There are no broadly effective vaccines available for prevention of disease caused by group B strains of N. meningitidis, which account for 50% or more of cases of meningococcal disease. Because the group B capsule is an autoantigen, alternative vaccine strategies are needed. We are investigating the vaccine- potential of factor H binding protein (fHbp) a surface-exposed lipoprotein previously called GNA1870. Serum anti-fHbp antibodies bind to the bacteria, activate complement-mediated bacteriolysis, and also inhibit binding of the human complement down-regulatory protein, factor H (fH). In the absence of bound fH, the organism becomes more susceptible to complement-mediated bacteriolysis. One limitation of fHbp as a vaccine is antigenic variability (3 groups with some subvariants within groups). Anti-fHbp antibodies elicited by fHbp in variant group 1 are not bactericidal against strains expressing variant 2 or 3 proteins. To circumvent this problem, we are constructing recombinant chimeric fHbp molecules that express epitopes from different variant groups. In mice, a prototype chimeric fHbp vaccine elicited serum bactericidal antibodies against strains expressing fHbp variant 1, 2 or 3. Because recombinant fHbp may not express all epitopes important for eliciting broad bactericidal activity, we also are preparing native outer membrane vesicle (OMV) vaccines from N. meningitidis strains engineered to over-express fHbp. Since detergent treatments used to remove endotoxin from conventional OMV vaccines extract fHbp, we attenuate endotoxin activity by inactivating a lipid A biosynthesis gene, LpxL1. A native OMV from the mutant was 1000- to 10,000-fold less active in stimulating human PBMCs to produce proinflammatory cytokines than OMV from the wildtype strain. In mice, a native OMV vaccine from an LpxL1 knockout mutant with over-expressed fHbp elicited broader bactericidal activity than control recombinant fHbp or detergent-extracted OMV vaccines. In this application, we will build on these genetic approaches to develop even safer and more broadly effective vaccines.
In Aim 1, we will define locations of epitopes of two anti-fHbp mAbs that are of special interest because the epitopes are conserved across fHbp variant groups and the mAbs mediate cooperative bactericidal activity with second anti-fHbp mAbs.
In Aim 2, we will construct second-generation recombinant chimeric fHbp vaccines designed to elicit even broader bactericidal antibody responses than the prototype chimeric vaccines prepared to date.
In Aim 3, we will construct additional N. meningitidis mutants with over-expressed fHbp from different variant groups, and in which genes encoding unwanted antigens are inactivated. The mutants will be used to produce highly immunogenic and safe OMV vaccines, which will be evaluated for immunogenicity in mice and, subsequently, in nonhuman infant primates. The proposed studies will determine whether these vaccine approaches have the potential to prevent all N. meningitidis disease, including group B. Since other pathogens also bind fH to circumvent innate host defenses, the lessons learned may be applicable to development of other vaccines.

Public Health Relevance

Neisseria meningitidis is a bacterium that invades the bloodstream and causes sepsis or meningitis, which can be fatal or lead to brain damage, amputations or other complications. 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 half of the cases in the U.S. and an even higher proportion in Europe. This proposal describes studies of two highly promising vaccine strategies for prevention of group B meningococcal disease, which could lead to a safe and broadly protective group B vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046464-11
Application #
8288814
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Taylor, Christopher E,
Project Start
1999-12-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
11
Fiscal Year
2012
Total Cost
$631,670
Indirect Cost
$219,642
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Beernink, Peter T; Shaughnessy, Jutamas; Stefek, Heather et al. (2014) Heterogeneity in rhesus macaque complement factor H binding to meningococcal factor H binding protein (FHbp) informs selection of primates to assess immunogenicity of FHbp-based vaccines. Clin Vaccine Immunol 21:1505-11
Shaughnessy, Jutamas; Vu, David M; Punjabi, Rahi et al. (2014) Fusion protein comprising factor H domains 6 and 7 and human IgG1 Fc as an antibacterial immunotherapeutic. Clin Vaccine Immunol 21:1452-9
Lewis, Lisa A; Vu, David M; Granoff, Dan M et al. (2014) Inhibition of the alternative pathway of nonhuman infant complement by porin B2 contributes to virulence of Neisseria meningitidis in the infant rat model. Infect Immun 82:2574-84
Costa, Isabella; Pajon, Rolando; Granoff, Dan M (2014) Human factor H (FH) impairs protective meningococcal anti-FHbp antibody responses and the antibodies enhance FH binding. MBio 5:e01625-14
Konar, Monica; Granoff, Dan M; Beernink, Peter T (2013) Importance of inhibition of binding of complement factor H for serum bactericidal antibody responses to meningococcal factor H-binding protein vaccines. J Infect Dis 208:627-36
Lewis, Lisa A; Vu, David M; Vasudhev, Shreekant et al. (2013) Factor H-dependent alternative pathway inhibition mediated by porin B contributes to virulence of Neisseria meningitidis. MBio 4:e00339-13
Giuntini, Serena; Vu, David M; Granoff, Dan M (2013) fH-dependent complement evasion by disease-causing meningococcal strains with absent fHbp genes or frameshift mutations. Vaccine 31:4192-9
Rossi, Raffaella; Granoff, Dan M; Beernink, Peter T (2013) Meningococcal factor H-binding protein vaccines with decreased binding to human complement factor H have enhanced immunogenicity in human factor H transgenic mice. Vaccine 31:5451-7
Granoff, Dan M; Ram, Sanjay; Beernink, Peter T (2013) Does binding of complement factor H to the meningococcal vaccine antigen, factor H binding protein, decrease protective serum antibody responses? Clin Vaccine Immunol 20:1099-107
Granoff, Dan M (2013) Commentary: European Medicines Agency recommends approval of a broadly protective vaccine against serogroup B meningococcal disease. Pediatr Infect Dis J 32:372-3

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