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Lymph Node Follicle-Targeting STING Agonist Nanoshells Enable Single-Shot M2e Vaccination for Broad and Durable
Hsiao-Han Tsai1,2, Ping-Han Huang3, Leon Cw Lin1,4
1Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
Abstract:
The highly conserved matrix protein 2 ectodomain (M2e) of influenza viruses presents a compelling vaccine antigen candidate for stemming the pandemic threat of the mutation-prone pathogen, yet the low immunogenicity of the diminutive M2e peptide renders vaccine development challenging. A highly potent M2e nanoshell vaccine that confers broad and durable influenza protectivity under a single vaccination is shown. Prepared via asymmetric ionic stabilization for nanoscopic curvature formation, polymeric nanoshells co-encapsulating high densities of M2e peptides and stimulator of interferon genes (STING) agonists are prepared. Robust and long-lasting protectivity against heterotypic influenza viruses is achieved with a single administration of the M2e nanoshells in mice. Mechanistically, molecular adjuvancy by the STING agonist and nanoshell-mediated prolongation of M2e antigen exposure in the lymph node follicles synergistically contribute to the heightened anti-M2e humoral responses. STING agonist-triggered T cell helper functions and extended residence of M2e peptides in the follicular dendritic cell network provide a favorable microenvironment that induces Th1-biased antibody production against the diminutive antigen. These findings highlight a versatile nanoparticulate design that leverages innate immune pathways for enhancing the immunogenicity of weak immunogens. The single-shot nanovaccine further provides a translationally viable platform for pandemic preparedness.
Insights
This study developed a potent influenza nanovaccine using M2e peptides and STING agonists. A single dose provides broad, durable protection against diverse influenza strains by enhancing immune responses.
Area of Science:
- Vaccinology
- Nanotechnology
- Immunology
Background:
- The matrix protein 2 ectodomain (M2e) is a conserved influenza antigen, but its low immunogenicity hinders vaccine development.
- Developing effective vaccines against mutation-prone influenza viruses remains a global health challenge.
Purpose of the Study:
- To create a potent nanovaccine using M2e peptides and STING agonists for broad and durable influenza protection.
- To investigate the mechanisms underlying the enhanced immunogenicity induced by the M2e nanoshell vaccine.
Main Methods:
- Polymeric nanoshells were synthesized via asymmetric ionic stabilization, co-encapsulating high densities of M2e peptides and STING agonists.
- The M2e nanoshell vaccine's efficacy and durability were evaluated in mice against heterotypic influenza viruses.
- Immunological responses, including humoral immunity and T cell functions, were analyzed.
Main Results:
- A single administration of M2e nanoshells conferred robust and long-lasting protection against heterotypic influenza viruses in mice.
- The STING agonist acted as a molecular adjuvant, prolonging M2e antigen exposure in lymph node follicles.
- Enhanced anti-M2e humoral responses were observed, characterized by Th1-biased antibody production.
Conclusions:
- The M2e nanoshell vaccine design effectively enhances the immunogenicity of weak antigens by leveraging innate immune pathways.
- This single-shot nanovaccine platform offers a translationally viable approach for pandemic preparedness against influenza.
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