-2 Immune Response

Abstract

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 original antigenic sin (OAS), including early IgG upregulation and cytokine-associated injury. Thus, the immunological memory of a previous infection was hypothesized to drive formation of suboptimal anti-Ep9 Abs in severe COVID-19 infections. This study identifies a putative original antigen capable of stimulating production of cross-reactive, anti-Ep9 Abs. From bioinformatics analysis, 21 potential original epitope regions were identified. Binding assays with patient blood samples directly show cross-reactivity between Abs binding to Ep9 and only one homologous potential antigen, a sequence derived from the neuraminidase protein of H3N2 Influenza A virus. This cross-reactive binding affinity is highly virus 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, OAS from a previous infection could underlie some cases of COVID-19 disease severity and explain the diversity observed in disease outcomes.

COVID-19 Convalescent Plasma Is More than Neutralizing Antibodies: A Narrative Review of Potential Beneficial and Detrimental Co-Factors

“…Another study found better outcomes in recipients of CCP units with higher anti-NL63 or anti-OC43 antibodies [39]; Influenza virus A(H 3 N 2 ): Antibody binding to an epitope region from SARS-CoV-2 nucleocapsid, termed Ep9, is associated with greater COVID-19 disease severity [40]. Bioinformatics analysis identified the neuraminidase protein (not present in the influenza vaccine) of influenza virus A(H3N2) as responsible, a strain that circulated widely in 2014 [41]; Acute malaria infection: Plasmodium infection induces cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 spike protein [42]; Natural ABO isoagglutinins: The ABO blood group affects COVID-19 incidence and severity, as well as the type and duration of the cellular immune response [43]. Analogous to the events of SARS-CoV-1, it was hypothesized that natural isoagglutinins act as neutralizing antibodies owing to ABO antigens being carried over on virion envelope [44], although the evidence to date is weak [45].…”

Casirivimab + imdevimab accelerates symptom resolution linked to improved COVID-19 outcomes across susceptible antibody and risk profiles

“…This work also supports the role of treatment with highly neutralizing monoclonal IgG antibodies at the earliest signs of disease to accelerate symptom resolution. Whether a potent neutralizing IgG combination of CAS + IMD can counteract low-titer antibody responses at baseline that may be misdirected, or represent cross-reactive antibodies from previous viral infections that are SARS-CoV-2 viral enhancing 54 , was not studied, but deserves further attention. Finally, and most importantly, in patients with risk factors for severe COVID-19 or in those who have inadequate early serologic responses, more rapid resolution of a set of symptoms following CAS + IMD treatment signaled reduction of risk of the worst outcomes of hospitalization and death.…”

A novel approach to designing viral precision vaccines applied to SARS-CoV-2

“…Careful selection of vaccinating antigens is important as some SARS-CoV-2 epitopes have been shown to generate deleterious immune response such as antibody-dependent enhancement (ADE) of the infection clinical course ( Karthik et al., 2020 ; Lee et al., 2020 ). ADE is generally secondary to the immune response to cross-reactive antigens encountered in previous exposure to coronavirus strains ( Fierz and Walz, 2020 ), or H3N2 Influenza A virus ( Sen et al., 2021 ). Therefore, a new design concept is needed to develop efficient precision vaccines against SARS-CoV-2 and other concerning viruses, particularly those prone to genetic variations.…”