A broadly-protective vaccine against meningococcal disease in sub-Saharan Africa based on Generalized Modules for Membrane Antigens (GMMA)

Koeberling, Oliver; Ispasanie, Emma; Hauser, Julia; Rossi, Omar; Pluschke, Gerd; Caugant, Dominique A.; Saul, Allan; MacLennan, Calman A.

doi:10.1016/j.vaccine.2014.03.068

Cited by 58 publications

(85 citation statements)

References 39 publications

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“…For a vaccine intended for use in humans, the expression of NspA in N. meningitidis is more likely to retain native folding and important epitopes for eliciting bactericidal antibodies than the expression of a purified recombinant NspA in E. coli (14). Thus, it should be possible to prepare a meningococcal NOMV-NspA vaccine from a mutant N. meningitidis strain with a genetically attenuated endotoxin and overexpressed NspA by methods similar to those used to prepare meningococcal NOMV vaccines with overexpressed FHbp (27,32,33) which are intended for use in humans.…”

Section: Discussionmentioning

confidence: 99%

Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice

2016

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Neisserial surface protein A (NspA) is a highly conserved outer membrane protein previously investigated as a meningococcal vaccine candidate. Despite eliciting serum bactericidal activity in mice, a recombinant NspA vaccine failed to elicit serum bactericidal antibodies in a phase 1 clinical trial in humans. The discordant results may be explained by the recent discovery that NspA is a human-specific ligand of the complement inhibitor factor H (FH). Therefore, in humans but not mice, NspA would be expected to form a complex with FH, which could impair human anti-NspA protective antibody responses. To investigate this question, we immunized human FH transgenic BALB/c mice with three doses of recombinant NspA expressed in Escherichia coli microvesicles, with each dose being separated by 3 weeks. Three of 12 (25%) transgenic mice and 13 of 14 wild-type mice responded with bactericidal titers of >1:10 in postimmunization sera (P ‫؍‬ 0.0008, Fisher's exact test). In contrast, human FH transgenic and wild-type mice immunized with a control meningococcal native outer membrane vesicle vaccine had similar serum bactericidal antibody responses directed at PorA, which is not known to bind human FH, and a mutant factor H binding protein ( T he 1990s witnessed the discovery of two promising recombinant protein meningococcal vaccine candidates capable of eliciting broad serum bactericidal antibody responses in mice: neisserial surface protein A (NspA) (1-3) and transferrin-binding protein (TbpB) (4-6). However, in phase 1 clinical trials, both recombinant protein vaccines failed to elicit serum bactericidal antibody responses in humans (7,8). NspA was subsequently shown to bind specifically to human complement factor H (FH) (9), and transferrin-binding protein was known to bind specifically to human and not mouse transferrin (10). The impaired serum bactericidal antibody responses to these vaccines in humans may have resulted in part from binding of the host proteins to the vaccine antigens. For example, human FH transgenic mice immunized with meningococcal factor H binding protein (FHbp) vaccines that bound human FH had lower serum anti-FHbp bactericidal antibody responses than wild-type mice whose mouse FH did not bind to FHbp (11,12). Rhesus macaques with FH that bound with a high avidity to FHbp also had lower serum antiFHbp bactericidal antibody responses than macaques with FH containing a polymorphism associated with low-avidity binding to FHbp (13). Pigs immunized with a mutant Haemophilus parasuis TbpB vaccine with decreased binding to porcine transferrin elicited higher T-and B-cell responses than pigs immunized with a native TbpB that bound porcine transferrin (12).NspA is highly conserved in Neisseria meningitidis (1) and, therefore, would be of interest for use as a component of a serogroup B vaccine if the antigen were capable of eliciting protective antibodies in humans. In the present study, we immunized wildtype and human FH transgenic BALB/c mice with a prototype recombinant NspA vaccine expressed in Esche...

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Section: Discussionmentioning

confidence: 99%

Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice

2016

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“…The assay was performed as previously described [23]. Reaction mixtures contained approximately 400 colony-forming units (CFU), 20% human serum with no detectable bactericidal activity against the test isolates as complement source and serial dilutions of the anti-ACWY capsule antiserum or the anti-LPS mAb in serial 4-fold dilutions (stock 1 mg/mL).…”

Section: Methodsmentioning

confidence: 99%

Spontaneous point mutations in the capsule synthesis locus leading to structural and functional changes of the capsule in serogroup A meningococcal populations

Ispasanie

Micoli²,

Lamelas

et al. 2018

Virulence

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Whole genome sequencing analysis of 100 Neisseria meningitidis serogroup A isolates has revealed that the csaABCD-ctrABCD-ctrEF capsule polysaccharide synthesis locus represents a spontaneous point mutation hotspot. Structural and functional properties of the capsule of 11 carriage and two disease isolates with non-synonymous point mutations or stop codons in capsule synthesis genes were analyzed for their capsular polysaccharide expression, recognition by antibodies and sensitivity to bactericidal killing. Eight of eleven carriage isolates presenting capsule locus mutations expressed no or reduced amounts of capsule. One isolate with a stop codon in the O-acetyltransferase gene expressed non-O-acetylated polysaccharide, and was not recognized by anti-capsule antibodies. Capsule and O-acetylation deficient mutants were resistant to complement deposition and killing mediated by anti-capsular antibodies, but not by anti-lipopolysaccharide antibodies. Two capsule polymerase mutants, one carriage and one case isolate, showed capsule over-expression and increased resistance against bactericidal activity of both capsule- and lipopolysaccharide-specific antibodies. Meningococci have developed multiple strategies for changing capsule expression and structure, which is relevant both for colonization and virulence. Here we show that point mutations in the capsule synthesis genes substantially contribute to the repertoire of genetic mechanisms in natural populations leading to variability in capsule expression.

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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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A broadly-protective vaccine against meningococcal disease in sub-Saharan Africa based on Generalized Modules for Membrane Antigens (GMMA)

Cited by 58 publications

References 39 publications

Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice

Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice

Spontaneous point mutations in the capsule synthesis locus leading to structural and functional changes of the capsule in serogroup A meningococcal populations

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

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