In vitro Human Immune Profiling to dissect the immunological response induced by GMMA candidate vaccines

Generalized Modules for Membrane Antigens (GMMA) are outer membrane vesicles purified from Gram-negative bacteria genetically mutated to increase blebbing and reduce risk of reactogenicity, through modification of the lipid A portion of lipopolysaccharide. GMMA resemble the bacteria outer membrane surface and can induce strong immunogenicity, since they are able to present multiple antigens to the immune system in a natural conformation that mimics the bacterial environment, but also due to their properties of self-adjuvanticity. However, further investigations are needed to elucidate their mechanism of action (MoA) and to understand their role in vaccine adjuvanticity when they interact and stimulate the immune system. For this purpose in this work we characterize in depth the immune response induced in human peripheral blood mononuclear cells (hPBMCs) after stimulation with two different variants of Shigella (S.) sonnei GMMA (with or without lipid A modification). Particularly, we demonstrated that S. sonnei GMMA directly target and activate monocytes, myeloid dendritic cells and B cells resulting in the production of a large array of cytokines, which in turn support NK and γδ T cells activation. These findings provide new understandings into the key human innate immune cells targeted by GMMA-based vaccines which could improve the magnitude, the quality and the persistence of the antigen-specific immune response and the subsequent protection from infection.