Abstract
GMMA are exosomes released from engineered Gram-negative bacteria resembling the composition of outer membranes. We applied the GMMA technology for the development of an O-Antigen (OAg) based vaccine against Shigella sonnei, the most epidemiologically relevant cause of shigellosis. S. sonnei OAg has been identified as a key antigen for protective immunity, and GMMA are able to induce anti-OAg-specific IgG response in animal models and healthy adults. The contribution of protein-specific antibodies induced upon vaccination with GMMA has never been fully elucidated. Anti-protein antibodies are induced in mice upon immunization with either OAg-negative and OAg-positive GMMA. Here we demonstrated that OAg chains shield the bacteria from anti-protein antibody binding and therefore anti-OAg antibodies were the main drivers of bactericidal activity against OAg-positive bacteria. Interestingly, antibodies that are not targeting the OAg are functional against OAg-negative bacteria. The immunodominant protein antigens were identified by proteomic analysis. Our study confirms a critical role of the OAg on the immune response induced by S. sonnei GMMA. However, little is known about OAg length and density regulation during infection and, therefore, protein exposure. Hence, the presence of protein antigens on S. sonnei GMMA represents an added value for GMMA vaccines compared to other OAg-based formulations.
Highlights
Generalized Modules for Membrane Antigens (GMMA) are exosomes released from engineered Gram-negative bacteria resembling the composition of outer membranes
GMMA displaying the OAg on their surface and carrying wild type lipid A were produced from a S. sonnei 53G strain (Ss OAg+) (Table 1)
The expected lipid A structure was confirmed by Matrix-Assisted Laser Desorption/Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF MS) analysis and the ability of the different GMMA to activate Toll-like receptor 4 (TLR-4) was verified in a Monocyte Activation Test (MAT) (Fig. S1b,c)
Summary
GMMA are exosomes released from engineered Gram-negative bacteria resembling the composition of outer membranes. We applied the GMMA technology for the development of an O-Antigen (OAg) based vaccine against Shigella sonnei, the most epidemiologically relevant cause of shigellosis. Anti-protein antibodies are induced in mice upon immunization with either OAg-negative and OAg-positive GMMA. Several bacteria are cause of devastating burden of disease in low- and middle-income countries (LMICs), for which vaccines are not available due to a lack of need in developed countries and consequent absence of financial reward derived from sales. One of such pathogens is Shigella sonnei, the most epidemiologically relevant causative agent of human shigellosis[1,2].
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