GMMA Is a Versatile Platform to Design Effective Multivalent Combination Vaccines

Abstract

Technology platforms are an important strategy to facilitate the design, development and implementation of vaccines to combat high-burden diseases that are still a threat for human populations, especially in low- and middle-income countries, and to address the increasing number and global distribution of pathogens resistant to antimicrobial drugs. Generalized Modules for Membrane Antigens (GMMA), outer membrane vesicles derived from engineered Gram-negative bacteria, represent an attractive technology to design affordable vaccines. Here, we show that GMMA, decorated with heterologous polysaccharide or protein antigens, leads to a strong and effective antigen-specific humoral immune response in mice. Importantly, GMMA promote enhanced immunogenicity compared to traditional formulations (e.g., recombinant proteins and glycoconjugate vaccines), without negative impact to the anti-GMMA immune response. Our findings support the use of GMMA as a “plug and play” technology for the development of effective combination vaccines targeting different bugs at the same time.

Glycoconjugate vaccines against Salmonella enterica serovars and Shigella species: existing and emerging methods for their analysis

“…For a full-sized antigen, the response was similar irrespective of protein conjugate, but in formulation with fragmented Vi, after second immunisation a booster response was only observed with TT but not with CRM 197 and DT that may be linked to the larger size of TT as well as its T-cell epitopes (Arcuri et al 2017 ; Wessels et al 1998 ; Lockyer et al 2020 ). With a CRM 197 conjugate, Vi PS of less than 50 kDa gave a booster dose, while full-length Vi PS led to hypo-responsiveness (Micoli et al 2020a , b ). Although Vi-CRM 197 and Vi- r EPA behaved differently when tested in infants, the source and size of Vi PS were different, and these factors should also be considered (Thiem et al 2011 ; Bhutta et al 2014 ; Micoli et al 2020a , b ).…”

“…With a CRM 197 conjugate, Vi PS of less than 50 kDa gave a booster dose, while full-length Vi PS led to hypo-responsiveness (Micoli et al 2020a , b ). Although Vi-CRM 197 and Vi- r EPA behaved differently when tested in infants, the source and size of Vi PS were different, and these factors should also be considered (Thiem et al 2011 ; Bhutta et al 2014 ; Micoli et al 2020a , b ). Another study has also confirmed that immune response to Vi-DT in mice was stronger with an increasing amount of cross-linking and the subsequent size of the conjugate (An et al 2011 ).…”

“…Moreover, for Vi-CRM 197 , studies in mice indicated that shorter polysaccharide have less risk of inducing unfavourable T-independent immune response and hypo-responsiveness compared to long-chain Vi conjugates. Therefore, the elimination of T-independent responses elucidated by potential glycan candidates may be the next important control used for rational vaccine design and testing (Micoli et al 2020a , b ). For Shigella , use of a succinylated carrier protein was found to produce more immunogenic glycoconjugates compared to the unaltered version so chemical modifications of carrier proteins are also important to consider and need to be analysed (Barel and Mulard 2019 ).…”

“…GMMA vaccines are already manufactured in GMP-quality conditions against S. sonnei , S. flexneri and nontyphoidal Salmonella strains (Gerke et al 2015 ). Novel GMMA formulations are usually characterised by conventional analytical methods used for other glycoconjugates, being verified for their use (Micoli et al 2020a , b ; Raso et al 2020 ). For GMMA, O-Ag core sugar content can be quantified by HPAEC-PAD, after performing acid hydrolysis directly on GMMA.…”

Outer Membrane Vesicle Induction and Isolation for Vaccine Development

“…Included in the term gOMVs are generalized modules for membrane antigens (GMMA), since this term likewise refers to OMVs from bacteria in which mutations induce hypervesiculation ( Gerke et al, 2015 ). These gOMVs can be produced by various mutations, for example, by deletion of the tolR gene, which is part of the Tol-Pal system discussed above ( Micoli et al, 2020 ). The Tol-Pal system has often been a target for creation of hypervesiculating mutants ( Henry et al, 2004 ; Chen et al, 2016 ; Stevenson et al, 2018 ).…”