Zarnegar and Carow et al. showed that the bark-derived, saponin-based adjuvant Matrix-M® (M®; used in COVID-19 and malaria vaccines) – comprising Matrix-A (A) and, to a lesser extent, Matrix-C (C) nanoparticles – colocalized with antigens in lysosomes following uptake by BM-derived DCs. In vitro, M®, A, and most strongly C induced lysosomal membrane permeabilization (LMP), which is required for IL-1β and IL-18 secretion, and A most strongly matured APCs. In vivo, M®, A, and C exhibited robust adjuvant effects in the presence and absence of the NLRP3 inflammasome. LMP induced by M®, A, and most strongly C enabled antigen cross-presentation to induce CD8+ T cell responses.
Contributed by Paula Hochman
ABSTRACT: Matrix-M® adjuvant, containing saponins, delivers a potent adjuvant effect and good safety profile. Given that Matrix-M is composed of Matrix-A and Matrix-C particles, comprising different saponin fractions, understanding their distinct roles can provide deeper insight into the mechanism of action of Matrix-M and guide future applications. Here, we demonstrate that the antigen and Matrix-M, Matrix-A, or Matrix-C colocalize in lysosomes following uptake by bone marrow-derived dendritic cells. Matrix-M, Matrix-A, and Matrix-C induce lysosomal membrane permeabilization (LMP), but Matrix-C shows the highest LMP potential. LMP is required for interleukin (IL)-1β and IL-18 secretion in vitro. In vivo, a robust adjuvant effect of Matrix-M, Matrix-A, and Matrix-C is observed, both in the presence and absence of the NLRP3 inflammasome. LMP induced by Matrix-M, as well as Matrix-A and Matrix-C, also enables antigen cross-presentation. Thus, Matrix-induced LMP explains the capability of Matrix-M-adjuvanted protein vaccines to induce CD8+ T-cell responses.
Author Info: (1) Novavax AB, Uppsala, Sweden. (2) Novavax AB, Uppsala, Sweden. bcarow@novavax.com. (3) Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Author Info: (1) Novavax AB, Uppsala, Sweden. (2) Novavax AB, Uppsala, Sweden. bcarow@novavax.com. (3) Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. (4) Novavax AB, Uppsala, Sweden. (5) Novavax AB, Uppsala, Sweden. (6) Novavax AB, Uppsala, Sweden. (7) Novavax AB, Uppsala, Sweden. (8) Novavax AB, Uppsala, Sweden. (9) Novavax AB, Uppsala, Sweden. (10) Novavax AB, Uppsala, Sweden. (11) Novavax AB, Uppsala, Sweden. (12) Novavax AB, Uppsala, Sweden. (13) Novavax AB, Uppsala, Sweden. (14) Novavax AB, Uppsala, Sweden. (15) Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Science for Life Laboratory, Uppsala, Sweden. (16) Novavax AB, Uppsala, Sweden. (17) Novavax AB, Uppsala, Sweden. (18) Novavax AB, Uppsala, Sweden.
