Abstract
BACKGROUND AND AIMS: SARS-CoV-2 continues to pose global challenges, and current vaccines face limitations (variant escape, waning immunity). This review evaluates immunostimulatory adjuvants and nano-adjuvants to enhance immune responses and optimize SARS-CoV-2 vaccine performance. METHODS: Narrative review of preclinical and clinical evidence on alum, emulsions (MF59, AS01/AS03), Montanide ISA-51, delta inulin, TLR agonists (e.g., CpG, TLR3), rOv-ASP-1, and nano/mucosal platforms (liposomes, polymeric or metal nanoparticles, Protollin) for SARS-CoV-2 and related coronaviruses. RESULTS: Alum and emulsions increased neutralizing antibodies; Th1-promoting combinations (e.g., CpG with Montanide or with protein antigens) mitigated Th2-biased immunopathology seen with some inactivated vaccines. MF59, AS01/AS03, and Matrix-type systems enhanced humoral and cellular responses, with early clinical data supporting acceptable safety and robust immunogenicity. Delta inulin (±CpG) boosted neutralization without lung injury in comparative models. TLR agonists and intranasal Protollin induced systemic IgG and mucosal IgA. Nano-adjuvants improved antigen presentation and enabled dose-sparing while supporting balanced, durable immunity. CONCLUSION: Immunostimulatory and nano-adjuvants substantially strengthen SARS-CoV-2 vaccine immunogenicity, support antigen-sparing, and favor balanced (often Th1-biased) protection. Prudent adjuvant selection and integration of conventional and nanotechnology-derived platforms are key to achieving safe, durable, and broadly protective COVID-19 vaccines.