Figure 1.

Proposed Matrix-M™ adjuvant mechanism of action.

Panel A. Injection of Matrix-M™-adjuvanted vaccine into the muscle (event 1) leads to a transient recruitment and activation of innate immune cells, including antigen-presenting cells, at the injection site. The presence of Matrix-M facilitates antigen uptake and transport to the draining lymph nodes (event 2), where the Matrix-M-induced immune environment of recruited and activated immune cells results in enhanced antigen presentation to CD4+ and CD8+ T cells (event 3). Activated CD4+ T cells then differentiate into CD4+ T helper (Th) 1, Th2, or T follicular helper cells (Tfh) (event 4), with the latter supporting germinal center formation (event 5). In these germinal centers, activated B cells interact with Tfh and follicular dendritic cells (FDC) and undergo affinity maturation and further differentiation (event 6). This leads to the formation of high-affinity and long-lasting antibody and memory responses (event 7). Similarly, CD4+ Th1 and Th2, as well as CD8+ memory T cells are generated (event 8).

Panel B. After being taken up by antigen-presenting cells (event 1), Matrix-M adjuvant and antigen localize to the lysosomes (event 2), where some portion of antigen is degraded by proteases. The acidic environment inside the lysosome also allows the release of “free” saponins (event 3), which in turn contributes to the induction of lysosomal membrane permeabilization and subsequent translocation of both intact and degraded antigen to the cytosol (event 4). Matrix-M induces upregulation of co-stimulatory and MHC molecules (event 5), thus promoting presentation of antigenic peptides by two routes. Antigenic peptides from the lysosome bind to MHC class II for presentation to CD4+ T cells, while degradation of intact antigen in the cytosol permits binding to MHC class I for cross-presentation to CD8+ T cells (event 6). In addition, Matrix-M induces activation of NLRP3 inflammasome leading to the release of IL-1β and IL-18 (event 7) as well as the production and secretion of other cytokines (event 8).

Ag, antigen; DAMPs, damage-associated molecular patterns; FDC, follicular dendritic cells; GC, germinal centers; IL, interleukin; MHCI/MHCII, major histocompatibility complex I/II; TCR, T-cell receptor; Tfh, T follicular helper cells; Th, T helper; TNF, tumor necrosis factor; ROS, reactive oxygen species.