Periodic mesoporous organosilica-loaded mincle agonists enhance the immunogenicity of COVID-19 subunit vaccines by dual activation of B cells and dendritic cells.

Effective vaccination is crucial for intervening in the COVID-19 pandemic. However, with the continuous mutation of the SARS-CoV-2, existing vaccines including subunit vaccines cannot effectively prevent virus infections. Hence, there is an urgent need to enhance the immunogenicity of existing vaccines to induce a more potent and durable immune response. We previously found that periodic mesoporous organosilica (PMO) could act as a potential nanoadjuvant for subunit vaccines, eliciting potent antigen-specific germinal center (GC) responses by activating naïve B cells. In this study, we describe the design of PMO decorated with TDB, a potent Macrophage-induced C-type lectin (Mincle) agonist, to improve the adjuvanticity of PMO for COVID-19 vaccines. We found that the TDB@PMO adjuvant can effectively deliver antigens to lymph nodes and promote antigen uptake by immune cells. More importantly, the TDB@PMO adjuvant vaccine could activate the innate immune of both naïve B cells and dendritic cells via the Mincle signaling pathway, and further enhance the GC responses and resulting in potent SARS-CoV-2 specific humoral and cellular immune responses. Overall, we have developed an effective and safe nanoadjuvant platform, laying the foundation for the design and development of subunit vaccines against pathogens such as SARS-CoV-2. STATEMENT OF SIGNIFICANCE: Adjuvants play a crucial role in enhancing the effectiveness of vaccines by boosting the immune response. The emergence of highly mutated viruses, such as coronaviruses, has presented new requirements for adjuvant design. This work designed a nanoadjuvant platform, TDB@PMO, to enhance the immune response of the COVID-19 subunit vaccine. The result demonstrated that TDB@PMO nanoadjuvant can simultaneously boost the activation effects of B cells and DC cells through the Mincle signaling pathway. Furthermore, immunization with TDB@PMO-RBD nanoadjuvanted vaccine in mice significantly enhanced germinal center responses and antibody production, while also eliciting a robust antigen-specific T cell immune response in spleen. This design provided a reference for the development of next-generation virus subunit vaccines.