Multiscale dynamic immunomodulation by a nanoemulsified Trojan-TLR7/8 adjuvant for robust protection against heterologous pandemic and endemic viruses.

The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19. To ensure long-term and broad protection against heterologous virus variants, antigen-specific polyfunctional T cells should be orchestrated with the activation of follicular helper T (TFH) cells and germinal center (GC) B cells. Herein, we suggest a novel engineered nanoadjuvant (SE(Trojan-TLR7/8a)) that enhances the migration of nonexhausted antigen-presenting cells (APCs) into lymph nodes and elicits the activation of TFH cells, the generation of GC B cells, and polyfunctional T cells via multiscale dynamic immunomodulation through squalene nanoemulsion (SE)-mediated macroscopic control of vaccine delivery and Trojan-TLR7/8a-enabled dynamic and sustained activation of APCs at the cellular level. SE(Trojan-TLR7/8a) can be lyophilized, reduce systemic toxicity, and outperform current commercial vaccine adjuvants (Alum or AS03) and mRNA vaccines. SE(Trojan-TLR7/8a) ensures cross-protection against diverse influenza and SARS-CoV-2 variants, providing 100% protection while maintaining a healthy state. SE(Trojan-TLR7/8a) also sustains a potent T-cell response in an aged ferret model of SFTSV infection. SE(Trojan-TLR7/8a) suggested herein provides a novel vaccine design principle for dynamic modulation at the multiscale level and demonstrates long-term and broad protective immunity against emerging pandemic and endemic infectious viruses.