Computationally designed mRNA-launched protein nanoparticle immunogens elicit protective antibody and T cell responses in mice

Messenger RNA (mRNA) vaccines and computationally designed protein nanoparticle vaccines were both clinically derisked and licensed for the first time during the coronavirus disease 2019 (COVID-19) pandemic. These vaccine modalities have complementary immunological benefits that provide strong motivation for their combination. Here, we demonstrate proof of concept for genetic delivery of computationally designed protein nanoparticle immunogens. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model system, we genetically fused a stabilized variant of the Wuhan-Hu-1 spike protein receptor binding domain (RBD) to a protein nanoparticle we previously designed for optimal secretion from human cells. Upon secretion, the nanoparticle formed monodisperse and antigenically intact assemblies displaying 60 copies of the RBD in an immunogenic array. Compared with mRNA vaccines encoding membrane-anchored spike protein and a secreted RBD trimer, an mRNA vaccine encoding the RBD nanoparticle elicited 5- to 28-fold higher titers of neutralizing antibodies in mice. In addition, the "mRNA-launched" RBD nanoparticle vaccine induced higher frequencies of antigen-specific CD8 T cells than the same immunogen delivered as adjuvanted protein and protected mice from either Wuhan-Hu-1 or Omicron BA.5 challenge. These results establish that delivering computationally designed protein nanoparticle immunogens through mRNA can combine the benefits of both vaccine modalities. More broadly, our data highlight the utility of computational protein design in genetic vaccination strategies.

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Publication Details

Journal
Science Translational Medicine
Published
2025-10-15
DOI
https://doi.org/10.1126/scitranslmed.adu2085
Citations
10
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
13.96
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Computationally designed mRNA-launched protein nanoparticle immunogens elicit protective antibody and T cell responses in mice

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Science Translational Medicine
SARS-CoV-2 and COVID-19 Research
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Computationally designed mRNA-launched protein nanoparticle immunogens elicit protective antibody and T cell responses in mice

Suna Cheng, John M. Powers, Marcos C. Miranda, Max Johnson, Elizabeth M. Leaf, Molly M. H. Sung, Neil P. King, Ralph Steven Baric, Alexandra C. Walls, Sebastian Ols, Lilit Grigoryan, Sidney Chan, Bali Pulendran, Melissa D. Mattocks, Daniel Ellis, Paulo J.C. Lin, Grace G. Hendricks, Jing Yang Wang, Jimin Lee, Nicholas Catanzaro, Ying K. Tam, Catherine Treichel, Samantha K. Zepeda, Norbert Pardi, Adian S. Valdez, Harold Hui, Alexandra Schäfer, Hiromi Muramatsu, David Veesler, Cara W. Chao, Victor Lujan, Shengyang Wu, Mary Jane Navarro, Christine Men, Miranda L. Hubbard
article en
10 citations

Abstract

Messenger RNA (mRNA) vaccines and computationally designed protein nanoparticle vaccines were both clinically derisked and licensed for the first time during the coronavirus disease 2019 (COVID-19) pandemic. These vaccine modalities have complementary immunological benefits that provide strong motivation for their combination. Here, we demonstrate proof of concept for genetic delivery of computationally designed protein nanoparticle immunogens. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model system, we genetically fused a stabilized variant of the Wuhan-Hu-1 spike protein receptor binding domain (RBD) to a protein nanoparticle we previously designed for optimal secretion from human cells. Upon secretion, the nanoparticle formed monodisperse and antigenically intact assemblies displaying 60 copies of the RBD in an immunogenic array. Compared with mRNA vaccines encoding membrane-anchored spike protein and a secreted RBD trimer, an mRNA vaccine encoding the RBD nanoparticle elicited 5- to 28-fold higher titers of neutralizing antibodies in mice. In addition, the "mRNA-launched" RBD nanoparticle vaccine induced higher frequencies of antigen-specific CD8 T cells than the same immunogen delivered as adjuvanted protein and protected mice from either Wuhan-Hu-1 or Omicron BA.5 challenge. These results establish that delivering computationally designed protein nanoparticle immunogens through mRNA can combine the benefits of both vaccine modalities. More broadly, our data highlight the utility of computational protein design in genetic vaccination strategies.

Science Translational MedicineVol. 17(820)
University of North Carolina at Chapel Hill (US), Howard Hughes Medical Institute (US), University of Washington (US), Acuitas Therapeutics (Canada) (CA), University of Pennsylvania (US), Stanford University (US)
Openalex Percentile: Top 1%
SARS-CoV-2 and COVID-19 Research
13.96
DOISourceOpenAlex
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