Immunogenicity of a meningococcal native outer membrane vesicle vaccine with attenuated endotoxin and over-expressed factor H binding protein in infant rhesus monkeys

Koeberling, Oliver; Seubert, Anja; Santos, George França dos; Colaprico, Annalisa; Ugozzoli, Mildred; Donnelly, John; Granoff, Dan M.

doi:10.1016/j.vaccine.2011.04.095

Cited by 40 publications

(31 citation statements)

References 37 publications

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“…The protocols were approved by the Institutional Animal Care and Use Committee at the California National Primate Research Center (Davis, CA). Details of one of the studies have been published (15). The macaques lived in outdoor social housing with their dams and extended families.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneity in Rhesus Macaque Complement Factor H Binding to Meningococcal Factor H Binding Protein (FHbp) Informs Selection of Primates To Assess Immunogenicity of FHbp-Based Vaccines

Beernink¹,

Shaughnessy

Stefek³

et al. 2014

Clin. Vaccine Immunol.

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Section: Methodsmentioning

confidence: 99%

Heterogeneity in Rhesus Macaque Complement Factor H Binding to Meningococcal Factor H Binding Protein (FHbp) Informs Selection of Primates To Assess Immunogenicity of FHbp-Based Vaccines

Beernink¹,

Shaughnessy

Stefek³

et al. 2014

Clin. Vaccine Immunol.

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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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“…Vaccination of infant RMs with meningococcal outer membrane vesicle results in the development of broadly protective serum antibodies (35). Testing candidates in the RM should allow a better prediction of human antibody responses than in rodents.…”

Section: Discussionmentioning

confidence: 99%

Neisseria infection of rhesus macaques as a model to study colonization, transmission, persistence, and horizontal gene transfer

Weyand

Wertheimer

Hobbs

et al. 2013

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

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The strict tropism of many pathogens for man hampers the development of animal models that recapitulate important microbehost interactions. We developed a rhesus macaque model for studying Neisseria-host interactions using Neisseria species indigenous to the animal. We report that Neisseria are common inhabitants of the rhesus macaque. Neisseria isolated from the rhesus macaque recolonize animals after laboratory passage, persist in the animals for at least 72 d, and are transmitted between animals. Neisseria are naturally competent and acquire genetic markers from each other in vivo, in the absence of selection, within 44 d after colonization. Neisseria macacae encodes orthologs of known or presumed virulence factors of human-adapted Neisseria, as well as current or candidate vaccine antigens. We conclude that the rhesus macaque model will allow studies of the molecular mechanisms of Neisseria colonization, transmission, persistence, and horizontal gene transfer. The model can potentially be developed further for preclinical testing of vaccine candidates.commensal Neisseria | nonhuman primate model | type IV pili M icrobe-host interactions are often refractory to investigation because of the exquisite tropism of many bacteria for the human host. Host-restriction has prevented the development of animal models that recapitulate colonization, transmission, and persistence; hampered studies of horizontal gene transfer (HGT); and prevented preclinical testing of vaccine candidates. One means to circumvent host restrictions is to develop an animal model of infection using a related species indigenous to that animal. For example, infections by human pathogens, such as Bordetella pertussis and Chlamydia trachomatis, have been effectively modeled in animals with Bordetella bronchiseptica and Chlamydia muridarum, respectively (1, 2).The genus Neisseria and the rhesus macaque provide us with this opportunity. Neisseria are Gram-negative, diplococcal β-Proteobacteria. This genus includes >10 human-adapted species, two of which are pathogens, and an unknown number of species that naturally colonize animals. These species are highly related: >40% of the genes in pathogenic species are also present in commensals, and many of these encode virulence genes and antibiotic resistance alleles. The species are naturally competent and transfer genetic information to each other in vitro (3, 4). HGT is widely assumed to play an important role in the spread of antibiotic resistance among pathogenic Neisseria; however, there is little information on the extent to which HGT occurs in vivo.Pathogens Neisseria meningitidis and Neisseria gonorrhoeae have an exquisite tropism for man. These pathogens do not naturally infect animals; inoculated into nonhuman hosts, the pathogens will colonize only for brief periods (5, 6). Neisseria species have been isolated from a number of animals (7-10), suggesting it may be possible to develop a model for studying Neisseria-host interactions in which there are no host-restriction barriers to overcome.The ...

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Immunogenicity of a meningococcal native outer membrane vesicle vaccine with attenuated endotoxin and over-expressed factor H binding protein in infant rhesus monkeys

Cited by 40 publications

References 37 publications

Heterogeneity in Rhesus Macaque Complement Factor H Binding to Meningococcal Factor H Binding Protein (FHbp) Informs Selection of Primates To Assess Immunogenicity of FHbp-Based Vaccines

Heterogeneity in Rhesus Macaque Complement Factor H Binding to Meningococcal Factor H Binding Protein (FHbp) Informs Selection of Primates To Assess Immunogenicity of FHbp-Based Vaccines

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

Neisseria infection of rhesus macaques as a model to study colonization, transmission, persistence, and horizontal gene transfer

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