Abstract
Neisseria meningitidis recruits host human complement inhibitors to its surface to down-regulate complement activation and enhance survival in blood. We have investigated whether such complement inhibitor binding occurs after vaccination with native outer membrane vesicles (nOMVs), and limits immunogenicity of such vaccines. To this end, nOMVs reactogenic lipopolysaccharide was detoxified by deletion of the lpxl1 gene (nOMVlpxl1). nOMVs unable to bind human complement factor H (hfH) were generated by additional deletions of the genes encoding factor H binding protein (fHbp) and neisserial surface protein A (NspA) (nOMVdis). Antibody responses elicited in mice with nOMVdis were compared to those elicited with nOMVlpxl1 in the presence of hfH. Results demonstrate that the administration of human fH to mice immunized with fHbp containing OMVlpxl1 decreased immunogenicity against fHbp (but not against the OMV as a whole). The majority of the OMV-induced bactericidal immune response (OMVlpxl1 or OMVdis) was versus PorA. Despite a considerable reduction of hfH binding to nOMVdis, and the absence of the vaccine antigen fHbp, immunogenicity in mice was not different from nOMVlpxl1, in the absence or presence of hfH (serum bactericidal titers of 1:64 vs 1:128 after one dose in the nOMVdis and nOMVlpxl1-immunized groups respectively). Therefore, partial inhibition of fH binding did not enhance immunity in this model.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibody Formation
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Bacterial Outer Membrane Proteins / immunology*
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Bacterial Outer Membrane Proteins / therapeutic use
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Complement Factor H / immunology
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Complement Inactivating Agents / immunology*
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Female
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Humans
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Immunization
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Meningitis, Meningococcal / immunology*
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Meningitis, Meningococcal / prevention & control*
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Meningococcal Vaccines / immunology*
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Meningococcal Vaccines / therapeutic use
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Mice
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Mice, Inbred C57BL
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Neisseria meningitidis / immunology*
Substances
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Bacterial Outer Membrane Proteins
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CFH protein, human
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Complement Inactivating Agents
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Meningococcal Vaccines
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Complement Factor H
Grants and funding
This work was supported by a project grant from Sparks for Children's Health (grant number 10OXF01). CR was also supported by research grants from Meningitis UK and Action Medical Research. She is a Jenner Institute Investigator and an Oxford Martin fellow. AJP and CR are supported by the NIHR Oxford Biomedical Research Centre (Vaccine theme). AJP is a Jenner Investigator and James Martin Senior Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Imaxio provided support in the form of salaries for author [FH], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author (FH) are articulated in the 'author contributions' section.