Phase I Safety and Immunogenicity Study of a Candidate Meningococcal Disease Vaccine Based on Neisseria lactamica Outer Membrane Vesicles

ABSTRACT Natural immunity to meningococcal disease in young children is associated epidemiologically with carriage of commensal Neisseria species, including Neisseria lactamica. We have previously demonstrated that outer membrane vesicles (OMVs) from N. lactamica provide protection against lethal challenge in a mouse model of meningococcal septicemia. We evaluated the safety and immunogenicity of an N. lactamica OMV vaccine in a phase I placebo-controlled, double-blinded clinical trial. Ninety-seven healthy young adult male volunteers were randomized to receive three doses of either an OMV vaccine or an Alhydrogel control. Subsequently, some subjects who had received the OMV vaccine also received a fourth dose of OMV vaccine, 6 months after the third dose. Injection site reactions were more frequent in the OMV-receiving group, but all reactions were mild or moderate in intensity. The OMV vaccine was immunogenic, eliciting rises in titers of immunoglobulin G (IgG) against the vaccine OMVs, together with a significant booster response, as determined by an enzyme-linked immunosorbent assay. Additionally, the vaccine induced modest cross-reactive immunity to six diverse strains of serogroup B Neisseria meningitidis, including IgG against meningococcal OMVs, serum bactericidal antibodies, and opsonophagocytic activity. The percentages of subjects showing ≥4-fold rises in bactericidal antibody titer obtained were similar to those previously reported for the Norwegian meningococcal OMV vaccine against the same heterologous meningococcal strain panel. In conclusion, this N. lactamica OMV vaccine is safe and induces a weak but broad humoral immune response to N. meningitidis.

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Neisseria lactamica Protects against Experimental Meningococcal Infection

Infection and Immunity ◽

10.1128/iai.70.7.3621-3626.2002 ◽

2002 ◽

Vol 70 (7) ◽

pp. 3621-3626 ◽

Cited By ~ 64

Author(s):

Kerry J. Oliver ◽

Karen M. Reddin ◽

Philippa Bracegirdle ◽

Michael J. Hudson ◽

Ray Borrow ◽

...

Keyword(s):

Outer Membrane ◽

Meningococcal Disease ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Meningococcal Infection ◽

Natural Immunity ◽

Lethal Challenge ◽

Diverse Range ◽

Whole Cells ◽

Bacteremic Infection

ABSTRACT Immunological and epidemiological evidence suggests that the development of natural immunity to meningococcal disease results from colonization of the nasopharynx by commensal Neisseria spp., particularly with N. lactamica. We report here that immunization with N. lactamica killed whole cells, outer membrane vesicles, or outer membrane protein (OMP) pools and protected mice against lethal challenge by a number of diverse serogroup B and C meningococcal isolates in a model of bacteremic infection. Sera raised to N. lactamica killed whole cells, OMPs, or protein pools were found to cross-react with meningococcal isolates of a diverse range of genotypes and phenotypes. The results confirm the potential of N. lactamica to form the basis of a vaccine against meningococcal disease.

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Immunogenicity of Intranasally Administered Meningococcal Native Outer Membrane Vesicles in Mice

Infection and Immunity ◽

10.1128/iai.67.1.113-119.1999 ◽

1999 ◽

Vol 67 (1) ◽

pp. 113-119 ◽

Cited By ~ 66

Author(s):

Nancy B. Saunders ◽

David R. Shoemaker ◽

Brenda L. Brandt ◽

E. Ellen Moran ◽

Thomas Larsen ◽

...

Keyword(s):

Immune Response ◽

Antibody Response ◽

Outer Membrane ◽

Membrane Vesicles ◽

Lavage Fluid ◽

Lung Lavage ◽

Outer Membrane Vesicles ◽

Enzyme Linked Immunosorbent Assay ◽

Natural Immunity ◽

Bactericidal Antibody

ABSTRACT Colonization of the human nasopharyngeal region by Neisseria meningitidis is believed to lead to natural immunity. Although the presence of bactericidal antibody in serum has been correlated with immunity to meningococcal disease, mucosal immunity at the portal of entry may also play an important role. This study was undertaken to examine in mice the possibility of safely using native outer membrane vesicles (NOMV) not exposed to detergent as an intranasal (i.n.) vaccine. The mucosal and systemic responses of mice to intranasal and intraperitoneal (i.p.) vaccination with NOMV were compared over a range of doses from 0.1 to 20 μg. Intranasal vaccination of mice with NOMV induced a strong systemic bactericidal antibody response, as well as a strong local immunoglobulin A immune response in the lung as determined by assay of lung lavage fluid by enzyme-linked immunosorbent assay and lung antibody secreting cells by enzyme-linked immunospot assay. However, 8- to 10-fold-higher doses of NOMV were required i.n. compared to i.p. to elicit an equivalent bactericidal antibody response in serum. Some NOMV vaccine was aspirated into the lungs of mice during i.n. immunization and resulted in an acute inflammatory response that peaked at 1 to 2 days postimmunization and was cleared by day 7. These results indicate that i.n. delivery of meningococcal NOMV in mice is highly effective in eliciting the production of both a mucosal immune response and a systemic bactericidal antibody response.

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Outer membrane vesicles of Neisseria lactamica as a potential mucosal adjuvant

Vaccine ◽

10.1016/j.vaccine.2005.07.064 ◽

2006 ◽

Vol 24 (2) ◽

pp. 206-214 ◽

Cited By ~ 18

Author(s):

Gretel Sardiñas ◽

Karen Reddin ◽

Rolando Pajon ◽

Andrew Gorringe

Keyword(s):

Outer Membrane ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Mucosal Adjuvant ◽

Neisseria Lactamica

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Expression of Heterologous Antigens in Commensal Neisseria spp.: Preservation of Conformational Epitopes with Vaccine Potential

Infection and Immunity ◽

10.1128/iai.72.11.6511-6518.2004 ◽

2004 ◽

Vol 72 (11) ◽

pp. 6511-6518 ◽

Cited By ~ 29

Author(s):

Clíona A. O'Dwyer ◽

Karen Reddin ◽

Denis Martin ◽

Stephen C. Taylor ◽

Andrew R. Gorringe ◽

...

Keyword(s):

Membrane Protein ◽

Outer Membrane ◽

Meningococcal Disease ◽

Protective Efficacy ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Heterologous Proteins ◽

Protein Vaccine ◽

Native Conformation ◽

Protein Antigens

ABSTRACT Commensal neisseriae share with Neisseria meningitidis (meningococcus) a tendency towards overproduction of the bacterial outer envelope, leading to the formation and release during growth of outer membrane vesicles (OMVs). OMVs from both meningococci and commensal neisseriae have shown promise as vaccines to protect against meningococcal disease. We report here the successful expression at high levels of heterologous proteins in commensal neisseriae and the display, in its native conformation, of one meningococcal outer membrane protein vaccine candidate, NspA, in OMVs prepared from such a recombinant Neisseria flavescens strain. These NspA-containing OMVs conferred protection against otherwise lethal intraperitoneal challenge of mice with N. meningitidis serogroup B, and sera raised against them mediated opsonophagocytosis of meningococcal strains expressing this antigen. This development promises to facilitate the design of novel vaccines containing membrane protein antigens that are otherwise difficult to present in native conformation that provide cross-protective efficacy in the prevention of meningococcal disease.

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MAb 9B3, Against Native Outer Membrane Vesicles of Neisseria lactamica

Hybridoma ◽

10.1089/hyb.2008.0052.mab ◽

2008 ◽

Vol 27 (5) ◽

pp. 409-409

Keyword(s):

Outer Membrane ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Neisseria Lactamica

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Cross-reactivity with Brazilian strains of Neisseria meningitidis B after immunization with outer membrane vesicles

Therapeutic Advances in Vaccines and Immunotherapy ◽

10.1177/2515135519894825 ◽

2019 ◽

Vol 7 ◽

pp. 251513551989482

Author(s):

Gabriela Trzewikoswki de Lima ◽

Amanda Izeli Portilho ◽

Elizabeth De Gaspari

Keyword(s):

Public Health ◽

Neisseria Meningitidis ◽

Outer Membrane ◽

Immunosorbent Assay ◽

Humoral Response ◽

Membrane Vesicles ◽

Cross Reactivity ◽

Outer Membrane Vesicles ◽

Antigen Recognition ◽

Enzyme Linked Immunosorbent Assay

Background: Immunization against Neisseria meningitidis is important for public health. Vaccines composed of cross-reactivity antigens avoid strain-specific responses, ensuring more comprehensive protection. Methods: The cross-reactivity between three strains from the last outbreak of N. meningitidis in Brazil was assessed in our studies, using enzyme-linked immunosorbent assay (ELISA) and immunoblotting assays. Results: Both assays verifed a similar humoral response between the strains evaluated. Patterns of antigen recognition differed with each dose evaluated. Conclusions: We observed that immunization with N. meningitidis B outer membrane vesicles (OMVs) led to the production of antibodies that recognized antigens of heterologous strains, indicating possible protection against these evaluated strains.

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Acellular outer membrane vesicles of Brucella abortus strain 19 elicits both humoral and cell mediated immune response in mice

Indian Journal of Animal Research ◽

10.18805/ijar.b-3428 ◽

2018 ◽

Author(s):

Losa Rose ◽

Bablu Kumar ◽

Ankita Jain ◽

M K Singh ◽

Abhishek .

Keyword(s):

Immune Response ◽

Outer Membrane ◽

Brucella Abortus ◽

Outer Membrane Proteins ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Biologically Active ◽

Cell Mediated Immunity ◽

Humoral Immune ◽

Sds Page

Outer membrane vesicles (OMVs) contain biologically active proteins, lipoolysaccharide (LPS), periplasmic and membrane-bound proteins and are known to perform diverse biological functions. OMVs from Brucella abortus S19 were isolated and characterized by transmission electron microscopy (TEM), SDS-PAGE and immunoreactivity was investigated by western blotting. On TEM, bilayered spherical structures of 50-200 nm were observed. SDS-PAGE of OMVs revealed approximate bands size of 82 kDa, 68 kDa, 38 kDa, 32 kDa, 29 kDa and 18 kDa. Western blot analysis of OMVs revealed a dominant immunoreactive band of 38 kDa that correspond to some major outer membrane proteins. Humoral immune response was measured by indirect ELISA which showed that OMV specific antibodies were detected from 7th day post immunization (DPI) onwards and showed a rising trend up to 35th DPI. Cell mediated immune (CMI) response against OMVs as evidenced by the proliferation of splenocytes have also been observed. Thus OMVs were found to possess immunogenic proteins which had potential to induce both humoral as well as cell mediated immunity. After correlating this immune response with protection it has been concluded that OMV can be used as one of the vaccine candidate against brucellosis.

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Naturally Produced Outer Membrane Vesicles from Pseudomonas aeruginosa Elicit a Potent Innate Immune Response via Combined Sensing of Both Lipopolysaccharide and Protein Components

Infection and Immunity ◽

10.1128/iai.00433-10 ◽

2010 ◽

Vol 78 (9) ◽

pp. 3822-3831 ◽

Cited By ~ 110

Author(s):

Terri N. Ellis ◽

Sara A. Leiman ◽

Meta J. Kuehn

Keyword(s):

Pseudomonas Aeruginosa ◽

Outer Membrane ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Host Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Response Analysis ◽

Specific Response ◽

Protein Components ◽

Vesicle Proteins

ABSTRACT Pseudomonas aeruginosa is a prevalent opportunistic human pathogen that, like other Gram-negative pathogens, secretes outer membrane vesicles. Vesicles are complex entities composed of a subset of envelope lipid and protein components that have been observed to interact with and be internalized by host cells. This study characterized the inflammatory responses to naturally produced P. aeruginosa vesicles and determined the contribution of vesicle Toll-like receptor (TLR) ligands and vesicle proteins to that response. Analysis of macrophage responses to purified vesicles by real-time PCR and enzyme-linked immunosorbent assay identified proinflammatory cytokines upregulated by vesicles. Intact vesicles were shown to elicit a profoundly greater inflammatory response than the response to purified lipopolysaccharide (LPS). Both TLR ligands LPS and flagellin contributed to specific vesicle cytokine responses, whereas the CpG DNA content of vesicles did not. Neutralization of LPS sensing demonstrated that macrophage responses to the protein composition of vesicles required the adjuvantlike activity of LPS to elicit strain specific responses. Protease treatment to remove proteins from the vesicle surface resulted in decreased interleukin-6 and tumor necrosis factor alpha production, indicating that the production of these specific cytokines may be linked to macrophage recognition of vesicle proteins. Confocal microscopy of vesicle uptake by macrophages revealed that vesicle LPS allows for binding to macrophage surfaces, whereas vesicle protein content is required for internalization. These data demonstrate that macrophage sensing of both LPS and protein components of outer membrane vesicles combine to produce a bacterial strain-specific response that is distinct from those triggered by individual, purified vesicle components.

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