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.

Towards a Four-Component GMMA-Based Vaccine against Shigella

“…However, Shigella epidemiology is not static and has been shown to be time-and geography-dependent, complicating vaccine design, already challenged by a limited up to date understanding of serotype burden, need for cross-reactivity of immune responses to different serotypes to simplify vaccine composition, and possible interference among multiple vaccine components. GMMA are highly immunogenic bacterial outer membrane exosomes used as an antigen delivery system [29,30]. Combinations of GMMA, manufactured at high yield and at low cost, seem to be a promising technology for addressing the goal of an affordable vaccine against Shigella for LMICs.…”

“…Here we present the journey towards the development of a potential low-cost fourcomponent Shigella vaccine, eliciting broad protection against the most prevalent Shigella serotypes, that makes use of the GMMA (Generalized Modules for Membrane Antigens) technology, a novel platform based on bacterial outer membranes for delivery of the OAg to the immune system [29,30].…”

GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus

“…Extracted GAC was purified by tangential flow filtration and anionic exchange chromatography, as previously described [17]. Purified GAC contained no hyaluronic acid, <4% protein and <1% DNA impurities (w/w with respect to GAC) and showed an average molecular size of 7.0 kDa, corresponding to an average of 14 repeating units per chain, as estimated by HPLC-SEC analysis (TSK gel G3000 PWXL column) using a calibration curve of dextrans (5,25,50,80, 150 kDa, Merck, Darmstadt, Germany).…”

“…Among these systems, Outer Membrane Vesicles (OMV) have been proposed, which also possess intrinsic adjuvant properties [ 22 , 23 , 24 ]. GMMA (Generalized Modules for Membrane Antigens) are OMV derived from bacteria genetically engineered to enhance their release and to reduce the risk of reactogenicity [ 25 ]. The GMMA manufacturing process is simple, robust and cost-effective, thus potentially leading to affordable vaccines, especially for low- and middle-income countries (LMIC) [ 26 ].…”

Dissecting in Vitro the Activation of Human Immune Response Induced by Shigella sonnei GMMA

“…In particular, in the case of Shigella, the required genetic modification is the deletion of tolR gene, encoding for a protein involved in the linking of inner and outer membranes (Bereswill et al, 2012;Rossi et al, 2014). GMMA represent an attractive vaccine technology (Rietschel et al, 1991;Schromm et al, 2000;Bereswill et al, 2012;Rossi et al, 2014;Mancini et al, 2020;Micoli and MacLennan, 2020;Antonelli et al, 2021;Fiorino et al, 2021), as they can naturally express the same bacteria antigens or can be carriers of protein antigens or polysaccharides to induce a specific immune response (Bereswill et al, 2012;Kis et al, 2019;Mancini et al, 2021). GMMA stimulate innate immune cells, as they are able to provide innate signals via ligands of toll-like receptors (TLRs) and via pathogen-associated molecular patterns (PAMPs) (Mancini et al, 2020).…”