Towards a Four-Component GMMA-Based Vaccine against Shigella

Micoli, Francesca; Nakakana, Usman; Scorza, Francesco Berlanda

doi:10.3390/vaccines10020328

Cited by 27 publications

(27 citation statements)

References 67 publications

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“…Recent studies of functional antibodies after immunization with protein-lipopolysaccharide outer membrane vesicles (OMV) S. sonnei vaccine based on generalized modules for membrane antigen (GMMA) have shown that anti-LPS antibodies are the main drivers of bactericidal activity. On the contrary, anti-protein antibodies had limited ability to either bind to Shigella cells or kill them in the presence of complement [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

A Pentavalent Shigella flexneri LPS-Based Vaccine Candidate Is Safe and Immunogenic in Animal Models

et al. 2023

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A multivalent vaccine is much needed to achieve protection against predominant Shigella serotypes. Recently, we demonstrated the clinical applicability and immunogenic potential of tri-acylated S. flexneri 2a lipopolysaccharide (Ac3-S-LPS). Using a similar approach, we designed a pentavalent LPS candidate vaccine against S. flexneri 1b, 2a, 3a, 6, and Y (PLVF). In this study, we performed molecular and antigenic characterization of the vaccine candidate and its preclinical evaluation. There were no signs of acute toxicity after subcutaneous administration of PLVF in rabbits at a proposed human dose of 125 μg. No pyrogenic reactions and adverse effects associated with chronic toxicity after repeated administration of PLVF were revealed either. The immunization of mice with PLVF led to ≥16-fold increase in S. flexneri 1b-, 2a-, 3a-, 6-, and Y-specific antibodies. In a serum bactericidal antibody (SBA) assay, we registered 54%, 66%, 35%, 60%, and 60% killing of S. flexneri 1b, 2a, 3a, 6, and Y, respectively. In the guinea pig keratoconjunctivitis model, the efficacy was 50% to 75% against challenge with all five S. flexneri serotypes. These studies demonstrate that PLVF is safe, immunogenic over a wide range of doses, and provides protection against challenge with homologous S. flexneri strains, thus confirming the validity of pentavalent design of the combined vaccine.

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Section: Discussionmentioning

confidence: 99%

A Pentavalent Shigella flexneri LPS-Based Vaccine Candidate Is Safe and Immunogenic in Animal Models

et al. 2023

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“…In this study, we have presented the optimization and characterization of L-SBA to detect bactericidal activity of human sera against three epidemiologically relevant S. flexneri strains: S. flexneri 1b, 2a and 3a. The assay will be used to assess the bactericidal activity of antibodies induced by the 4-component GMMA-based vaccine currently being tested in a Ph1/2 clinical trial [ 23 ], and can be used to better characterize the immune response elicited by other vaccines in development. The assay, firstly developed for S. sonnei [ 20 ], has been easily extended here to the other three S. flexneri serotypes.…”

Section: Discussionmentioning

confidence: 99%

“…The assay, firstly developed for S. sonnei [ 20 ], has been easily extended here to the other three S. flexneri serotypes. Based on this we expect that it could be rapidly adapted to additional Shigella serotypes [ 20 , 23 ], antibodies; moreover, the high-throughput L-SBA method can be applied to investigate in depth the immune response to several Shigella serotypes in adults and children naturally exposed to these bacteria allowing to determine if there is a correlation between anti-OAg IgG and SBA responses in different age populations in endemic countries.…”

Section: Discussionmentioning

confidence: 99%

“…We have characterized the method intra-laboratory by assessing its specificity, linearity, and precision. The developed assays will be used to determine the functionality of sera from adults intramuscularly immunized with a four-component Shigella vaccine that makes use of the GMMA technology [ 23 ], and could be easily expanded to further clinical studies or sero-epidemiological studies.…”

Section: Introductionmentioning

confidence: 99%

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Setup and Characterization of a High-Throughput Luminescence-Based Serum Bactericidal Assay (L-SBA) to Determine Functionality of Human Sera against Shigella flexneri

Mancini

Micoli

Rossi

2022

BioTech

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Shigellosis represents a major public health problem worldwide. The morbidity of the disease, especially in children in developing countries, together with the increase of antimicrobial resistance make a vaccine against Shigella an urgent medical need. Several vaccines under development are targeting Shigella lipopolysaccharide (LPS), whose extreme diversity renders necessary the development of multivalent vaccines. Immunity against Shigella LPS can elicit antibodies capable of killing bacteria in a serotype-specific manner. Therefore, although a correlation of protection against shigellosis has not been established, demonstration of vaccine-elicited antibody bactericidal activity may provide one means of vaccine protection against Shigella. To facilitate Shigella vaccine development, we have set up a high-throughput serum bactericidal assay based on luminescence readout (L-SBA), which has been already used to determine the functionality of antibodies against S. sonnei in multiple clinical trials. Here we present the setup and intra-laboratory characterization of L-SBA against three epidemiologically relevant Shigella flexneri serotypes using human sera. We assessed the linearity, repeatability and reproducibility of the method, demonstrating high assay specificity to detect the activity of antibodies against each homologous strain without any heterologous aspecificity against species-related and non-species-related strains; this assay is ready to be used to determine bactericidal activity of clinical sera raised by multivalent vaccines and in sero-epidemiological studies.

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“…OAg is considered the dominant protective antigen and is the main target of vaccine development strategies ( 16 , 17 ). Several mono- or multicomponent candidate vaccines against Shigella species are currently under development ( 18 – 24 ) to address this unmet medical need. The investigational vaccine against S. sonnei (1790GAHB) developed using the Generalized Modules for Membrane Antigens (GMMA) technology was demonstrated to be well tolerated and immunogenic in healthy adults from both Shigella endemic and non-endemic regions ( 25 – 27 ).…”

Section: Introductionmentioning

confidence: 99%

Complement-mediated serum bactericidal activity of antibodies elicited by the Shigella sonnei GMMA vaccine in adults from a shigellosis-endemic country: Exploratory analysis of a Phase 2a randomized study

et al. 2022

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Shigella is associated with a significant burden of disease worldwide among individuals of all ages and is the major cause of moderate and severe diarrhea in children under five years of age in low- and middle-income countries. Several candidate vaccines against Shigella species are currently under clinical development. The investigational 1790GAHB vaccine against Shigella sonnei is based on GMMA (Generalized Modules for Membrane Antigens) technology. The vaccine was well tolerated and induced high antibody levels in early-phase clinical trials in both Shigella-endemic and non-endemic settings. The present analysis assessed the bactericidal activity of antibodies induced by 1790GAHB in healthy Kenyan adults during a phase 2a, controlled, randomized study (NCT02676895). Participants received two doses of 1790GAHB 4 weeks apart containing either 1.5/25 µg or 6/100 µg O antigen/protein, or active comparator vaccines (Control). Serum bactericidal activity (SBA) against S. sonnei was assessed at pre-vaccination (D1), 28 days post-first dose (D29) and 28 days post-second dose (D57), using a luminescence-based assay. Most participants had SBA titers above the lower limit of quantification of the assay at D1. SBA geometric mean titers increased 3.4-fold in the 1.5/25 µg group and 6.3-fold in the 6/100 µg group by D29 and were maintained at D57. There was no increase in SBA geometric mean titers in the Control group. A strong correlation was observed between SBA titers and anti-S. sonnei lipopolysaccharide serum immunoglobulin G antibody concentrations (Pearson correlation coefficient = 0.918), indicating that SBA can effectively complement enzyme-linked immunosorbent assay data by indicating the functionality of 1790GAHB-induced antibodies.

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Towards a Four-Component GMMA-Based Vaccine against Shigella

Cited by 27 publications

References 67 publications

A Pentavalent Shigella flexneri LPS-Based Vaccine Candidate Is Safe and Immunogenic in Animal Models

A Pentavalent Shigella flexneri LPS-Based Vaccine Candidate Is Safe and Immunogenic in Animal Models

Setup and Characterization of a High-Throughput Luminescence-Based Serum Bactericidal Assay (L-SBA) to Determine Functionality of Human Sera against Shigella flexneri

Complement-mediated serum bactericidal activity of antibodies elicited by the Shigella sonnei GMMA vaccine in adults from a shigellosis-endemic country: Exploratory analysis of a Phase 2a randomized study

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