Modulation of Endotoxicity of Shigella Generalized Modules for Membrane Antigens (GMMA) by Genetic Lipid A Modifications

Rossi, Omar; Pesce, Isabella; Giannelli, Carlo; Aprea, Susanna; Caboni, Mariaelena; Citiulo, Francesco; Valentini, Sara; Ferlenghi, Ilaria; MacLennan, Calman A.; D’Oro, Ugo; Saul, Allan; Gerke, Christiane

doi:10.1074/jbc.m114.566570

Cited by 81 publications

(134 citation statements)

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“…Generalized Modules for Membrane Antigens (GMMA) are OMVs engineered to enhance native OMV formation (by deletion of the gna33 in meningococcus and tolR in Shigella sonnei and Salmonella ), reduce reactogenicity and toxicity (by modifying the acylation pattern of lipid A) and over‐express immunogenic antigens . GMMA contain pathogen‐associated molecular patterns, including toll‐like receptor ligands, which can act as self‐adjuvants in the immune responses they elicit .…”

Section: Outer Membrane Vesicle Vaccines Generalized Modules For Memmentioning

confidence: 99%

“…GMMA contain pathogen‐associated molecular patterns, including toll‐like receptor ligands, which can act as self‐adjuvants in the immune responses they elicit . GMMA are highly immunogenic, effective, have low reactogenicity, are safe, and can be manufactured at low cost in a scalable process . The main limitation of GMMA is that it cannot perform human‐like post‐translational modifications (e.g., glycosylation).…”

Section: Outer Membrane Vesicle Vaccines Generalized Modules For Memmentioning

confidence: 99%

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Emerging Technologies for Low‐Cost, Rapid Vaccine Manufacture

Kis

Shattock

Shah

et al. 2018

Biotechnology Journal

116

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To stop the spread of future epidemics and meet infant vaccination demands in low‐ and middle‐income countries, flexible, rapid and low‐cost vaccine development and manufacturing technologies are required. Vaccine development platform technologies that can produce a wide range of vaccines are emerging, including: a) humanized, high‐yield yeast recombinant protein vaccines; b) insect cell‐baculovirus ADDomer vaccines; c) Generalized Modules for Membrane Antigens (GMMA) vaccines; d) RNA vaccines. Herein, existing and future platforms are assessed in terms of addressing challenges of scale, cost, and responsiveness. To assess the risk and feasibility of the four emerging platforms, the following six metrics are applied: 1) technology readiness; 2) technological complexity; 3) ease of scale‐up; 4) flexibility for the manufacturing of a wide range of vaccines; 5) thermostability of the vaccine product at tropical ambient temperatures; and 6) speed of response from threat identification to vaccine deployment. The assessment indicated that technologies in the order of increasing feasibility and decreasing risk are the yeast platform, ADDomer platform, followed by RNA and GMMA platforms. The comparative strengths and weaknesses of each technology are discussed in detail, illustrating the associated development and manufacturing needs and priorities.

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Section: Outer Membrane Vesicle Vaccines Generalized Modules For Memmentioning

confidence: 99%

Section: Outer Membrane Vesicle Vaccines Generalized Modules For Memmentioning

confidence: 99%

Emerging Technologies for Low‐Cost, Rapid Vaccine Manufacture

Kis

Shattock

Shah

et al. 2018

Biotechnology Journal

116

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“…Because humans are more sensitive to LPS than mice, a reaction of human tissues to LPS contained in the vaccine may happen, and this will carefully be examined in future developments. LPS detoxification by deletion of msbB or htrB genes controlling lipid-A acylation could be considered, as previously reported in Shigella [18].…”

Section: Vtnf1 Causes Little Side Effects and Disseminates Transientlmentioning

confidence: 84%

Subcutaneous vaccination with a live attenuated Yersinia pseudotuberculosis plague vaccine

Derbise

Guillas

Gerke

et al. 2019

Preprint

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A single oral inoculation to mice of the live attenuated Yersinia pseudotuberculosis VTnF1 strain producing an F1 pseudocapsule protects against bubonic and pneumonic plague.However oral vaccination can fail in humans exposed to frequent intestinal infections. We evaluated in mice the efficacy of subcutaneous vaccine injection as an alternative way to induce protective immunity, while reducing the dose and avoiding strain release in nature. A single subcutaneous dose of up to 10 8 CFU induced dose-dependent antibody production. At the dose of 10 7 CFU, i.e. 10 times less than via the oral route, it caused a modest skin reaction and protected 100% against bubonic and 80% against pneumonic plague, caused by high doses of Yersinia pestis. Bacteria migrating to lymph nodes and spleen, but not feces, were rapidly eliminated. Thus, subcutaneous injection of VTnF1 would represent a good alternative when dissemination in nature and human intestinal responsiveness are limitations.

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“…Several approaches are currently in development to deliver the O-antigen to the immune system, including whole cell attenuated bacteria (6), vaccines in which the O-antigen are chemically-(7) or bio-conjugated to carrier proteins (8), synthetic vaccine conjugates (9), and GMMA based vaccines (10). GMMA are outer membrane exosomes from Gram-negative bacteria, genetically modified to induce hyperblebbing and to reduce the reactogenic potential of lipid A (11, 12). GMMA are easy and inexpensive to produce, and highly immunogenic (10, 13–16).…”

Section: Introductionmentioning

confidence: 99%

Intralaboratory evaluation of luminescence based high-throughput Serum Bactericidal Assay (L-SBA) to determine bactericidal activity of human sera againstShigella

Rossi

Molesti

Saul

et al. 2020

Preprint

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17Despite the huge decrease in deaths caused by Shigella worldwide in the last decades, shigellosis is 18 still causing over 200,000 deaths every year. No vaccine is currently available, and the morbidity of 19 disease coupled with the rise of antimicrobial resistance renders the introduction of an effective 20 vaccine extremely urgent. Although a clear immune correlate of protection against shigellosis has not 21 been established yet, the demonstration of bactericidal activity of antibodies induced upon 22 vaccination may provide one means of functionality of antibodies induced on protecting against 23 Shigella. The method of choice to evaluate the complement-mediated functional activity of vaccine-24 induced antibodies is the Serum Bactericidal Assay (SBA). 25Here we present the development and intra-laboratory characterisation of a high-throughput 26 luminescence-based SBA (L-SBA) method, based on the detection of ATP as a proxy of surviving 27 bacteria, to evaluate the complement-mediated killing of human sera. We demonstrated the high 28 specificity of the assay against homologous strain without any heterologous aspecificity detected 29 against species-related and not species-related strains. We assessed linearity, repeatability and 30 reproducibility of L-SBA on human sera. 31This work will guide the bactericidal activity assessment of clinical sera raised against S. sonnei. The 32 method has the potential of being applicable with similar performances to determine bactericidal 33 activity of any non-clinical and clinical sera that rely on complement mediated killing. 34 35 IMPORTANCE 36Shigella is an important cause of diarrhoea worldwide and antimicrobial resistance is on rise, thus 37 efforts by several groups are ongoing to produce a safe and effective vaccine against shigellosis. 38Although a clear immune correlate of protection has not been established, demonstration of 39 bactericidal capacity of sera from patients immunised with Shigella vaccines may provide one means 40 characterisation L-SBA on human sera of protecting against shigellosis. We have developed and fully characterised a novel high-throughput 41 L-SBA method for evaluation of functionality of antibodies raised against S. sonnei in human sera. 42This work will allow the clinical testing of human sera raised against GMMA-based and potentially 43 all vaccines producing antibodies than can work via complement mediated manner. 44 45 46 47 48 Diarrheal diseases, such as shigelloses and salmonelloses, are the second leading cause of death 49 worldwide, resulting in millions of deaths per year, mostly in developing countries (1). Shigella is 50 major cause of sustained endemic bacterial diarrhoea, especially in low and middle-income countries 51 where accessibility to clean water is restricted. Although the improvement of hygienic conditions in 52 the last decade has dramatically reduced the burden of the disease, Shigella is still responsible for 53 more than 200,000 deaths, with a third of them being in young children (1). On top of deaths...

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Modulation of Endotoxicity of Shigella Generalized Modules for Membrane Antigens (GMMA) by Genetic Lipid A Modifications

Cited by 81 publications

References 50 publications

Emerging Technologies for Low‐Cost, Rapid Vaccine Manufacture

Emerging Technologies for Low‐Cost, Rapid Vaccine Manufacture

Subcutaneous vaccination with a live attenuated Yersinia pseudotuberculosis plague vaccine

Intralaboratory evaluation of luminescence based high-throughput Serum Bactericidal Assay (L-SBA) to determine bactericidal activity of human sera againstShigella

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