Rational Design of Multiclade Coronavirus Spike Immunodominant Domain Nanoparticles Elicit Broad Antibody Responses

Dzuvor, C. K. O.; Moak, S.; McManus, L. R.; Thomas, A.; Dzordzorme, A. E.; Kim, T.; Joseph, J.; Foley, V.; Gordon, I. J.; Novik, L.; Holman, L. A.; Dropulic, L. K.; McNamara, R. P.; Corbett-Helaire, K. S.

doi:10.1101/2025.10.01.679649

bioRxiv · 10.1101/2025.10.01.679649

Rational Design of Multiclade Coronavirus Spike Immunodominant Domain Nanoparticles Elicit Broad Antibody Responses

Dzuvor, C. K. O.·Moak, S.·McManus, L. R.·Thomas, A.·Dzordzorme, A. E.·Kim, T.·Joseph, J.·Foley, V.·Gordon, I. J.·Novik, L.·Holman, L. A.·Dropulic, L. K.·McNamara, R. P.·Corbett-Helaire, K. S.

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Abstract

Four seasonal endemic human coronaviruses (EhCoVs), HKU1-CoV, OC43-CoV, 229E-CoV, and NL63-CoV, are culprits of mild upper respiratory and periodic severe diseases in vulnerable populations. Despite their prevalence, understanding EhCoVs antigenic and immune signatures remains elusive. SARS-CoV-2 has evolved as the fifth EhCoV, requiring seasonal vaccination in most parts of the world, and currently, no other EhCoV vaccines are available. SARS-CoV-2 co-infection with EhCoVs increases disease severity; thus, combined vaccination may provide increased protection against seasonal EhCoVs overall. Here, we explored Spike (S) receptor binding domain (RBD) vs. N-terminal domain (NTD) B-cell immunodominance in EhCoV-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 EhCoV S sequences evolve into two main clades and designed chimeric immunodominant domains (IDDs) from both clades for each EhCoV. IDDs were scaffolded onto two-component nanoparticles (NPs) displaying each IDD separately (monovalent IDD NP); three {beta}-EhCoV IDDs (Mosaic-3 IDD NP); or five EhCoVs 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 EhCoVs, 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 de novo 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 EhCoV vaccine candidates, with potential to decrease frequent SARS-CoV-2 sequence updates and protect against other EhCoVs. Moreover, elicitation of Ab breadth that spans pandemic-threat Sarbecoviruses gives mosaic IDD NPs promise towards pandemic preparedness.

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Dzuvor, C. K. O., Moak, S., McManus, L. R., Thomas, A., Dzordzorme, A. E., Kim, T., Joseph, J., Foley, V., Gordon, I. J., Novik, L., Holman, L. A., Dropulic, L. K., McNamara, R. P., Corbett-Helaire, K. S.. 2025-10-01. Rational Design of Multiclade Coronavirus Spike Immunodominant Domain Nanoparticles Elicit Broad Antibody Responses. https://doi.org/10.1101/2025.10.01.679649

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