Design and evaluation of meningococcal vaccines through structure-based modification of host and pathogen molecules
Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regula...
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Published in | PLoS pathogens Vol. 8; no. 10; p. e1002981 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
Public Library of Science
01.10.2012
Public Library of Science (PLoS) |
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Abstract | Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps. |
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AbstractList | Neisseria meningitis
remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps.
Vaccines are currently available against several serogroups of
Neisseria meningitidis
. However broadly effective serogroup B vaccines are still required as capsule-based approaches cannot be implemented with this serogroup because of the risks of auto-immunity. As a result, vaccines based on proteins in the bacterial outer membrane are being developed. Factor H binding protein (fHbp) is an important meningococcal immunogen which is able to bind the human complement regulator factor H (fH) at high affinity; this interaction could impair the efficacy of fHbp-based vaccines. Here we perform structure:function analyses to define non-functional fHbps and to explain the basis for the host specificity of the fHbp:fH interaction. The vaccine candidacy of non-functional fHbps was compared with wild-type proteins in a relevant transgenic model. These findings should allow the design and evaluation of future fHbp vaccines against this important human pathogen. Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein;while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Nonfunctional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps. Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps. Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps. |
Audience | Academic |
Author | Trivedi, Kaushali Bai, Xilian Ufret-Vincenty, Rafael Cumber, Elspeth Johnson, Steven van der Veen, Stijn Caesar, Joseph Ruivo, Nicola Tang, Christoph M Newham, Luke Borrow, Ray Harding, Rachel J Staunton, David Lea, Susan M Jones, Rhian Pickering, Matthew C Tan, Lionel Goicoechea De Jorge, Elena Ward, Philip N Exley, Rachel M |
AuthorAffiliation | 2 Centre for Molecular Microbiology and Infection, Imperial College, London, United Kingdom 3 Centre for Complement and Inflammation Research (CCIR), Department of Medicine, Imperial College, London, United Kingdom 5 Department of Biochemistry, University of Oxford, Oxford, United Kingdom 6 Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, United States of America 1 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom 4 Vaccine Evaluation Unit, Public Health Laboratory, Manchester Medical Microbiology Partnership, Manchester, United Kingdom Faculté de Médecine Paris Descartes, site Necker, France |
AuthorAffiliation_xml | – name: 2 Centre for Molecular Microbiology and Infection, Imperial College, London, United Kingdom – name: Faculté de Médecine Paris Descartes, site Necker, France – name: 4 Vaccine Evaluation Unit, Public Health Laboratory, Manchester Medical Microbiology Partnership, Manchester, United Kingdom – name: 3 Centre for Complement and Inflammation Research (CCIR), Department of Medicine, Imperial College, London, United Kingdom – name: 6 Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, United States of America – name: 1 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom – name: 5 Department of Biochemistry, University of Oxford, Oxford, United Kingdom |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23133374$$D View this record in MEDLINE/PubMed |
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ContentType | Journal Article |
Copyright | COPYRIGHT 2012 Public Library of Science 2012 Johnson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Johnson S, Tan L, van der Veen S, Caesar J, Goicoechea De Jorge E, et al. (2012) Design and Evaluation of Meningococcal Vaccines through Structure-Based Modification of Host and Pathogen Molecules. PLoS Pathog 8(10): e1002981. doi:10.1371/journal.ppat.1002981 2012 Johnson et al 2012 Johnson et al |
Copyright_xml | – notice: COPYRIGHT 2012 Public Library of Science – notice: 2012 Johnson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Johnson S, Tan L, van der Veen S, Caesar J, Goicoechea De Jorge E, et al. (2012) Design and Evaluation of Meningococcal Vaccines through Structure-Based Modification of Host and Pathogen Molecules. PLoS Pathog 8(10): e1002981. doi:10.1371/journal.ppat.1002981 – notice: 2012 Johnson et al 2012 Johnson et al |
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Notes | Work in CMT's and SML's laboratories is funded by Novartis. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials. Conceived and designed the experiments: SJ RME RB MCP SML CMT. Performed the experiments: SJ LT SvdV JC EGJ RJH XB PNW NR KT EC RJ LN DS RME. Analyzed the data: SJ LT SvdV JC EGJ RJH XB PNW NR KT EC RJ LN DS RB MCP SML CMT. Contributed reagents/materials/analysis tools: RU-V. Wrote the paper: SJ EGJ RJH CMT. |
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Snippet | Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor... Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor... Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen.... |
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SubjectTerms | Amino Acid Sequence Amino Acid Substitution Amino acids Animals Antibodies, Bacterial - immunology Antigens, Bacterial - immunology Bacterial Proteins - immunology Binding Sites Biology Complement Factor H - immunology Complement Factor H - metabolism Female Health aspects Host-parasite relationships Humans Medicine Meningitis Meningitis, Meningococcal - immunology Meningitis, Meningococcal - prevention & control Meningococcal Vaccines - immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Mortality Neisseria meningitidis Neisseria meningitidis - immunology Physiological aspects Protein Binding - immunology Protein Isoforms - genetics Protein Structure, Secondary Proteins Vaccines Values Virulence (Microbiology) |
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Title | Design and evaluation of meningococcal vaccines through structure-based modification of host and pathogen molecules |
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