Serum Bactericidal Antibody Responses of Adults Immunized with the MenB-4C Vaccine against Genetically Diverse Serogroup B Meningococci

Abstract

MenB-4C is a meningococcal vaccine for the prevention of serogroup B disease. The vaccine contains factor H binding protein (FHbp) and three other antigens that can elicit serum bactericidal antibodies (SBA). For vaccine licensure, efficacy was inferred from the SBA responses against three antigen-specific indicator strains. The relation between those results and broad protection against circulating genetically diverse strains is not known. Twenty adults were immunized with two doses of MenB-4C given 1 to 2 months apart. SBA activity against 3 reference strains and 15 serogroup B test strains (6 from college outbreaks) was measured. Compared to the preimmunization titers, 70%, 95%, and 95% of subjects had ≥4-fold increases in the titers of anti-PorA P1.4, anti-NadA, and anti-FHbp antibodies against the reference strains, respectively. In contrast, only 25 to 45% of the subjects had ≥4-fold increases in responses to 10 of the 15 test strains, including 8 that expressed one to three of the antigens in the vaccine. At 1 month, the majority of subjects with <4-fold titer increases had serum titers of ≥1:4, which are considered sufficient for protection. However, the titers against four strains declined to <1:4 by 4 to 6 months in one-third to greater than 50% of the subjects tested. Clinically relevant isolates are often more resistant to SBA than the indicator strains used to measure antigen-specific SBA. A working model is that the percentage of subjects with titers of ≥1:4 at 1 month postimmunization correlates with short-term protection against that strain, whereas the percentage of subjects with ≥4-fold titer increases represents a more robust response. (The protocol used at the Oxford Vaccine Group has been registered at ClinicalTrials.gov under registration no. NCT02398396.).

Keywords: Bexsero; FH; FHbp; MenB-4C; autoantibody; complement factor H; factor H binding protein; meningococcal vaccine.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Percentage of vaccinated adults with 4-fold or greater increases in the serum bactericidal antibody titer. Fourfold responses were determined by comparison of the titers 1 month after the administration of dose 2 to the respective preimmunization titers. Strain expression of other MenB-4C antigens are designated by * (NHba), † (NadA), and # (PorA P1.4). (A) Results for reference indicator strains H44/76 WT (FHbp), 5/99 (NadA), and ant-PorA P1.4 (SK106 for the current study and strain NZ98/254 for historical data; see the text). Data for historical studies 1 and 2 are from the U.S. FDA MenB-4C package insert. (B) Relationship between FHbp sequence variants. Unrooted maximum-likelihood phylogram of strain FHbp amino acid sequence variants (ID numbers are indicated) computed with the MEGA (version 7) program. 1, ID 1 sequence of the FHbp in MenB-4C. The scale bar indicates 5% amino acid sequence divergence. (C) Results for seven FHbp subfamily A test strains. The Rutgers University isolate and the H44/76 mutant are mismatched for all four MenB-4C antigens reported to elicit serum bactericidal activity. (D) Results for eight FHbp subfamily B test strains. The H44/76 mutant has ∼50% the level of expression of FHbp ID 1 as its parent WT strain (see panel A). Further details on strain antigens and clonal complexes are provided in Table 1 and Table S1 in the supplemental material. CI, confidence interval.

FIG 2

Serum bactericidal antibody responses to 9 representative strains. Each symbol represents the serum titer of an individual before and 1 and 4 to 6 months after two doses of MenB-4C. The numbers at the tops of the panels indicate GMTs. Data are stratified on the basis of titers of ≤1:8 or >1:8 in preimmunization sera (Pre). (A) Titers against three reference indicator strains, H44/76 wild type, 5/99, and SK016, each matched with only one MenB-4C antigen (FHbp, NadA, and PorA P1.4, respectively). (B) Titers against three representative strains with subfamily A FHbp (mismatched for the subfamily B FHbp antigen in the vaccine). Strain 03s-0673 has two vaccine antigens (NadA and NHba), strain M4407 has one vaccine antigen (NHba), and the Rutgers University isolate is mismatched for all four antigens. (C) Titers against three representative strains with subfamily B FHbp matched for the subfamily B of the FHbp antigen in the vaccine. All three strains have NadA and NHba.

FIG 3

Geometric mean serum bactericidal titers. (A) Titers against three reference strains, the H44/76 wild type, 5/99, and SK016, each matched with only one MenB-4C antigen (FHbp, NadA, and PorA P1.4, respectively). (B) Titers against seven test strains with subfamily A FHbp (mismatched for the subfamily B FHbp antigen in vaccine). (C) Titers against eight test strains with subfamily B FHbp matched for the subfamily B FHbp antigen in the vaccine. The data shown are for subjects with preimmunization titers of ≤1:8. The numbers above the bars indicate the FHbp sequence ID, and the symbols indicate the expression of other MenB-4C antigens, as described in the legend to Fig. 1. Note that the y axis of panel A is from <4 to 1,000 and that of panels B and C is from <4 to 100.

FIG 4

Percentage of subjects with serum bactericidal titers of ≥1:4. The vaccine antigens expressed by each strain are as described in the legend to Fig. 1. Data are for subjects with preimmunization titers of ≤1:8. For each strain, the first number above the bars indicates the number of subjects with preimmunization titers of ≤1:8 included in the analyses of the preimmunization titers and the titers 1 month after the administration of dose 2, and the second number refers to the number of subjects included in the analysis of the serum titers at 4 to 6 months after the administration of dose 2.

FIG 5

Serum bactericidal titers of subjects with preimmunization titers of