Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding

ABSTRACT The meningococcal 4CMenB vaccine (Bexsero; Novartis) contains four antigens that can elicit serum bactericidal activity, one of which is factor H (FH)-binding protein (FHbp). FHbp specifically binds human complement FH. When humans are immunized, FHbp is expected to form a complex with FH,...

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Autores principales:	Isabella Costa, Rolando Pajon, Dan M. Granoff
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f4b001426ffd418f8855483e05502b28
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spelling	oai:doaj.org-article:f4b001426ffd418f8855483e05502b282021-11-15T15:45:55ZHuman Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding10.1128/mBio.01625-142150-7511https://doaj.org/article/f4b001426ffd418f8855483e05502b282014-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01625-14https://doaj.org/toc/2150-7511ABSTRACT The meningococcal 4CMenB vaccine (Bexsero; Novartis) contains four antigens that can elicit serum bactericidal activity, one of which is factor H (FH)-binding protein (FHbp). FHbp specifically binds human complement FH. When humans are immunized, FHbp is expected to form a complex with FH, which could affect immunogenicity and safety. Wild-type mice (whose FH does not bind to FHbp) and human FH transgenic mice were immunized with three doses of 4CMenB, and their responses were compared. There were no significant differences between the serum bactericidal responses of transgenic and wild-type mice to strains with all of the antigens mismatched for 4CMenB except PorA or NadA. In contrast, against a strain mismatched for all of the antigens except FHbp, the transgenic mice had 15-fold weaker serum bactericidal antibody responses (P = 0.0006). Binding of FH downregulates complement. One explanation for the lower anti-FHbp serum bactericidal activity in the transgenic mice is that their postimmunization serum samples enhanced the binding of FH to FHbp, whereas the serum samples from the wild-type mice inhibited FH binding. Control antiserum from transgenic mice immunized with a low-FH-binding mutant FHbp (R41S) vaccine inhibited FH binding. Two 4CMenB-vaccinated transgenic mice developed serum IgM autoantibodies to human FH. Thus, human FH impairs protective serum anti-FHbp antibody responses, in part by skewing the antibody repertoire to FHbp epitopes outside the FH binding site. FHbp vaccines that bind FH may elicit FH autoantibodies. Mutant FHbp antigens with low FH binding could improve protection and, potentially, vaccine safety in humans. IMPORTANCE Two serogroup B meningococcal vaccines contain a novel antigen called factor H (FH)-binding protein (FHbp). FHbp specifically binds human FH, a plasma protein that downregulates complement. One vaccine (4CMenB; Novartis) is licensed in Europe, Canada, and Australia. When humans are immunized, FHbp can complex with FH. We compared the immunogenicity of 4CMenB vaccine in wild-type mice, whose own FH does not bind to FHbp, and human FH transgenic mice. Transgenic mice had respective antibody responses similar to those of wild-type mice to 4CMenB antigens that do not bind FH. However, the protective antibody responses of the transgenic mice to FHbp were impaired, largely because the antibodies did not inhibit but rather enhanced the binding of FH to FHbp. Two transgenic mice developed serum IgM autoantibodies to FH. Mutant FHbp antigens with low FH binding likely will elicit greater protection in humans than FHbp vaccines that bind FH and have a lower risk of FH autoantibodies.Isabella CostaRolando PajonDan M. GranoffAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 5 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Isabella Costa Rolando Pajon Dan M. Granoff Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding
description	ABSTRACT The meningococcal 4CMenB vaccine (Bexsero; Novartis) contains four antigens that can elicit serum bactericidal activity, one of which is factor H (FH)-binding protein (FHbp). FHbp specifically binds human complement FH. When humans are immunized, FHbp is expected to form a complex with FH, which could affect immunogenicity and safety. Wild-type mice (whose FH does not bind to FHbp) and human FH transgenic mice were immunized with three doses of 4CMenB, and their responses were compared. There were no significant differences between the serum bactericidal responses of transgenic and wild-type mice to strains with all of the antigens mismatched for 4CMenB except PorA or NadA. In contrast, against a strain mismatched for all of the antigens except FHbp, the transgenic mice had 15-fold weaker serum bactericidal antibody responses (P = 0.0006). Binding of FH downregulates complement. One explanation for the lower anti-FHbp serum bactericidal activity in the transgenic mice is that their postimmunization serum samples enhanced the binding of FH to FHbp, whereas the serum samples from the wild-type mice inhibited FH binding. Control antiserum from transgenic mice immunized with a low-FH-binding mutant FHbp (R41S) vaccine inhibited FH binding. Two 4CMenB-vaccinated transgenic mice developed serum IgM autoantibodies to human FH. Thus, human FH impairs protective serum anti-FHbp antibody responses, in part by skewing the antibody repertoire to FHbp epitopes outside the FH binding site. FHbp vaccines that bind FH may elicit FH autoantibodies. Mutant FHbp antigens with low FH binding could improve protection and, potentially, vaccine safety in humans. IMPORTANCE Two serogroup B meningococcal vaccines contain a novel antigen called factor H (FH)-binding protein (FHbp). FHbp specifically binds human FH, a plasma protein that downregulates complement. One vaccine (4CMenB; Novartis) is licensed in Europe, Canada, and Australia. When humans are immunized, FHbp can complex with FH. We compared the immunogenicity of 4CMenB vaccine in wild-type mice, whose own FH does not bind to FHbp, and human FH transgenic mice. Transgenic mice had respective antibody responses similar to those of wild-type mice to 4CMenB antigens that do not bind FH. However, the protective antibody responses of the transgenic mice to FHbp were impaired, largely because the antibodies did not inhibit but rather enhanced the binding of FH to FHbp. Two transgenic mice developed serum IgM autoantibodies to FH. Mutant FHbp antigens with low FH binding likely will elicit greater protection in humans than FHbp vaccines that bind FH and have a lower risk of FH autoantibodies.
format	article
author	Isabella Costa Rolando Pajon Dan M. Granoff
author_facet	Isabella Costa Rolando Pajon Dan M. Granoff
author_sort	Isabella Costa
title	Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding
title_short	Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding
title_full	Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding
title_fullStr	Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding
title_full_unstemmed	Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding
title_sort	human factor h (fh) impairs protective meningococcal anti-fhbp antibody responses and the antibodies enhance fh binding
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/f4b001426ffd418f8855483e05502b28
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Human Factor H (FH) Impairs Protective Meningococcal Anti-FHbp Antibody Responses and the Antibodies Enhance FH Binding

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