AS04-adjuvanted semisynthetic glycoconjugate vaccine against Pseudomonas aeruginosa.

The immunogenicity limitation has underscored the critical need for human vaccine adjuvants that can elicit potent and durable humoral and cellular immunity tailored to semisynthetic glycoconjugates. To circumvent the toxicity of Freund's adjuvant (FA) and advance a broad-spectrum, oligomannuronic acid-based semisynthetic glycoconjugate toward a clinically viable vaccine against multidrug-resistant Pseudomonas aeruginosa for at-risk populations, the identification of an adjuvant that can enhance both humoral and cellular immunity and confer durable protection for semisynthetic glycoconjugates is imperative. Here, the oligomannuronic acid-based semisynthetic glycoconjugate vaccine formulated with clinically relevant adjuvants (AS04 and Alum) was systematically evaluated in comparison to the FA formulation. The AS04-adjuvanted glycoconjugate could induce a robust and balanced Th1/Th2/Th17 immune profile, characterized by high and sustained IgG titers comparable to those elicited by Alum and FA. It also generated robust CD4+ and CD8+ effector memory T (TEM) cell responses similar to the patterns observed with Alum and FA formulations, a feature essential for long-term protection against reinfection. In mouse challenge models, the semisynthetic glycoconjugate formulated with AS04 significantly reduced pulmonary bacterial loads, attenuated proinflammatory cytokine secretion, diminished immunopathology, and improved survival rates against both mucoid and nonmucoid P. aeruginosa strains, establishing its viability as a clinically relevant vaccine candidate.