Enhanced Systemic Humoral Immune Response Induced in Mice by Generalized Modules for Membrane Antigens (GMMA) Is Associated with Affinity Maturation and Isotype Switching

Piccioli, Diego; Buricchi, Francesca; Bacconi, Marta; Bechi, Nicoletta; Galli, Barbara; Ferlicca, Francesca; Luzzi, Enrico; Cartocci, Elena; Marchi, Sara; Romagnoli, Giacomo; Alfini, Renzo; Benedetto, Roberta Di; Gallorini, Simona; Savino, Silvana; Brunelli, Brunella; Bartolini, Erika; Micoli, Francesca

doi:10.3390/vaccines11071219

Cited by 3 publications

(2 citation statements)

References 26 publications

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“…When adsorbed on Alhydrogel, serotype specific IgG responses became comparable but GMMA continued to elicit significantly higher SBA titers than glycoconjugates. Higher functionality could be linked to a broader IgG isotype switch observed with GMMA (Piccioli et al, 2023). These results are in agreement with those previously observed comparing Salmonella GMMA and glycoconjugates in mice (Micoli et al, 2018b).…”

Section: Discussionsupporting

confidence: 92%

Comparison of Shigella GMMA and glycoconjugate four-component formulations in animals

Di Benedetto,

Mancini,

Caradonna

et al. 2023

Front. Mol. Biosci.

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Shigellosis is leading bacterial cause of diarrhea with high prevalence in children younger than 5 years in low- and middle-income countries, and increasing number of reports of Shigella cases associated to anti-microbial resistance. No vaccines against Shigella are still licensed, but different candidates based on the O-antigen portion of lipopolysaccharides are in clinic. Generalized Modules for Membrane Antigens (GMMA) have been proposed as an alternative delivery system for the O-antigen, and a 4-component vaccine candidate (altSonflex1-2-3), containing GMMA from S. sonnei and S. flexneri 1b, 2a and 3a is being tested in a phase 1/2 clinical trial, with the aim to elicit broad protection against the most prevalent Shigella serotypes. Here, the 4-component GMMA vaccine candidate has been compared to a more traditional glycoconjugate formulation for the ability to induce functional antibodies in mice and rabbits. In mice, in the absence of Alhydrogel, GMMA induce higher IgG antibodies than glycoconjugates and stronger bactericidal titers against all Shigella serotypes. In the presence of Alhydrogel, GMMA induce O-antigen specific IgG levels similar to traditional glycoconjugates, but with a broader range of IgG subclasses, resulting in stronger bactericidal activity. In rabbits, GMMA elicit higher functional antibodies than glycoconjugates against S. sonnei, and similar responses to S. flexneri 1b, 2a and 3a, independently from the presence of Alhydrogel. Different O-antigen based vaccines against Shigella are now in clinical stage and it will be of particular interest to understand how the preclinical findings in the different animal models translate in humans.

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Section: Discussionsupporting

confidence: 92%

Comparison of Shigella GMMA and glycoconjugate four-component formulations in animals

Di Benedetto,

Mancini,

Caradonna

et al. 2023

Front. Mol. Biosci.

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“…Moreover, we showed that the presence of aluminium salt-based adjuvants reduced the levels of IgG3 induced by GMMA in mice, which had a strong correlation with bactericidal activity (Table 1), and this may be a possible explanation for the observed results. Consistently, we have previously demonstrated in a Meningococcus B model (MenB) that, when immunising mice with GMMA harbouring the antigen factor H-binding protein (fHbp) on the surface, the bactericidal activity mediated by fHbp was increased compared to fHbp alone or fHbp physically mixed with GMMA, and this increase was associated with the higher production of IgG subclasses with superior bactericidal potential against MenB, including IgG3 [35].…”

Section: Discussionsupporting

confidence: 74%

Testing S. sonnei GMMA with and without Aluminium Salt-Based Adjuvants in Animal Models

Mancini,

Caradonna,

Alfini

et al. 2024

Pharmaceutics

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Shigellosis is one of the leading causes of diarrheal disease in low- and middle-income countries, particularly in young children, and is more often associated with antimicrobial resistance. Therefore, a preventive vaccine against shigellosis is an urgent medical need. We have proposed Generalised Modules for Membrane Antigens (GMMA) as an innovative delivery system for Shigella sonnei O-antigen, and an Alhydrogel formulation (1790GAHB) has been extensively tested in preclinical and clinical studies. Alhydrogel has been used as an adsorbent agent with the main purpose of reducing potential GMMA systemic reactogenicity. However, the immunogenicity and systemic reactogenicity of this GMMA-based vaccine formulated with or without Alhydrogel have never been compared. In this work, we investigated the potential adjuvant effect of aluminium salt-based adjuvants (Alhydrogel and AS37) on S. sonnei GMMA immunogenicity in mice and rabbits, and we found that S. sonnei GMMA alone resulted to be strongly immunogenic. The addition of neither Alhydrogel nor AS37 improved the magnitude or the functionality of vaccine-elicited antibodies. Interestingly, rabbits injected with either S. sonnei GMMA adsorbed on Alhydrogel or S. sonnei GMMA alone showed a limited and transient body temperature increase, returning to baseline values within 24 h after each vaccination. Overall, immunisation with unadsorbed GMMA did not raise any concern for animal health. We believe that these data support the clinical testing of GMMA formulated without Alhydrogel, which would allow for further simplification of GMMA-based vaccine manufacturing.

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Outer membrane vesicles as a platform for the discovery of antibodies to bacterial pathogens

Lei,

Azmat,

Henry

et al. 2024

Appl Microbiol Biotechnol

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Bacterial outer membrane vesicles (OMVs) are nanosized spheroidal particles shed by gram-negative bacteria that contain biomolecules derived from the periplasmic space, the bacterial outer membrane, and possibly other compartments. OMVs can be purified from bacterial culture supernatants, and by genetically manipulating the bacterial cells that produce them, they can be engineered to harbor cargoes and/or display molecules of interest on their surfaces including antigens that are immunogenic in mammals. Since OMV bilayer-embedded components presumably maintain their native structures, OMVs may represent highly useful tools for generating antibodies to bacterial outer membrane targets. OMVs have historically been utilized as vaccines or vaccine constituents. Antibodies that target bacterial surfaces are increasingly being explored as antimicrobial agents either in unmodified form or as targeting moieties for bactericidal compounds. Here, we review the properties of OMVs, their use as immunogens, and their ability to elicit antibody responses against bacterial antigens. We highlight antigens from bacterial pathogens that have been successfully targeted using antibodies derived from OMV-based immunization and describe opportunities and limitations for OMVs as a platform for antimicrobial antibody development. Key points • Outer membrane vesicles (OMVs) of gram-negative bacteria bear cell-surface molecules • OMV immunization allows rapid antibody (Ab) isolation to bacterial membrane targets • Review and analysis of OMV-based immunogens for antimicrobial Ab development

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Enhanced Systemic Humoral Immune Response Induced in Mice by Generalized Modules for Membrane Antigens (GMMA) Is Associated with Affinity Maturation and Isotype Switching

Cited by 3 publications

References 26 publications

Comparison of Shigella GMMA and glycoconjugate four-component formulations in animals

Comparison of Shigella GMMA and glycoconjugate four-component formulations in animals

Testing S. sonnei GMMA with and without Aluminium Salt-Based Adjuvants in Animal Models

Outer membrane vesicles as a platform for the discovery of antibodies to bacterial pathogens

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