BACKGROUND: Waning Spike-elicited immunity and emerging COVID-19 variants underscore the need for vaccines leveraging multiple SARS-CoV-2 antigens, rapidly adaptable to evolving strains. Herein, we evaluated the safety and immunogenicity of a CpG ODN-adjuvanted, alum-adsorbed, virus-like particle (VLP) vaccine displaying the hexaproline stabilized Spike (S) protein and the Nucleocapsid, Membrane, and Envelope proteins of SARS-CoV-2. METHODS: In phase 1 randomized, double-blind, placebo-controlled, dose-escalation trial, participants (N = 38, aged 18-59) received two subcutaneous injections of either 10 μg or 40 μg of VLP or placebo, 21 days apart. The primary and secondary objectives of the study was to evaluate the safety, reactogenicity and immunogenicity, respectively. In the double blind, multi-center phase-2 study, participants (N = 349, aged 18-55) were randomized into three cohorts receiving two doses of 40 μg VLPs displaying Wuhan-Spike, Alpha-Spike, or a combination. The primary and secondary objectives were humoral, and cell mediated immunogenicity (CMI) and safety, respectively. Antibody responses were analyzed using ELISA while ELIspot and CBA assays were used to assess the CMI. RESULTS: The VLP vaccine demonstrated a good safety profile, with 255 non-serious adverse events in phase 1 and 308 in phase 2. Five serious AEs were reported in phase 2, all of which were resolved completely. The VLP vaccine, in phase 2, was well-tolerated, elicited moderate but sustained anti-S and anti-N antibody titers for 180 days and induced T-helper-1 biased cellular responses in participants. CONCLUSIONS: The VLP platform is rapidly adaptable to accommodate stabilized Spike proteins from emerging variants and inclusion of other structural SARS-CoV-2 proteins could broaden the breadth of T cell-mediated immunity. CLINICALTRIALS: gov; NCT04818281 and NCT04962893.