SpyStapler-mediated assembly of nanoparticle vaccines

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has wreaked havoc around the globe, with no end in sight. The rapid emergence of viral mutants, marked by rapid transmission and effective immune evasion, has also posed unprecedented challenges for vaccine development, not least in its speed, mass production, and distribution. Here we report a versatile “plug-and-display” strategy for creating protein vaccines, including those against malaria parasites and SARS-CoV-2, through the combined use of the intrinsically disordered protein ligase SpyStapler and computationally designed viral-like particles. The resulting protein nanoparticles harboring multiple antigens induce potent neutralizing antibody responses in mice, substantially stronger than those induced by the corresponding free antigens. This modular vaccine design enabled by SpyStapler furnishes us with a new weapon for combatting infectious diseases. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (further details of the protein sequences, cloning procedures, TEM imaging, ELISA details, and reaction controls) is available in the online version of this article at 10.1007/s12274-022-4951-9.