The Effect of Human Factor H on Immunogenicity of Meningococcal Native Outer Membrane Vesicle Vaccines with Over-Expressed Factor H Binding Protein

Beernink, Peter T.; Shaughnessy, Jutamas; Pajón, Rolando; Braga, Emily M.; Ram, Sanjay; Granoff, Dan M.

doi:10.1371/journal.ppat.1002688

Cited by 42 publications

(65 citation statements)

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“…Binding of human FH decreases FHbp immunogenicity (24)(25)(26), and FHbp mutants with decreased binding of FH elicit higher protective antibody responses in human FH transgenic mice (16,24,27). Because R130 is an FH binding residue in variant group 1 proteins (28), we tested binding of human FH to the doublemutant FHbp.…”

Section: Resultsmentioning

confidence: 99%

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A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

Konar

Pajón

Beernink

2015

Proc. Natl. Acad. Sci. U.S.A.

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Factor H binding protein (FHbp) is part of two vaccines recently licensed for prevention of sepsis and meningitis caused by serogroup B meningococci. FHbp is classified in three phylogenic variant groups that have limited antigenic cross-reactivity, and FHbp variants in one of the groups have low thermal stability. In the present study, we replaced two amino acid residues, R130 and D133, in a stable FHbp variant with their counterparts (L and G) from a less stable variant. The single and double mutants decreased thermal stability of the amino- (N-) terminal domain compared with the wild-type protein as measured by scanning calorimetry. We introduced the converse substitutions, L130R and G133D, in a less stable wild-type FHbp variant, which increased the transition midpoint (Tm) for the N-terminal domain by 8 and 12 °C; together the substitutions increased the Tm by 21 °C. We determined the crystal structure of the double mutant FHbp to 1.6 Å resolution, which showed that R130 and D133 mediated multiple electrostatic interactions. Monoclonal antibodies specific for FHbp epitopes in the N-terminal domain had higher binding affinity for the recombinant double mutant by surface plasmon resonance and to the mutant expressed on meningococci by flow cytometry. The double mutant also had decreased binding of human complement Factor H, which in previous studies increased the protective antibody responses. The stabilized mutant FHbp thus has the potential to stabilize protective epitopes and increase the protective antibody responses to recombinant FHbp vaccines or native outer membrane vesicle vaccines with overexpressed FHbp.

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Section: Resultsmentioning

confidence: 99%

“…FHbp mutants with decreased binding of human FH were shown to have enhanced immunogenicity in human FH transgenic mice (15,16,24,27). The stabilized double-mutant FHbp had approximately sevenfold lower affinity for human FH than the WT FHbp (Fig.…”

Section: Discussionmentioning

confidence: 95%

A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

Konar

Pajón

Beernink

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Subsequently, NspA was shown by Lewis and colleagues to bind specifically to human FH (9). Since binding of human FH to another meningococcal vaccine antigen, FHbp, impaired protective anti-FHbp antibody responses (11,13,26,28,29), we considered whether the binding of human FH to the NspA vaccine might also impair anti-NspA bactericidal antibody responses. In the present study, we immunized wild-type and human FH transgenic mice with a recombinant NspA vaccine expressed in E. coli vesicles.…”

Section: Discussionmentioning

confidence: 99%

“…The E. coli microvesicle/recombinant NspA vaccine tested in the present study contained a fully functional NspA that bound human FH and, therefore, provided a convenient means to investigate the possible effect of human FH binding on NspA immunogenicity. Further, in future studies this approach could also be used to investigate the immunogenicity of low-FH-binding mutant recombinant NspA vaccines in human FH transgenic mice (as was done for FHbp antigens [11,26,30,31]). 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).…”

Section: Discussionmentioning

confidence: 99%

“…As described above, to determine whether the impaired anti-NspA bactericidal antibody responses of the human FH transgenic mice were specific for NspA, we immunized groups of wild-type and human FH transgenic mice with a control meningococcal NOMV vaccine with overexpressed mutant R41S FHbp that had low levels of FH binding (11,26). Based on previous data, we expected that most of the serum bactericidal antibody would be directed at subfamily B FHbp (16) or PorA P1.5,2 (26,27). Figure 5 shows the serum bactericidal titers of antibodies against BZ198 measured in individual wild-type and human FH transgenic mice immunized with the meningococcal NOMV vaccine (Fig.…”

Section: Fig 2 Characterization Of E Coli Microvesicle Vaccines Contmentioning

confidence: 99%

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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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Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

Lewis

Ram

2020

FEBS Letters

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Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea, while Neisseria meningitidis is an important cause of bacterial meningitis and sepsis. Complement is a central arm of innate immune defenses and plays an important role in combating Neisserial infections. Persons with congenital and acquired defects in complement are at a significantly higher risk for invasive Neisserial infections such as invasive meningococcal disease and disseminated gonococcal infection compared to the general population. Of note, Neisseria gonorrhoeae and Neisseria meningitidis can only infect humans, which in part may be related to their ability to evade only human complement. This review summarizes the epidemiologic and clinical aspects of Neisserial infections in persons with defects in the complement system. Mechanisms used by these pathogens to subvert killing by complement and preclinical studies showing how these complement evasion strategies may be used to counteract the global threat of meningococcal and gonococcal infections are discussed.

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The Effect of Human Factor H on Immunogenicity of Meningococcal Native Outer Membrane Vesicle Vaccines with Over-Expressed Factor H Binding Protein

Cited by 42 publications

References 43 publications

A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

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

Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

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