Efficacy of Immunostimulatory Adjuvants and Nano‐Adjuvants in Current SARS‐CoV‐2 Vaccines: A Comprehensive Review

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.