SARS-CoV-2 engages host cell receptors with the receptor binding domain (RBD) of its spike glycoprotein. Several subunit vaccines based on the RBD antigen are in clinical development to address the ongoing COVID-19 pandemic. Multivalent antigen display drives B-cell activation and can promote antibody cross-reactivity as well as long-term immunity in response to subunit vaccines. However, our understanding of the nanoscale parameters governing B-cell receptor (BCR) signaling and downstream antibody responses remains limited. DNA origami provides independent control over these parameters, namely valency and spacing at constant particle size and geometry. Here, we report on the covalent functionalization of icosahedral DNA-based virus-like particles (DNA-VLPs) with RBD to probe B-cell activation. Toward this end, two recombinant B-cell lines expressing clinically relevant antibodies were established. We observed valency-dependent BCR signaling enhancement compared to monomeric RBD for both cell lines. DNA-VLPs bearing 30 RBDs further elicited enhanced antibody responses in mice, correlating with our <i>in vitro</i> observations. These observations were corroborated by the VLP-dependent cross-neutralization of several SARS-CoV-2 pseudoviruses including the immune evasive Beta variant. In summary, we demonstrate the utility of DNA origami for <i>in vivo </i>antigen delivery and its potential to elucidate the nanoscale parameters of antigen display.

Enhancing antibody responses against SARS-CoV-2 antigens using DNA origami

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ACS Fall 2022

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