Project Summary/Abstract Current influenza vaccines mainly induce strain-specific protection. Universal influenza vaccines are under active development to induce broad cross-protection. Extracellular ectodomain of matrix protein 2 (M2e) and intracellular nucleoprotein (NP) are highly conserved across viral strains and are attractive targets in universal influenza vaccine development. Various preclinical and clinical studies support the induction of anti-M2e antibodies and anti-NP cytotoxic T lymphocytes (CTLs) to induce broad cross-protective immunity. Due to the low immunogenicity of M2e and NP, highly immunogenic vaccine carriers are demanded to present these conserved vaccine antigens to induce potent cross-reactive immune responses. This proposal explores our recently developed high-density flagellin-displayed hepatitis b core (HBc) virus-like particles (VLPs) (FH VLPs) in combination with a clinical CpG adjuvant (FHc VLPs) for universal influenza vaccine development. FH VLPs show better immunogenicity and safety than FljB and more versatility than HBc VLPs for vaccine development. Furthermore, a clinical CpG adjuvant will be encapsulated into the core of FH VLPs to potentiate vaccine- induced humoral immune responses and at the same time to induce potent CTL responses. This proposal prepares M2e and NP-displayed FHc VLP-based universal influenza vaccines (Specific aim 1) and explore their safety, immunogenicity, and cross-protective efficacy in murine models (Specific aim 2). This proposal is in response to National Institute of Allergy and Infectious Diseases (NIAID)'s call for Advancing Research Needed to Develop a Universal Influenza Vaccine (PA-18-858).