SARS-CoV-2 infections elicit higher levels of original antigenic sin antibodies compared to SARS-CoV-2 mRNA vaccinations

SUMMARYSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines elicit higher levels of antibodies compared to natural SARS-CoV-2 infections in most individuals; however, the specificities of antibodies elicited by vaccination versus infection remain incompletely understood. Here, we characterized the magnitude and specificity of SARS-CoV-2 spike-reactive antibodies from 10 acutely infected health care workers and 23 participants who received mRNA-based SARS-CoV-2 vaccines. We found that infection and primary mRNA vaccination elicited S1 and S2-reactive antibodies, while secondary vaccination boosted mostly S1 antibodies. Using magnetic bead-based absorption assays, we found that SARS-CoV-2 infections elicited a large proportion of original antigenic sin-like antibodies that bound efficiently to common seasonal human coronaviruses but poorly to SARS-CoV-2. In converse, vaccination only modestly boosted antibodies reactive to common seasonal human coronaviruses and these antibodies bound efficiently to SARS-CoV-2. Our data indicate that SARS-CoV-2 mRNA vaccinations elicit fundamentally different antibody responses compared to SARS-CoV-2 infections.Abstract FigureHIGHLIGHTSSARS-CoV-2 mRNA vaccines elicit higher levels of antibodies compared to SARS-CoV-2 infectionsThe first dose of an mRNA vaccine generates both S1 and S2 responses while the second dose boosts primarily S1-specific antibodiesSARS-CoV-2 infections, but not mRNA vaccinations, elicit high levels of antibodies that bind strongly to seasonal coronaviruses but weakly to SARS-CoV-2

Original antigenic sin responses to Betacoronavirus spike proteins are observed in a mouse model, but are not apparent in children following SARS-CoV-2 infection

Background The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies. Results Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies. Conclusions Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.

The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 B.1.351 and other variants of concern in preclinical studies.

There is an ongoing global effort, to design, manufacture, and clinically assess vaccines against SARS-CoV-2. Over the course of the ongoing pandemic a number of new SARS-CoV-2 virus isolates or variants of concern (VoC) have been identified containing mutations that negatively impact the role of neutralising antibodies. In this study we describe the generation and preclinical assessment of a ChAdOx1-vectored vaccine against the variant of concern B.1.351 (AZD2816). We demonstrate AZD2816 is immunogenic after a single dose and when used as a booster dose in animals primed with original vaccine AZD1222, we see no evidence of original antigenic sin but high titre antibodies against a number of variant spike proteins. In addition, neutralisation titres against B.1.351 (Beta), B.1.617.1 (Kappa) and B.1.617.2 (Delta), are induced in these boost regimens. These data support the ongoing clinical development and testing of this new variant vaccine.

Evidence for Deleterious Original Antigenic Sin in SARS-CoV-2 Immune Response

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.

Original antigenic sin responses to heterologous Betacoronavirus spike proteins are observed in mice following intramuscular administration, but are not apparent in children following SARS-CoV-2 infection

Background: The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives: We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods: Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n=14 per group) were analyzed for these same antibodies. Results: Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P=0.012), these titers correlated positively with both SARS-CoV-2 binding (r=0.7577, P<0.001) and neutralizing (r=0.6201, P=0.001) antibodies. Conclusions: Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.