A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial

Marsay, Leanne; Dold, Christina; Green, Christopher; Rollier, Christine S.; Norheim, Gunnstein; Sadarangani, Manish; Shanyinde, Milensu; Brehony, Carina; Thompson, Amber; Sanders, Holly; Chan, Hannah; Haworth, Kim E.; Derrick, Jeremy P.; Feavers, Ian M.; Maiden, Martin C. J.; Pollard, Andrew J.

doi:10.1016/j.jinf.2015.05.006

Cited by 37 publications

(43 citation statements)

References 46 publications

(51 reference statements)

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“…Moreover, a combined OMV-based vaccine against ETEC and V. cholerae has been developed and shown to successfully protect against both pathogens (Leitner et al, 2015). However, a lot of additional work remains to be done before OMV-based vaccines against EHEC and ETEC infections can be used in clinical studies as it is already the case for vaccines against Neisseria meningitidis and Neisseria gonorrhoeae infections (Marsay et al, 2015;Petousis-Harris et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Secretion and Delivery of Intestinal Pathogenic Escherichia coli Virulence Factors via Outer Membrane Vesicles

Rueter

Bielaszewska

2020

Front. Cell. Infect. Microbiol.

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Outer membrane vesicles (OMVs) are nanoscale proteoliposomes secreted from the cell envelope of all Gram-negative bacteria. Originally considered as an artifact of the cell wall, OMVs are now recognized as a general secretion system, which serves to improve the fitness of bacteria and facilitate bacterial interactions in polymicrobial communities as well as interactions between the microbe and the host. In general, OMVs are released in increased amounts from pathogenic bacteria and have been found to harbor much of the contents of the parental bacterium. They mainly encompass components of the outer membrane and the periplasm including various virulence factors such as toxins, adhesins, and immunomodulatory molecules. Numerous studies have clearly shown that the delivery of toxins and other virulence factors via OMVs essentially influences their interactions with host cells. Here, we review the OMV-mediated intracellular deployment of toxins and other virulence factors with a special focus on intestinal pathogenic Escherichia coli. Especially, OMVs ubiquitously produced and secreted by enterohemorrhagic E. coli (EHEC) appear as a highly advanced mechanism for secretion and simultaneous, coordinated and direct delivery of bacterial virulence factors into host cells. OMV-associated virulence factors are not only stabilized by the association with OMVs, but can also often target previously unknown target structures and perform novel activities. The toxins are released by OMVs in their active forms and are transported via cell sorting processes to their specific cell compartments, where they can develop their detrimental effects. OMVs can be considered as bacterial "long distance weapons" that attack host tissues and help bacterial pathogens to establish the colonization of their biological niche(s), impair host cell function, and modulate the defense of the host. Thus, OMVs contribute significantly to the virulence of the pathogenic bacteria.

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Section: Discussionmentioning

confidence: 99%

Secretion and Delivery of Intestinal Pathogenic Escherichia coli Virulence Factors via Outer Membrane Vesicles

Rueter

Bielaszewska

2020

Front. Cell. Infect. Microbiol.

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“…A key focus will however be to study the relative contribution of FetA antibodies to the induction of protective immunity. We have recently proceeded to evaluate this vaccine in phase I human studies with the data supporting the safety and immunogenicity of this approach, and demonstrating the induction of FetA bactericidal antibodies in humans [ 40 ] Further studies are required to investigate the species-specific differences of the ability of FetA to induce bactericidal antibodies, and to which extent the FetA dose level and source of complement affects this evaluation.…”

Section: Discussionmentioning

confidence: 99%

An OMV Vaccine Derived from a Capsular Group B Meningococcus with Constitutive FetA Expression: Preclinical Evaluation of Immunogenicity and Toxicity

et al. 2015

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Following the introduction of effective protein-polysaccharide conjugate vaccines against capsular group C meningococcal disease in Europe, meningococci of capsular group B remain a major cause of death and can result in debilitating sequelae. The outer membrane proteins PorA and FetA have previously been shown to induce bactericidal antibodies in humans. Despite considerable antigenic variation among PorA and FetA OMPs in meningococci, systematic molecular epidemiological studies revealed this variation is highly structured so that a limited repertoire of antigenic types is congruent with the hyperinvasive meningococcal lineages that have caused most of the meningococcal disease in Europe in recent decades. Here we describe the development of a prototype vaccine against capsular group B meningococcal infection based on a N. meningitidis isolate genetically engineered to have constitutive expression of the outer membrane protein FetA. Deoxycholate outer membrane vesicles (dOMVs) extracted from cells cultivated in modified Frantz medium contained 21.8% PorA protein, 7.7% FetA protein and 0.03 μg LPS per μg protein (3%). The antibody response to the vaccine was tested in three mouse strains and the toxicological profile of the vaccine was tested in New Zealand white rabbits. Administration of the vaccine, MenPF-1, when given by intramuscular injection on 4 occasions over a 9 week period, was well tolerated in rabbits up to 50 μg/dose, with no evidence of systemic toxicity. These data indicated that the MenPF-1 vaccine had a toxicological profile suitable for testing in a phase I clinical trial.

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“…112 Another phase I trial demonstrated that OMV vaccines from a FetA modified strain conferred protective effect against N. meningitides. 113 The phase I clinical trial results showed an excellent immune response and mild side effects induced by OMV-based vaccines. These findings indicate that further exploration is essential before using OMVs as vaccines or DDSs.…”

Section: Clinical Trials: Progress and Challengesmentioning

confidence: 98%

Extracellular vesicles as an efficient nanoplatform for the delivery of therapeutics

Liu

Gao

et al. 2017

Human Vaccines & Immunotherapeutics

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Extracellular vesicles (EVs) are membrane-derived vesicles that are enriched with RNAs, proteins and other functional molecules. We exploit the unique physical properties of EVs as a promising and advantageous nanoplatform for the delivery of therapeutic drugs and genetic materials. Early successes in the discovery of various disease-related characteristics of EVs have driven a new wave of innovation in developing nanoscale drug-delivery systems (DDSs). Nevertheless, there are several issues that need to be considered during the development of these alternative DDSs, such as standardized isolation and preservation methods, efficient drug encapsulation, mechanisms of drug release and so on. In this mini-review, we summarize the current status and progress of EV-based DDSs as an efficient nanoplatform for therapeutics delivery, followed by a discussion on their challenges and future prospects for clinical translation and applications.

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A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial

Cited by 37 publications

References 46 publications

Secretion and Delivery of Intestinal Pathogenic Escherichia coli Virulence Factors via Outer Membrane Vesicles

Secretion and Delivery of Intestinal Pathogenic Escherichia coli Virulence Factors via Outer Membrane Vesicles

An OMV Vaccine Derived from a Capsular Group B Meningococcus with Constitutive FetA Expression: Preclinical Evaluation of Immunogenicity and Toxicity

Extracellular vesicles as an efficient nanoplatform for the delivery of therapeutics

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