GMMA-Based Vaccines: The Known and The Unknown

Abstract

Generalized Modules for Membrane Antigens (GMMA) are outer membrane vesicles derived from Gram-negative bacteria engineered to provide an over-vesiculating phenotype, which represent an attractive platform for the design of affordable vaccines. GMMA can be further genetically manipulated to modulate the risk of systemic reactogenicity and to act as delivery system for heterologous polysaccharide or protein antigens. GMMA are able to induce strong immunogenicity and protection in animal challenge models, and to be well-tolerated and immunogenic in clinical studies. The high immunogenicity could be ascribed to their particulate size, to their ability to present to the immune system multiple antigens in a natural conformation which mimics the bacterial environment, as well as to their intrinsic self-adjuvanticity. However, GMMA mechanism of action and the role in adjuvanticity are still unclear and need further investigation. In this review, we discuss progresses in the development of the GMMA vaccine platform, highlighting successful applications and identifying knowledge gaps and potential challenges.

Keywords: GMMA; Generalized modules for membrane antigens; OMV; mode of action; reactogenicity; vaccine.

Figure 1

GMMA mechanism of action. (A) GMMA vaccines have been administered intramuscularly. At the injection site, GMMA may be coated by proteins present in the interstitial fluid. The kind and amount of these proteins is influenced by GMMA size and physico-chemical properties. GMMA trafficking to the lymph node (LN) may require cellular transport from antigen presenting cells (APCs) (A-I) but GMMA can also be able to drain freely to the LN (A-II). (B) Upon arrival into the LN, GMMA and APCs circulate into the LN subcapsular sinus where subcapsular sinus macrophages (SCSM) reside. SCSM can uptake GMMA in complex with IgG and can reach the LN follicular area where they transfer the antigen to B cells. B cell receptor crosslinking and B cell activation is facilitated by repetitive display of optimally spaced antigen on GMMA. Also follicular dendritic cells (FDCs) play a major role in germinal center (GC) kinetics and in the development of humoral responses. GMMA delivered to the LN via active transport are presented to naïve T cells with antigen-cognate T cell receptors in the T cell zone. T cells also interact with activated B cells, that present them antigen-derived peptides thus providing T cell ‘help’ to B cells, sustaining their activation and driving the formation of GCs. (C) GMMA drive the selection of B cell clones with high antigen affinity into long-lasting memory B cells and/or long-lived antibody-producing plasma cells and possibly the differentiation of T cells in different subsets of T helper (Th) cells.