Factor H-binding protein (fHbp) is part of two vaccines in clinical development for prevention of group B meningococcal disease for which currently there is no licensed vaccine. Meningococci use fHbp to bind complement factor H (fH) to evade host immunity;binding is specific for human fH. Antibodies to fHbp can inhibit binding of fH and increase susceptibility of the organisms to complement-mediated bacteriolysis. Our preliminary studies in newly created human fH transgenic mice showed that binding of human fH to fHbp decreased the protective antibody responses. A single amino acid substitution in fHbp eliminated fH binding and increased the protective responses.
In Aim 1 we will use random mutagenesis to identify and investigate the vaccine potential of additional mutants that eliminate fH binding. Sequence variants of fHbp are classified in two antigenic sub-families;the mutation that eliminated fH binding in one sub-family had no effect in the other. Therefore in Aim 2 we will use site-specific and random mutagenesis to generate mutants in the fHbp from the other sub- family. Binding of fH to fHbp may create neoantigens capable of eliciting autoantibodies to fH.
In Aim 3, we will test whether the native fHbp that binds human fH elicits autoantibodies in transgenic animals, which would provide a strong rationale for the use of fH non-binding fHbp mutants as vaccines. By making relatively minor modifications to fHbp antigens already in clinical development, the proposed studies will illuminate the relationship between binding of fH to a vaccine antigen and vaccine safety and efficacy.

Public Health Relevance

Neisseria meningitidis is a bacterium that causes sepsis or meningitis, which can be fatal or lead to brain damage, amputations or other permanent damage. Vaccines are available for prevention of disease caused by some strains of the bacteria but no vaccine is available against group B strains, which cause one-third of the cases in the U.S. and up to 90% of cases in Europe. This proposal describes approaches to eliminate binding of a host protein to a highly promising group B vaccine antigen, which could increase the safety and efficacy of broadly protective group B vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI099125-01
Application #
8273504
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Taylor, Christopher E,
Project Start
2012-03-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$478,536
Indirect Cost
$180,235
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Rossi, Raffaella; Konar, Monica; Beernink, Peter T (2016) Meningococcal Factor H Binding Protein Vaccine Antigens with Increased Thermal Stability and Decreased Binding of Human Factor H. Infect Immun 84:1735-42
Granoff, Dan M; Giuntini, Serena; Gowans, Flor A et al. (2016) Enhanced protective antibody to a mutant meningococcal factor H-binding protein with low-factor H binding. JCI Insight 1:e88907
Giuntini, S; Granoff, D M; Beernink, P T et al. (2016) Human IgG1, IgG3, and IgG3 Hinge-Truncated Mutants Show Different Protection Capabilities against Meningococci Depending on the Target Antigen and Epitope Specificity. Clin Vaccine Immunol 23:698-706
Rossi, Raffaella; Beernink, Peter T; Giuntini, Serena et al. (2015) Susceptibility of Meningococcal Strains Responsible for Two Serogroup B Outbreaks on U.S. University Campuses to Serum Bactericidal Activity Elicited by the MenB-4C Vaccine. Clin Vaccine Immunol 22:1227-34
Konar, Monica; Rossi, Raffaella; Walter, Helen et al. (2015) A Mutant Library Approach to Identify Improved Meningococcal Factor H Binding Protein Vaccine Antigens. PLoS One 10:e0128185
Granoff, Dan M; Costa, Isabella; Konar, Monica et al. (2015) Binding of Complement Factor H (FH) Decreases Protective Anti-FH Binding Protein Antibody Responses of Infant Rhesus Macaques Immunized With a Meningococcal Serogroup B Vaccine. J Infect Dis 212:784-92
Giuntini, Serena; Beernink, Peter T; Granoff, Dan M (2015) Effect of complement Factor H on anti-FHbp serum bactericidal antibody responses of infant rhesus macaques boosted with a licensed meningococcal serogroup B vaccine. Vaccine 33:7168-75
Konar, Monica; Pajon, Rolando; Beernink, Peter T (2015) A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes. Proc Natl Acad Sci U S A 112:14823-8
Konar, Monica; Beernink, Peter T; Granoff, Dan M (2015) A Newly-Identified Polymorphism in Rhesus Macaque Complement Factor H Modulates Binding Affinity for Meningococcal FHbp. PLoS One 10:e0135996
Beernink, Peter T; Giuntini, Serena; Costa, Isabella et al. (2015) Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein. MBio 6:e00842

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