Do plants used for vaccine production contribute to immunogenicity and immunoprotection beyond antigen expression?

Plant-based systems have proved to be a versatile platform for recombinant vaccine production. Numerous species of model and agronomic edible plants have been engineered to express antigens targeting diverse pathogens. Leaves, fruits, tubers, and seeds have served as expression tissues, while subcellularly, the endoplasmic reticulum, chloroplasts, and vacuoles have been targeted to enhance antigen yield and stability. Furthermore, most of the studies have demonstrated the immunogenicity of vaccines produced and administered within plant tissue. Interestingly, certain studies of wild-type (near-isogenic and non-transgenic) plant tissues used as experimental controls consistently exhibit intrinsic immunostimulatory properties. These effects, often overlooked, include enhanced antibody production, cytokine modulation, and partial protection during pathogen challenge. Bioactive compounds such as alkaloids, flavonoids, terpenoids, glycoalkaloids, polysaccharides, glucosinolates, carotenoids, and phenolics may contribute to these responses, varying across species. Evidence from multiple animal models shows that WT plant matrices can influence immune outcomes, sometimes outperforming inert controls. Recognizing the immunomodulatory contribution of plant-derived compounds is essential for accurately evaluating plant-made vaccines and for optimizing future formulations in both human and veterinary applications.