mRNA nanoparticles drive potent SARS-CoV-2 immunity in mice

A multi-institutional team led by University of Washington scientists have engineered a new vaccine platform combining mRNA and computational protein design, producing in mice a potent immune defense against both Wuhan-Hu-1 and omicron BA.5 SARS-CoV-2.

Messenger RNA vaccines proved effective during the COVID-19 pandemic. Ways to further optimize the encoded proteins have remained an ongoing pursuit. Protein nanoparticle immunogens, which can display multiple antigen copies in precise arrays, amplify antibody responses by clustering B cell receptors. Integrating these two approaches could yield vaccines that trigger both strong antibody and T cell immunity while retaining the speed and scalability of mRNA production.

In the study, “Computationally designed mRNA-launched protein nanoparticle immunogens elicit protective antibody and T cell responses in mice,” published in Science Translational Medicine, researchers genetically fused a stabilized SARS-CoV-2 receptor binding domain variant, Rpk9, to a computationally optimized 60-subunit scaffold nanoparticle, I3-01NS.

BALB/c mice served as the primary model for evaluating protection. Each immunogenicity group contained 10 animals receiving either lipid nanoparticles–encapsulated mRNA or adjuvanted protein formulations, with 5 animals receiving empty lipid nanoparticles as negative controls. Challenge experiments used mice in 5 groups of 4 to 6 animals per group per time point for Wuhan-Hu-1 MA10 and in 5 groups of 4 or 5 animals per group per time point for omicron BA.5 MA10.

C57BL/6 mice were used to measure antigen-specific T cell responses, with 5 animals per group for lung and spleen assays after prime and boost immunizations.

mRNA-launched RBD nanoparticles outperformed the comparator mRNA vaccines across experiments. In the single-dose Wuhan-Hu-1 arm, Rpk9–I3-01NS mRNA elicited ~28× higher titers than membrane-anchored S-2P mRNA and ~11× higher than secreted RBD-trimer mRNA.

Even the lowest mRNA dose produced responses comparable to or greater than those achieved with substantially higher doses of standard spike-encoding formulations. Serum analyses after boosting showed persistent neutralization against Wuhan-Hu-1, while additional assays demonstrated cross-reactivity to omicron BA.5.

C57BL/6 mice receiving the nanoparticle mRNA displayed abundant antigen-specific CD8 T cells in both lungs and spleen. Protein-delivered counterparts did not elicit these responses, indicating distinct engagement of cellular immunity by the mRNA platform.

Single-dose vaccination protected mice from lethal challenge with mouse-adapted Wuhan-Hu-1 SARS-CoV-2, preventing weight loss and eliminating detectable virus in lung tissue. Two-dose immunization blocked severe disease after an omicron BA.5 challenge, suppressing viral replication in respiratory tissue and preserving body weight across observation days.

Authors present mRNA-launched protein nanoparticle immunogens as a way to combine multivalent antigen display with nucleic acid manufacturing speed. Their I3-01NS results are a proof of concept, showing a genetically deliverable, computationally designed scaffold that could serve across pathogens when paired with appropriately engineered antigens.

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