A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression

Keiser, Paul B.; Biggs-Cicatelli, Susan; Morán, Elizabeth; Schmiel, Deborah H.; Pinto, Valerian B.; Burden, Robert; Miller, Lori; Moon, James E.; Bowden, Robert A.; Cummings, James F.; Zollinger, Wendell D.

doi:10.1016/j.vaccine.2010.12.039

Cited by 128 publications

(108 citation statements)

References 30 publications

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“…In a phase 1 trial, Keiser et al immunized adults with an NOMV vaccine from a mutant with attenuated endotoxin activity (⌬LpxL1), which also was engineered to overexpress fHbp (21,48). The LOS of the mutant also had a truncated oligosaccharide chain.…”

Section: Discussionmentioning

confidence: 99%

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

Koeberling

Delany

Granoff³

2011

Clin. Vaccine Immunol.

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Native outer membrane vesicles (NOMV) (not detergent treated), which are prepared from recombinant strains with attenuated endotoxin activity and overexpressed factor H binding protein (fHbp), elicited broad serum bactericidal antibody responses in mice. The amount of overexpressed fHbp required for optimal immunogenicity is not known. In this study we prepared NOMV vaccines from LpxL1 knockout (⌬LpxL1) mutants with penta-acylated lipooligosaccharide and attenuated endotoxin activity. The recombinant strains had wild-type (1؋) fHbp expression or were engineered for 3-fold-or 10-fold-increased fHbp expression (3؋ or 10؋ fHbp). Control vaccines included NOMV from ⌬LpxL1/⌬fHbp mutants or recombinant fHbp. In mice, only the 10؋ fHbp NOMV vaccine elicited significantly higher serum IgG anti-fHbp antibody titers than the corresponding 1؋ fHbp NOMV or recombinant fHbp vaccine. The 10؋ fHbp NOMV vaccine also elicited higher bactericidal responses (P < 0.05) against five group B strains with heterologous PorA than the recombinant fHbp or 1؋ fHbp NOMV vaccine. The 3؋ fHbp NOMV vaccine gave higher bactericidal titers against only one strain. Serum bactericidal titers in mice immunized with the control ⌬fHbp NOMV vaccines were <1:10, and bactericidal titers in mice immunized with the 10؋ fHbp NOMV vaccine were <1:10 after adsorption of anti-fHbp antibodies. Mixing antiserum to NOMV vaccines from fHbp knockout mutants with antiserum to recombinant fHbp did not increase anti-fHbp bactericidal titers. Thus, a critical threshold of increased fHbp expression is required for NOMV vaccines to elicit broad serum bactericidal responses, and the antibodies conferring protection are directed primarily at fHbp.

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Section: Discussionmentioning

confidence: 99%

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

Koeberling

Delany

Granoff³

2011

Clin. Vaccine Immunol.

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“…Instead the vaccine can be made tolerable for humans with genetic manipulation of LPS (lpx1-mutants) [89]. Preclinical studies with NOMV vaccines have shown higher protective titres and broader immune responses, resulting in better capacity to kill strains with fHbp variants that are substantially different from the vaccine antigen selected for the vaccine [91,[93][94][95]. These observations served as inspiration for further studies of the OMV-concept and use of NOMV as a "platform" for various other antigens.…”

Section: Vaccines Against Meningococcal Disease; Status and Perspectivesmentioning

confidence: 99%

Current Trends In Research, Development And Production Of Prophylactic Vaccines: Report of Vaccipharma 2015 Congress

Acevedo

Landys

García-Rivera

et al. 2016

SOJI

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“…The same group has generated another genetically detoxified native OMV vaccine with overexpressed fHBP, stabilized OpcA, and expression of a second PorA. This vaccine has completed phase 1 clinical trials and was found to be safe and effective at generating cross-reactive bactericidal activity to different strains (139,140). Recently, Koeberling et al tested an OMVbased vaccine that expressed penta-acetylated LOS and overexpressed lipidated fHBP variants 1.1 (B24) and 2.77 (subfamily A) in infant rhesus macaque monkeys (141).…”

Section: Development Of Fhbp Vaccines For Broad Protection Against Mnmentioning

confidence: 99%

Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

McNeil

Zagursky

Lin

et al. 2013

Microbiol Mol Biol Rev

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SUMMARY Neisseria meningitidis is a Gram-negative microorganism that exists exclusively in humans and can cause devastating invasive disease. Although capsular polysaccharide-based vaccines against serogroups A, C, Y, and W135 are widely available, the pathway to a broadly protective vaccine against serogroup B has been more complex. The last 11 years has seen the discovery and development of the N. meningitidis serogroup B (MnB) outer membrane protein factor H binding protein (fHBP) as a vaccine component. Since the initial discovery of fHBP, a tremendous amount of work has accumulated on the diversity, structure, and regulation of this important protein. fHBP has proved to be a virulence factor for N. meningitidis and a target for functional bactericidal antibodies. fHBP is critical for survival of meningococci in the human host, as it is responsible for the primary interaction with human factor H (fH). Binding of hfH by the meningococcus serves to downregulate the host alternative complement pathway and helps the organism evade host innate immunity. Preclinical studies have shown that an fHBP-based vaccine can elicit serum bactericidal antibodies capable of killing MnB, and the vaccine has shown very encouraging results in human clinical trials. This report reviews our current knowledge of fHBP. In particular, we discuss the recent advances in our understanding of fHBP, its importance to N. meningitidis , and its potential role as a vaccine for preventing MnB disease.

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A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression

Cited by 128 publications

References 30 publications

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

Current Trends In Research, Development And Production Of Prophylactic Vaccines: Report of Vaccipharma 2015 Congress

Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

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