Production, characterization and control of a Neisseria meningitidis hexavalent class 1 outer membrane protein containing vesicle vaccine

doi:10.1016/0264-410X(96)00020-5

Vaccine

Volume 14, Issue 10, July 1996, Pages 1001-1008

https://doi.org/10.1016/0264-410X(96)00020-5 Get rights and content

Abstract

An experimental serogroup B meningococcal vaccine was prepared from two genetically engineered strains; each expressing three different class 1 outer membrane proteins (OMPs) (PorA). The two strains expressed the subtypes P1.7,16;P1.5,2;P1.19,15 and P1.5^c,10;P1.12,13;P1.7^h,4, respectively. Outer membrane vesicles (OMV) were prepared from these strains by deoxycholate extraction, mixed with aluminiumphosphate as adjuvant and formulated to final vaccines. The class 1 OMPs represent ca 90% of the protein in the vaccine. The vaccine was found safe for human use and induced a bactericidal immune response in mice against five of the six wild type strains, which served as donors for the various porA genes.

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Citation Excerpt :
The immunogenicity of these OMV vaccines relied upon an immunodominant antigen, PorA, that exhibits high strain-to-strain variability, and resulted in vaccine strain-specificity130. Subsequently, bacteria were bioengineered to produce OMVs vaccines in which multivalent OMVs display six different PorA subtypes, and evoked a strong humoral immune response and protective effect in a phase Ⅰ trial131. Recently, studies have investigated the potential utility of B. pertussis OMV vaccines since current vaccines do not evoke the same immune response as infection, exhibit waning immunity, and provide individual protection without preventing transmission132.
Extracellular vesicles (EVs) are secreted by both eukaryotes and prokaryotes, and are present in all biological fluids of vertebrates, where they transfer DNA, RNA, proteins, lipids, and metabolites from donor to recipient cells in cell-to-cell communication. Some EV components can also indicate the type and biological status of their parent cells and serve as diagnostic targets for liquid biopsy. EVs can also natively carry or be modified to contain therapeutic agents (e.g., nucleic acids, proteins, polysaccharides, and small molecules) by physical, chemical, or bioengineering strategies. Due to their excellent biocompatibility and stability, EVs are ideal nanocarriers for bioactive ingredients to induce signal transduction, immunoregulation, or other therapeutic effects, which can be targeted to specific cell types. Herein, we review EV classification, intercellular communication, isolation, and characterization strategies as they apply to EV therapeutics. This review focuses on recent advances in EV applications as therapeutic carriers from in vitro research towards in vivo animal models and early clinical applications, using representative examples in the fields of cancer chemotherapeutic drug, cancer vaccine, infectious disease vaccines, regenerative medicine and gene therapy. Finally, we discuss current challenges for EV therapeutics and their future development.
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Tuberculosis (TB) is one of the most widely prevalent infectious diseases that cause significant mortality. Bacillus Calmette-Guérin (BCG), the current TB vaccine used in clinics, shows variable efficacy and has safety concerns for immunocompromised patients. There is a need to develop new and more effective TB vaccines. Outer membrane vesicles (OMVs) are vesicles released by Mycobacteria that contain several lipids and membrane proteins and act as a good source of antigens to prime immune response. However, the use of OMVs as vaccines has been hampered by their heterogeneous size and low stability. Here we report that mycobacterial OMVs can be stabilized by coating over uniform-sized 50 nm gold nanoparticles. The OMV-coated gold nanoparticles (OMV-AuNP) show enhanced uptake and activation of macrophages and dendritic cells. Proteinase K and TLR inhibitor studies demonstrated that the enhanced activation was attributed to proteins present on OMVs and was mediated primarily by TLR2 and TLR4. Mass spectrometry analysis revealed several potential membrane proteins that were common in both free OMVs and OMV-AuNP. Such strategies may open up new avenues and the utilization of novel antigens for developing TB vaccines.
Outer membrane vesicle vaccines
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Outer Membrane Vesicles (OMV) have received increased attention in recent years as a vaccine platform against bacterial pathogens. OMV from Neisseria meningitidis serogroup B have been extensively explored. Following the success of the MeNZB OMV vaccine in controlling an outbreak of N. meningitidis B in New Zealand, additional research and development resulted in the licensure of the OMV-containing four-component 4CMenB vaccine, Bexsero. This provided broader protection against multiple meningococcal B strains. Advances in the field of genetic engineering have permitted further improvements in the platform resulting in increased yields, reduced endotoxicity and decoration with homologous and heterologous antigens to enhance immuno genicity and provide broader protection. The OMV vaccine platform has been extended to many other pathogens. In this review, we discuss progress in the development of the OMV vaccine delivery platform, highlighting successful applications, together with potential challenges and gaps.
Bacterial outer membrane vesicles as a platform for biomedical applications: An update
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Outer membrane vesicles (OMVs) are produced by Gram-negative bacteria both in vitro and in vivo. OMVs are nano-sized spherical vehicles formed by lipid bilayer membranes and contain multiple parent bacteria-derived components. Based on the presence of bacterial antigens, pathogen-associated molecular patterns (PAMPs), adhesins, various proteins and the vesicle structure, OMVs have been developed for biomedical applications as bacterial vaccines, adjuvants, cancer immunotherapy agents, drug delivery vehicles, and anti-bacteria adhesion agents. In this review, we analyze the contributions of the structure and composition of OMVs to their applications, summarize the methods used to isolate and characterize OMVs, and highlight recent progress and future perspectives of OMVs in biomedical applications.
Bacterial membrane vesicles as promising vaccine candidates
2019, European Journal of Pharmaceutics and Biopharmaceutics
Both Gram-positive and Gram-negative bacteria can release nano-sized lipid bilayered structures, known as membrane vesicles (MVs). These MVs play an important role in bacterial survival by orchestrating interactions between bacteria and between bacteria and host. The major constituents of MVs are proteins, lipids and nucleic acids. Due to the immunogenicity of the membrane lipids and/or proteins of the MVs, in combination with adjuvant danger signals and the repeating patterns on the nanosized surface, MVs can effectively stimulate the innate and adaptive immune system. Since they are non-replicating, they are safer than attenuated vaccines. In addition, by genetic engineering of the donor cells, further improvements to their safety profile, immunogenicity and yield can be achieved. To date, one MV-based vaccine against Neisseria meningitidis (N. meningitidis) serogroup B was approved. Other (engineered) MVs in the pipeline study are mostly in the preclinical phase.
Spontaneously released Neisseria meningitidis outer membrane vesicles as vaccine platform: production and purification
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Outer membrane vesicles (OMVs) are nanoparticles produced by Gram-negative bacteria that can be used as vaccines. The application of OMVs as vaccine component can be expanded by expressing heterologous antigens on OMVs, creating an OMV-based antigen presenting platform. This study aims to develop a production process for such OMV-based vaccines and studies a production method based on meningococcal OMVs that express heterologous antigens on their surface. As a proof of concept, the Borrelia burgdorferi antigens OspA and OspC were expressed on Neisseria meningitidis OMVs to create a concept anti-Lyme disease vaccine. Production of OMVs released in the culture supernatant was induced by high dissolved oxygen concentrations and purification was based on scalable unit operations. A crude recovery of 90 mg OMV protein could be obtained per liter culture. Expressing heterologous antigens on the OMVs did result in minor reduction of bacterial growth, while OMV production remained constant. The antigen expression did not alter the OMV characteristics. This study shows that production of well characterized OMVs containing heterologous antigens is possible with high yields by combining high oxygen concentrations with an optimized purification process. It is concluded that heterologous OMVs show potential as a vaccine platform.

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Vaccine

Abstract

References (29)

Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway

Lancet

Neisseria meningitidis group B serosubtyping using monoclonal antibodies whole-cell ELISA

Microbiol. Pathogen.

Construction of Neisseria Meningitidis strains carrying multiple chromosomal copies of the porA gene for use in the production of a multivalent outer membrane protein vaccine

Vaccine

A new variant of serosubtype P1.16 in Neisseria meningitidis from Norway, associated with increased resistance to bactericidal antibodies induced by a serogroup B outer membrane protein vaccine

Microb. Pathogen.

Cloning and characterization of Neisseria meningitidis genes encoding the transferrin binding proteins Tbp1 and Tbp2

Gene

A simplification of the protein assay of Lowry et al. which is more generally applicable

Anal. Biochem.

Silver staining of proteins in polyacrylamide gels

Anal. Biochem.

A sensitive silver stain for detecting lipopolysaccharides in polyacrylamide gels

Anal. Biochem.

Analysis of lipopolysaccharides by methanolysis, trifluoroacetylation and gas chromatography on a fused-silica capillary column

J. Chromatogr.

Meningococcal disease in The Netherlands, 1958–1990. Steady increase of the incidence rate since 1982 partially caused by new serotypes and subtypes of Neisseria meningitidis

J. Clin. Infect.

Meningococcal disease: still with us

Rev. Infect. Dis.

Immunological response in man to group B meningococcal polysaccharide vaccines

J. Infect. Dis.

Induction of meningococcal group B polysaccharide-specific IgG antibodies in mice using an N-proprionylated B polysaccharide tetanus toxoid conjugated vaccine

J. Immunol.

Meningococcal serogroup B vaccine protection trial and follow-up studies in Chile

NIPH Ann.

Cited by (151)

Extracellular vesicles: Emerging tools as therapeutic agent carriers

Immunomodulatory effect of mycobacterial outer membrane vesicles coated nanoparticles

Outer membrane vesicle vaccines

Bacterial outer membrane vesicles as a platform for biomedical applications: An update

Bacterial membrane vesicles as promising vaccine candidates

Spontaneously released Neisseria meningitidis outer membrane vesicles as vaccine platform: production and purification

PaperProduction, characterization and control of a Neisseria meningitidis hexavalent class 1 outer membrane protein containing vesicle vaccine

Abstract

Lancet

Microbiol. Pathogen.

Vaccine

Microb. Pathogen.

Gene

Anal. Biochem.

Anal. Biochem.

Anal. Biochem.

J. Chromatogr.

Meningococcal disease in The Netherlands, 1958–1990. Steady increase of the incidence rate since 1982 partially caused by new serotypes and subtypes of Neisseria meningitidis

J. Clin. Infect.

Meningococcal disease: still with us

Rev. Infect. Dis.

Immunological response in man to group B meningococcal polysaccharide vaccines

J. Infect. Dis.

Induction of meningococcal group B polysaccharide-specific IgG antibodies in mice using an N-proprionylated B polysaccharide tetanus toxoid conjugated vaccine

J. Immunol.

Meningococcal serogroup B vaccine protection trial and follow-up studies in Chile

NIPH Ann.

Paper
Production, characterization and control of a Neisseria meningitidis hexavalent class 1 outer membrane protein containing vesicle vaccine