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TitleRational Design of Multiclade Coronavirus Spike Immunodominant Domain Nanoparticles to Elicit Broad Antibody Responses.
Journal, issue, pagesRes Sq, Year 2025
Publish dateDec 10, 2025
AuthorsChristian K O Dzuvor / Sydney Moak / Lindsay R McManus / Abigail Thomas / Abigail E Dzordzorme / Taewoo Kim / Jeswin Joseph / Valerie Foley / Ingelise J Gordon / Laura Novik / LaSonji A Holman / Lesia K Dropulic / Ryan P McNamara / Kizzmekia S Corbett-Helaire /
PubMed AbstractFour seasonal endemic human coronaviruses (HCoVs), HCoV-HKU1, HCoV-OC43, HCoV-229E, and HCoV-NL63, are culprits of mild upper respiratory and periodic severe diseases in vulnerable populations. ...Four seasonal endemic human coronaviruses (HCoVs), HCoV-HKU1, HCoV-OC43, HCoV-229E, and HCoV-NL63, are culprits of mild upper respiratory and periodic severe diseases in vulnerable populations. Despite their prevalence, understanding HCoVs' antigenic and immune signatures remains elusive. SARS-CoV-2 has evolved as the fifth HCoV, requiring seasonal vaccination, and currently, no other HCoV vaccines are available. SARS-CoV-2 co-infection with HCoVs increases disease severity; thus, combined vaccination may provide increased protection against seasonal HCoVs overall. Here, we explored spike (S) receptor binding domain (RBD) vs. N-terminal domain (NTD) B-cell immunodominance in HCoV-positive convalescent donors and immunogenicity in mice. We found that while antibody and B-cell isotypes were relatively dominant to S NTD, mice immunized with S RBD elicited significantly higher binding and neutralizing antibody (nAb) responses. With that knowledge, we used computational methods to infer that HCoV S sequences evolve into two main clades and designed chimeric immunodominant domains (IDDs) from both clades for each HCoV. IDDs were scaffolded onto two-component nanoparticles (NPs) displaying each IDD separately (monovalent IDD NP); three ß-HCoV IDDs (Mosaic-3 IDD NP); or five HCoVs IDDs (Mosaic-5 IDD NP). Mice immunized with mosaic IDD NPs, but not soluble IDD antigens nor monovalent IDD NPs, elicited potent, broadly cross-reactive binding and neutralizing antibody (Ab) responses against SARS-CoV-2 variants, other HCoVs, and Sarbecoviruses. System serology revealed that all four IDD immunogens elicited distinct Ab subclasses and Fc-effector functions, with mosaic-5 IDD NPs eliciting the most Ab subclasses, distributions, and broader Fc-mediated immune mechanisms. Dissection of vaccine-immune sera revealed polyclonal Ab responses against multiple non-overlapping cross-reactive S epitopes. Due to elicitation of broad Ab responses with combinatory functionality, IDD NPs open new horizons for developing first-in-class supraseasonal HCoV vaccine candidates, with potential to decrease frequent SARS-CoV-2 sequence updates and protect against other HCoVs. Moreover, elicitation of Ab breadth that spans pandemic-threat Sarbecoviruses gives mosaic IDD NPs promise towards pandemic preparedness.
External linksRes Sq / PubMed:41472675 / PubMed Central
MethodsEM (single particle)
Resolution3.92 - 4.42 Å
Structure data

EMDB-73662: Structure of Mosaic -5 IDD NPs
Method: EM (single particle) / Resolution: 3.92 Å

EMDB-73675: Structure of SS-L2-I53-50NP
Method: EM (single particle) / Resolution: 4.42 Å

Source
  • Mammalian expression vector Flag-MCS-pcDNA3.1 (others)

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