Overcoming Immunodominance by A Nanoparticle Adjuvant for Universal Influenza Vaccine Development 2255617

Abstract Introduction The immunodominance hierarchy of influenza antigens remains a major obstacle in developing broadly protective vaccines. Current flu vaccines primarily elicit antibody responses against variable head regions of hemagglutinin (HA), leading to strain-specific immunity and limited cross-protection. Cyclic dinucleotides (CDNs), potent agonists of the stimulator of interferon genes (STING) pathway, have emerged as promising adjuvants that can enhance both humoral and cellular immunity. In this study, we sought to investigate the capacity of CDN nanoparticle formulations to overcome immunodominance in influenza vaccination by combining CDN nanoparticles with influenza antigens. Methods Female C57BL/6 mice were immunized subcutaneously twice, with a 4-week interval between doses. Each group received either inactivated influenza vaccine (IIV) or hemagglutinin (HA) subunit antigen formulated with or without CDN nanoparticles. Serum samples were collected at defined time points to quantify antigen-specific IgG responses by ELISA. At the study endpoint, draining lymph nodes (inguinal lymph nodes) were harvested to assess germinal center B cell responses by flow cytometry, while bone marrow samples were collected to evaluate the frequencies of long-lived plasma cells reactive to influenza antigens by ELISpot. Results CDN nanoparticles not only enhanced the GC formation in draining lymph nodes, resulting in increased frequencies of stem-specific B cells within the GC, but also increased the frequencies of long-lived plasma cells (LLPCs) in the bone marrow. Consequently, serum antibody responses were broader and more durable. Conclusion CDN nanoparticle adjuvants broadened antibody specificity, enhanced germinal center reactions, and promoted durable long-lived plasma cell formation. This strategy overcomes the immunodominance of conventional vaccines and represents a promising approach for developing next-generation influenza vaccines with broader and longer-lasting protection. Funding Source NIH Topic Categories Vaccines and Immunotherapy (VAC)