(250c) Polymersomes Decorated with Sars-Cov-2 Spike Protein Receptor Binding Domain Elicit Robust Humoral and Cellular Immunity

Motivation: Since the emergence of the novel coronavirus SARS-CoV-2, researchers across the world have sought to rapidly develop vaccine candidates. The primary antigen targets are the Spike protein or its constituent receptor binding domain (RBD) which is responsible for ACE-2 binding and viral entry into the host cell. While several highly potent neutralizing antibodies against RBD have been isolated, RBD has also been shown to have lower immunogenicity than the full spike protein. Materials science and engineering approaches, particularly strategies involving nanotechnology, may improve RBD immunogenicity and are expected to aid in the development of new subunit vaccines.

Methods: We have previously reported the development of polymersomes (PS) that self-assemble from the oxidation-responsive block copolymer PEG-PPS and shown their efficacy in activating dendritic cells, inducing robust T cell immunity, and eliciting high antibody titers with broad epitope coverage. To further improve the humoral response of PS while retaining their ability to induce T cell immunity, we engineered their surface to display multiple copies of antigen, mimicking the physical form of the virus (Fig. 1a). We hypothesized that these surface-conjugated PS would result in the crosslinking of B cell receptors and subsequent production of neutralizing antibodies. Here, we evaluate RBD-surface-bound PS (RBD_surf) and RBD-encapsulated PS (RBD_encap) adjuvanted with MPLA PS compared to adjuvanted and unadjuvanted free RBD as vaccine candidates in mice.

Results: While all groups receiving adjuvanted RBD regardless of antigen formulation produced high titers of RBD-specific IgGs, only RBD-surface-conjugated PS elicited antibodies that neutralized live SARS-CoV-2 in vitro (Fig. 1b). These antibodies bound to linear epitopes found within the receptor binding motif, which is primarily responsible for interacting with ACE-2. Furthermore, RBD-surface-conjugated PS also showed robust antigen-specific germinal center responses and both CD4⁺and CD8⁺ T cell immunity.

Implications: This work provides insights into differing B cell and T cell immunity of different antigen formulations in the context of COVID-19 and can thus be used to inform the design of next-generation subunit nanovaccines.