Immunopotentiation by Natural Extracts: Mechanisms and Applications in Influenza Vaccine Adjuvant Development.

Despite the widespread use of seasonal influenza vaccines, their efficacy remains limited particularly among the elderly, immunocompromised individuals, and in the face of antigenically drifted or shifted viral strains. Traditional adjuvants enhance vaccine efficacy but may have limitations related to safety, tolerability, or restricted immune activation. Natural extracts derived from plants, marine organisms, fungi, and algae are gaining attention as novel adjuvants due to their ability to modulate both innate and adaptive immunity with low toxicity. This review highlights key natural compounds such as polysaccharides (fucoidan, chitosan, Advax), saponins (QS-21, Matrix-M), and flavonoids (naringenin) and their mechanisms of action, including activation of dendritic cells, cytokine induction, and enhancement of T and B cell responses. These extracts promote balanced Th1/Th2 polarization, memory cell formation, and improved mucosal and systemic immunity. We also summarize in vitro and in vivo methods used for adjuvant screening, including immune cell activation assays, T/B cell co-culture systems, and murine vaccination models. Natural extract-based adjuvants offer formulation flexibility for various vaccine platforms and delivery routes, including intranasal and intramuscular administration. Their favorable safety profiles, immunostimulatory potency, and capacity to enhance cross-protective immunity position them as strong candidates for next-generation adjuvants for influenza vaccines. Ongoing research may enable their broader application in improving vaccine performance across diverse populations.