GMMA as Novel Carrier for Polysaccharides Toward the Development of Effective Multivalent Vaccines

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GMMA as Novel Carrier for Polysaccharides Toward the Development of Effective Multivalent Vaccines

Renzo Alfini 1 , Francesca Necchi 1 , Roberta Di Benedetto 1 , Fabiola Schiavo 1 , Martina Carducci 1, Francesca Mancini 1 , Cristiana Balocchi 2 , Brunella Brunelli 2 , Diego Piccioli 2 , Paolo Costantino 2,3 , Roberto Adamo 2 , Allan Saul 1 , Francesca Micoli 1

1 GVGH - GSK Vaccines Institute for Global Health, Siena, Italy, 2 GSK , Siena, Italy, 3 PC is retired and was employee of GSK group of companies when this work was performed.

Nanoparticle systems are being explored for the display of carbohydrate antigens, characterized by presentation of saccharide epitopes in multiplicity and special chemico-physical properties of nano-sized particles. Among them, outer membrane vesicles (OMVs), combining antigen presentation to the immunopotentiator effect of the Toll-like receptors naturally present on these systems, are receiving great attention [1]. In this context, we are testing GMMA (Generalized Modules for Membrane Antigens) as carrier for polysaccharides [2]. GMMA are OMVs naturally released from Gram-negative bacteria mutated to increase blebbing, allowing high yields and reduced costs of production [3, 4].

Here we have identified easy methods for covalent linkage of serogroup A and C meningococcal oligosaccharides (MenA and MenC) to surface protein or lipo-oligosaccharide sites of Neisseria meningitidis serogroup B GMMA. A panel of analytical tools has been put in place for full physico-chemical characterization of the purified GMMA conjugates, including determination of oligosaccharides number per GMMA particle.

When tested in mice, GMMA conjugates resulted able to induce total polysaccharide specific IgG titers not inferior to corresponding more traditional CRM197 conjugates, and with stronger functionality. Differently from CRM197 conjugates, GMMA induced strong response after only one dose, even in the absence of adjuvant. Also, six months after primary immunization antibodies induced by GMMA-conjugates showed stronger bactericidal activity compared to CRM197 conjugates. Number of saccharide chains per GMMA particle can be modulated and this can be important to preserve immune response induced by GMMA itself. No impact of sugar length on the immune response has been verified for meningococcal A oligosaccharides, while linkage to proteins is preferable to linkage at lipo-oligosaccharide sites resulting in higher anti-polysaccharide specific IgG titers.

When MenA and MenC oligosaccharides were linked to the same GMMA particle no immune interference for the anti-polysaccharide response was found. These features have not been found with other nanoparticle systems. Work is ongoing to extend these findings to polysaccharides and GMMA from different sources, supporting the development of low cost and effective multivalent vaccines through this novel technology.

Micoli, F.; Adamo, R.; Costantino, P. Molecules 2018, 23(6), 1451.

Micoli, F.; et al. Proc. Natl. Acad. Sci. U S A 2018, 115(41), 10428.

Gerke, C.; et al. PLoS One 2015, 10(8): e0134478.

Kis, Z.; et al. Biotechnol. J. 2019, 14, 1800376.

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