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
Pajon, Rolando; Lujan, Eduardo; Granoff, Dan M (2016) A meningococcal NOMV-FHbp vaccine for Africa elicits broader serum bactericidal antibody responses against serogroup B and non-B strains than a licensed serogroup B vaccine. Vaccine 34:643-9
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
Lujan, Eduardo; Pajon, Rolando; Granoff, Dan M (2016) Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice. Infect Immun 84:452-8
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
Pajon, Rolando; Buckwalter, Carolyn M; Johswich, Kay O et al. (2015) A native outer membrane vesicle vaccine confers protection against meningococcal colonization in human CEACAM1 transgenic mice. Vaccine 33:1317-23
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
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; 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
Giuntini, Serena; Pajon, Rolando; Ram, Sanjay et al. (2015) Binding of complement factor H to PorB3 and NspA enhances resistance of Neisseria meningitidis to anti-factor H binding protein bactericidal activity. Infect Immun 83:1536-45

Showing the most recent 10 out of 88 publications