biostudies-literatureBangaru SNCRR NIH HHSNational Institute of Allergy and Infectious Diseases Division of Intramural ResearchNIAID NIH HHSGates FoundationNIGMS NIH HHS115986https://www.ebi.ac.uk/biostudies/studies/S-EPMC12486969biostudies-literatureUnknown44(7)Design and development of improved COVID-19 vaccines that can induce broad, durable immunity against emerging variants require an in-depth understanding of the antigenic and immunogenic properties of vaccines utilizing existing platforms. Here, we examine the antigenicity of two original COVID-19 vaccines by performing secondary analyses of the clinical trials for mRNA-1273 (this study was registered at ClinicalTrials.gov NCT04283461) and NVX-CoV2373 (this study was registered at ClinicalTrials.gov NCT04368988) using electron microscopy-based polyclonal epitope mapping (EMPEM). Both vaccines induce diverse polyclonal antibody (pAb) responses to the N-terminal domain (NTD) in addition to the receptor-binding domain of the Spike protein, with the NTD supersite being an immunodominant epitopeCell reportsStructural serology of polyclonal antibody responses to mRNA-1273 and NVX-CoV2373 COVID-19 vaccines.PMC12486969R01 AI127521UM1 AI144462INV-004923P41 RR001081R24 GM154185Fernandez-Quintero MLGuebre-Xabier MEdwards DKDas RSmith GBangaru STorrents de la Pena AGraham BSSeder RATorres JLSewall LMPatel NGirard BJackson AMNogal BCopps JRehman ACorbett-Helaire KSWard ABRichey STfalseStructural serology of polyclonal antibody responses to mRNA-1273 and NVX-CoV2373 COVID-19 vaccines.Design and development of improved COVID-19 vaccines that can induce broad, durable immunity against emerging variants require an in-depth understanding of the antigenic and immunogenic properties of vaccines utilizing existing platforms. Here, we examine the antigenicity of two original COVID-19 vaccines by performing secondary analyses of the clinical trials for mRNA-1273 (this study was registered at ClinicalTrials.gov NCT04283461) and NVX-CoV2373 (this study was registered at ClinicalTrials.gov NCT04368988) using electron microscopy-based polyclonal epitope mapping (EMPEM). Both vaccines induce diverse polyclonal antibody (pAb) responses to the N-terminal domain (NTD) in addition to the receptor-binding domain of the Spike protein, with the NTD supersite being an immunodominant epitope2025-01-01T00:00:00Z2025 Jul2026-06-04T01:47:34.584Z2026-05-04T03:13:54.364ZS-EPMC124869694063265410.1016/j.celrep.2025.115986