Breadth and Duration of Meningococcal Serum Bactericidal Activity in Health Care Workers and Microbiologists Immunized with the MenB-FHbp Vaccine

Abstract

MenB-FHbp is a meningococcal serogroup B vaccine with two factor H binding protein (FHbp) antigens from subfamilies A and B. For licensure, efficacy was inferred from serum bactericidal antibody (SBA) responses to four reference strains. Only limited information is available on the breadth or duration of protective SBA responses to genetically diverse disease-causing strains. Seventeen health care or laboratory workers were immunized with two (n = 2) or three (n = 15) doses of MenB-FHbp at 0, 2, and 6 months. SBA levels were measured against 14 serogroup B case isolates, including 6 from U.S. college outbreaks and 2 from Quebec during hyperendemic disease. Compared with preimmunization titers, the proportion of subjects with ≥4-fold increases in SBA titer 1 month after 2 doses of vaccine ranged from 35% to 94% for six isolates with FHbp subfamily A and from 24% to 76% for eight isolates with subfamily B FHbp. The respective proportions with ≥4-fold titer increases at 1 month after dose 3 were 73% to 100% and 67% to 100%. At that time point, the proportion of subjects with titers of ≥1:4 (presumed sufficient for short-term protection) ranged from 93% to 100% for all 14 isolates. By 9 to 11 months after dose 3, 50% or fewer of the subjects with follow-up sera had protective titers of ≥1:4 for 4 of 9 isolates tested. Three doses of MenB-FHbp elicited short-term protective SBA responses to diverse disease-causing serogroup B strains. For some strains, serum titers declined to <1:4 by 9 to 11 months, which raises concerns about the duration of broad, long-term protection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02569632.).

Keywords: FHbp; Neisseria meningitidis; Trumenba; factor H binding protein; meningococcal vaccine; vaccines.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Percentages of vaccinated subjects with 4-fold or greater increases in serum bactericidal antibody titer. Four-fold responses were determined by comparing the titers seen 1 month (Mo) after administration of 2 or 3 doses of MenB-FHbp with the respective preimmunization titers. Error bars represent the 95% CI (confidence interval). The numbers above the bars in panels A and B indicate the FHbp sequence ID, as described in Table 1. (A) Six FHbp subfamily A case isolates. Univ., University. (B) Eight subfamily B case isolates and a mutant of strain H44/76 with ∼50% less FHbp expression than the parental wild-type (WT) strain (6). UC, University of California; RI, Rhode Island. (C) Unrooted maximum likelihood phylogram of strain FHbp amino acid sequence variants (ID numbers are indicated) computed with MEGA software (version 7). The scale bar indicates 5% amino acid sequence divergence. ID 45 and ID 55, which are shown in boxes, are the FHbp sequence variants from subfamilies A and B, respectively, in the MenB-FHbp vaccine.

FIG 2

Serum bactericidal antibody responses of individual subjects measured against 6 representative strains. Each symbol represents the serum titer of an individual before immunization and at 1 month after doses 2 or 3 and, for some subjects, at 4 to 6 months after dose 2 of MenB-FHbp (see Materials and Methods). The numbers above the symbols indicate the reciprocal GMTs. (A) Three case isolates with FHbp subfamily A. (B) Two case isolates with FHbp subfamily B and a mutant of H44/76 with 50% lower expression of FHbp subfamily B. Data for the remaining 9 case isolates are provided in Fig. S1 in the supplemental material.

FIG 3

Geometric mean serum bactericidal titers. (A) Strains with FHbp subfamily A sequence variants. (B) Strains with FHbp subfamily B sequence variants. Subjects with preimmunization titers of >1:8 were excluded. The numbers above the bars indicate the FHbp sequence ID, as described in Table 1. Further details regarding the number of sera tested against each strain at different time points can be found in Table S1 in the supplemental material.

FIG 4

Persistence of serum bactericidal antibody titers of ≥1:4 at 9 to 11 months after dose 3. (A) Three case isolates with FHbp subfamily A sequence variants. (B) Six case isolates with FHbp subfamily B and one H44/76 mutant with ∼50% lower expression of FHbp subfamily B than the parental strain. Strain FHbp sequence variant (peptide ID) and expression data are summarized in Table 1. Subjects with preimmunization titers of >1:8 were excluded. Numbers in parentheses below the x axis represent the numbers of tested subjects with samples collected before administration of dose 3, 1 month after dose 3, and 9 to 11 months after dose 3 (three sera from each subject). The horizontal line represents 50% of subjects with protective titers of ≥1:4.

FIG 5

Investigation of the basis for resistance of the Quebec 2013 strain to anti-FHbp bactericidal activity. (A) Pooled sera collected before and 1 month after administration of dose 2 from 9 adults immunized with MenB-FHbp. Flow cytometry was performed as previously described using live bacteria (4) and 1:300 dilutions of the serum pools. In 12 assays, the reciprocal GMT of the postpool SBA was higher against the 2009 strain than against the 2013 strain (27 versus 11, P < 0.0001). (B) mouse MAbs to different meningococcal antigens. The MAb to PorA P1.19 was purchased from the National Institute for Biological Standards and Control, United Kingdom (catalog no. 04/248) and tested in the flow assay at a concentration of 5 μg/ml. The anti-FHbp JAR 5 MAb is broadly reactive with FHbp subfamily B but individually lacks complement-mediated bactericidal activity (40, 41). JAR 5 was tested in the flow assay at 10 μg/ml but was not tested for bactericidal activity (Not Done). The anti-NspA MAb 14C7 (tested at 50 μg/ml in the flow assay) was from a previous study (42). Orange lines and symbols, Quebec 2009 strain; blue lines and symbols, Quebec 2013 strain.