Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein

ABSTRACT Two licensed serogroup B meningococcal vaccines contain factor H binding protein (FHbp). The antigen specifically binds human FH, which downregulates complement. In wild-type mice whose mouse FH does not bind to FHbp vaccines, the serum anti-FHbp antibody response inhibited binding of human...

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Autores principales:	Peter T. Beernink, Serena Giuntini, Isabella Costa, Alexander H. Lucas, Dan M. Granoff
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5ab94d1bfd9a40c8ad446477965f1842
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spelling	oai:doaj.org-article:5ab94d1bfd9a40c8ad446477965f18422021-11-15T15:49:03ZFunctional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein10.1128/mBio.00842-152150-7511https://doaj.org/article/5ab94d1bfd9a40c8ad446477965f18422015-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00842-15https://doaj.org/toc/2150-7511ABSTRACT Two licensed serogroup B meningococcal vaccines contain factor H binding protein (FHbp). The antigen specifically binds human FH, which downregulates complement. In wild-type mice whose mouse FH does not bind to FHbp vaccines, the serum anti-FHbp antibody response inhibited binding of human FH to FHbp. The inhibition was important for eliciting broad anti-FHbp serum bactericidal activity. In human FH transgenic mice and some nonhuman primates, FHbp was able to form a complex with FH and FHbp vaccination elicited anti-FHbp antibodies that did not inhibit FH binding. To investigate the human anti-FHbp repertoire, we cloned immunoglobulin heavy- and light-chain-variable-region genes of individual B cells from three adults immunized with FHbp vaccines and generated 10 sequence-distinct native anti-FHbp antibody fragments (Fabs). All 10 Fabs bound to live meningococci; only 1 slightly inhibited binding of human FH, while 4 enhanced FH binding. Affinity-purified anti-FHbp antibody from serum of a fourth immunized adult also enhanced binding of human FH to live meningococcal bacteria. Despite the bound FH, the affinity-purified serum anti-FHbp antibodies elicited human complement-mediated bactericidal activity that was amplified by the alternative pathway. The lack of FH inhibition by the human anti-FHbp Fabs and serum antibodies suggests that binding of human FH to the vaccine antigen skews the anti-FHbp antibody repertoire to epitopes outside the FH-binding site. Mutant FHbp vaccines with decreased FH binding may represent a means to redirect the human antibody repertoire to epitopes within the FH binding site, which can inhibit FH binding and, potentially, increase safety and protective activity. IMPORTANCE Two meningococcal vaccines contain factor H binding protein (FHbp). Immunized mice whose mouse factor H (FH) does not bind to FHbp develop serum anti-FHbp antibodies that block binding of human FH to the bacteria. With less bound FH, the bacteria become more susceptible to complement killing. To investigate human responses, we isolated 10 recombinant anti-FHbp antibody fragments (Fabs) from immune cells of three immunized adults. One slightly inhibited binding of FH to the bacteria, and four enhanced FH binding. Purified serum anti-FHbp antibodies from a fourth immunized adult also enhanced FH binding. Although bound FH would be expected to block the alternative pathway, the human anti-FHbp antibodies retained bactericidal activity and the ability to activate the alternative pathway. Mutant FHbp vaccines with decreased binding to human FH may redirect the human antibody repertoire to epitopes within the FH binding site that inhibit FH binding, which are expected to increase protective activity.Peter T. BeerninkSerena GiuntiniIsabella CostaAlexander H. LucasDan M. GranoffAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 3 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Peter T. Beernink Serena Giuntini Isabella Costa Alexander H. Lucas Dan M. Granoff Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein
description	ABSTRACT Two licensed serogroup B meningococcal vaccines contain factor H binding protein (FHbp). The antigen specifically binds human FH, which downregulates complement. In wild-type mice whose mouse FH does not bind to FHbp vaccines, the serum anti-FHbp antibody response inhibited binding of human FH to FHbp. The inhibition was important for eliciting broad anti-FHbp serum bactericidal activity. In human FH transgenic mice and some nonhuman primates, FHbp was able to form a complex with FH and FHbp vaccination elicited anti-FHbp antibodies that did not inhibit FH binding. To investigate the human anti-FHbp repertoire, we cloned immunoglobulin heavy- and light-chain-variable-region genes of individual B cells from three adults immunized with FHbp vaccines and generated 10 sequence-distinct native anti-FHbp antibody fragments (Fabs). All 10 Fabs bound to live meningococci; only 1 slightly inhibited binding of human FH, while 4 enhanced FH binding. Affinity-purified anti-FHbp antibody from serum of a fourth immunized adult also enhanced binding of human FH to live meningococcal bacteria. Despite the bound FH, the affinity-purified serum anti-FHbp antibodies elicited human complement-mediated bactericidal activity that was amplified by the alternative pathway. The lack of FH inhibition by the human anti-FHbp Fabs and serum antibodies suggests that binding of human FH to the vaccine antigen skews the anti-FHbp antibody repertoire to epitopes outside the FH-binding site. Mutant FHbp vaccines with decreased FH binding may represent a means to redirect the human antibody repertoire to epitopes within the FH binding site, which can inhibit FH binding and, potentially, increase safety and protective activity. IMPORTANCE Two meningococcal vaccines contain factor H binding protein (FHbp). Immunized mice whose mouse factor H (FH) does not bind to FHbp develop serum anti-FHbp antibodies that block binding of human FH to the bacteria. With less bound FH, the bacteria become more susceptible to complement killing. To investigate human responses, we isolated 10 recombinant anti-FHbp antibody fragments (Fabs) from immune cells of three immunized adults. One slightly inhibited binding of FH to the bacteria, and four enhanced FH binding. Purified serum anti-FHbp antibodies from a fourth immunized adult also enhanced FH binding. Although bound FH would be expected to block the alternative pathway, the human anti-FHbp antibodies retained bactericidal activity and the ability to activate the alternative pathway. Mutant FHbp vaccines with decreased binding to human FH may redirect the human antibody repertoire to epitopes within the FH binding site that inhibit FH binding, which are expected to increase protective activity.
format	article
author	Peter T. Beernink Serena Giuntini Isabella Costa Alexander H. Lucas Dan M. Granoff
author_facet	Peter T. Beernink Serena Giuntini Isabella Costa Alexander H. Lucas Dan M. Granoff
author_sort	Peter T. Beernink
title	Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein
title_short	Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein
title_full	Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein
title_fullStr	Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein
title_full_unstemmed	Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein
title_sort	functional analysis of the human antibody response to meningococcal factor h binding protein
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/5ab94d1bfd9a40c8ad446477965f1842
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Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein

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