Enhanced protective antibody to a mutant meningococcal factor H-binding protein with low-factor H binding
Dan M. Granoff, Serena Giuntini, Flor A. Gowans, Eduardo Lujan, Kelsey Sharkey, Peter T. Beernink
Dan M. Granoff, Serena Giuntini, Flor A. Gowans, Eduardo Lujan, Kelsey Sharkey, Peter T. Beernink
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Research Article Vaccines

Enhanced protective antibody to a mutant meningococcal factor H-binding protein with low-factor H binding

Abstract

Meningococcal factor H-binding protein (FHbp) is an antigen in 2 serogroup B meningococcal vaccines. FHbp specifically binds human and some nonhuman primate complement FH. To investigate the effect of binding of FH to FHbp on protective antibody responses, we immunized infant rhesus macaques with either a control recombinant FHbp antigen that bound macaque FH or a mutant antigen with 2 amino acid substitutions and >250-fold lower affinity for FH. The mutant antigen elicited 3-fold higher serum IgG anti-FHbp titers and up to 15-fold higher serum bactericidal titers than the control FHbp vaccine. When comparing sera with similar IgG anti-FHbp titers, the antibodies elicited by the mutant antigen gave greater deposition of complement component C4b on live meningococci (classical complement pathway) and inhibited binding of FH, while the anti-FHbp antibodies elicited by the control vaccine enhanced FH binding. Thus, the mutant FHbp vaccine elicited an anti-FHbp antibody repertoire directed at FHbp epitopes within the FH binding site, which resulted in greater protective activity than the antibodies elicited by the control vaccine, which targeted FHbp epitopes outside of the FH combining site. Binding of a host protein to a vaccine antigen impairs protective antibody responses, which can be overcome with low-binding mutant antigens.

Authors

Dan M. Granoff, Serena Giuntini, Flor A. Gowans, Eduardo Lujan, Kelsey Sharkey, Peter T. Beernink

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Figure 3

Serum bactericidal antibody responses against meningococcal strains with divergent FHbp sequences or lower FHbp expression.

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Serum bactericidal antibody responses against meningococcal strains with...
(A) Unrooted, maximum-likelihood phylogram of 70 representative FHbp amino acid sequence variants (57) computed with MEGA 7 (32). The subfamily B sequence variants expressed by the 3 test strains in B–D are indicated with labels; ID 1 represents the sequence of the control WT FHbp vaccine. Three representative subfamily A sequence variants also are shown for comparison. The scale bar indicates 5% amino acid sequence divergence. (B–D) Serum bactericidal antibody responses 3 weeks after 3 doses of a recombinant WT or mutant FHbp vaccine. Each symbol represents the titer of an individual animal; the number of animals per groups is the same as in Figure 2. The horizontal lines and numbers in the panel indicate the reciprocal GMTs. (B) Mutant of strain H44/76 with 50% expression of FHbp ID 1 compared with parental WT strain (30). (C) Mutant of strain H44/76 with high (100%) expression of FHbp ID 13 compared with parental WT strain. (D) WT strain CH860 with high expression of FHbp ID 15. ***P < 0.001; ****P < 0.0001 (2-tailed), comparing respective WT and mutant FHbp vaccines by t test of log10-transformed titers. For exact probabilities, see text. Data in B are titers measured in one assay in which all sera from pairs of control FHbp and mutant FHbp immunized animals were tested in parallel. Data in C and D represent mean titers for each individual animal from 2 or 3 replicate assays.