The induction of respiratory mucosal immunity, characterized by secretory IgA (sIgA) and lung-resident memory T (TRM) cells, is essential for establishing robust first-line defence against viruses. While it is regarded as a critical target for next-generation SARS-CoV-2 vaccine development, current intramuscular vaccines often fail to elicit potent mucosal responses, and subunit antigens usually exhibit poor immunogenicity and limited protection against emerging variants when administered alone.
To that, an approach based on the modular "plug-and-display" assembly utilizing bacterial lipidation offers an attractive strategy to create self-adjuvanting platforms and enhance the mucosal immune response. In a study published in Glycoscience & Therapy, a team of researchers in China designed a new type of bacterial lipidation-based SARS-CoV-2 mucosal nanovaccine (lipoSC-RBDST). It was constructed through orthogonal assembly, and evaluated for its long-term protective efficacy and rapid adaptability to variants.
"Unlike conventional mucosal formulations that rely on exogenous adjuvants or viral vectors with pre-existing immunity risks, our approach targets the spontaneous, covalent display of antigens on a self-adjuvanting nanostructure—a critical feature for potent TLR2 signaling activation," explains lead author Huifang Xu. "The resulting lipoSC-RBDST nanovaccine demonstrates exceptional structural integrity and immunogenic potency, eliciting robust secretory IgA (sIgA) and lung-resident memory T (TRM) cells necessary for a first line of defense."
Notably, the new lipoSC-RBDST nanovaccine elicits exceptionally high levels of respiratory sIgA and systemic neutralizing antibody titers, activates potent lung-resident memory T (TRM) cell responses, and mediates significant protective effects including long-lasting immunity for at least eight months.
"Mechanistically, the vaccine utilizes a self-adjuvanting bacterial lipidation scaffold to activate the TLR2 pathway, facilitating the establishment of comprehensive respiratory protection in the lungs, demonstrating high clinical relevance for pandemic preparedness," adds Xu.
This approach not only provides a promising candidate for further development against SARS-CoV-2 variants like XEC but also establishes a generalizable modular assembly strategy—orthogonal construction on a lipidated protein scaffold—that could be applied to other respiratory pathogens, thereby expanding the arsenal of mucosal vaccine developments.
