Prevalence of factor H-binding protein variants and NadA among meningococcal group B isolates from the United States: implications for the development of a multicomponent group B vaccine

Abstract

Background: Two promising recombinant meningococcal protein vaccines are in development. One contains factor H-binding protein (fHBP) variants (v.) 1 and 2, whereas the other contains v.1 and 4 other antigens discovered by genome mining (5 component [5C]). Antibodies against fHBP are bactericidal against strains within a variant group. There are limited data on the prevalence of strains expressing different fHBP variants in the United States.

Methods: A total of 143 group B isolates from patients hospitalized in the United States were tested for fHBP variant by quantitative polymerase chain reaction, for reactivity with 6 anti-fHBP monoclonal antibodies (MAb) by dot immunoblotting, and for susceptibility to bactericidal activity of mouse antisera.

Results: fHBP v.1 isolates predominated in California (83%), whereas isolates expressing v.1 (53%) or v.2 (42%) were common in 9 other states. Isolates representative of 5 anti-fHBP MAb-binding phenotypes (70% of isolates) were highly susceptible to anti-fHBP v.1 or v.2 bactericidal activity, whereas 3 phenotypes were approximately 50% susceptible. Collectively, antibodies against the fHBP v.1 and v.2 vaccine and the 5C vaccine killed 76% and 83% of isolates, respectively.

Conclusions: Susceptibility to bactericidal activity can be predicted, in part, on the basis of fHBP phenotypes. Both vaccines have the potential to prevent most group B disease in the United States.

Figure 1

Percentage of fHBP variant (v.) 1, 2, or 3 genes (A) and nadA genes (B), as determined by quantitative polymerase chain reaction. Error bars indicate 95% confidence intervals. Shaded bars, California isolates; hatched bars, Maryland isolates; white bars, multicenter isolates.

Figure 2

Anti–factor H–binding protein (fHBP) monoclonal antibody (MAb) reactivity with representative Neisseria meningitidis group B strains. Heat-killed, whole meningococci were applied to a membrane, which was probed with polyclonal antibody or MAb. Wild-type (WT) and fHBP knockout (KO) mutant strains from each variant group were tested. α-fHBP variant (v.) 1,2,3, mouse antisera raised against the individual fHBP v.1, v.2, and v.3 proteins and pooled; JAR 1, 3, and 5, MAbs raised against recombinant fHBP v.1; JAR 10, 11, 13, MAbs raised against recombinant fHBP v.2.

Figure 3

Bactericidal activity of anti–factor H–binding protein (fHBP) antisera against fHBP variant (v.) 1 isolates, by fHBP phenotype (n =8–21 isolates/group). A, Percentage of strains giving a titer ≥1:8; B, Reciprocal geometric mean titers (GMTs). Error bars indicate 95% confidence intervals. Shaded bars, anti–fHBP v.1 antiserum; hatched bars, anti–fHBP v.2; white bars, anti–fHBP v.3.

Figure 4

Bactericidal activity of anti–factor H–binding protein (fHBP) antiserum against isolates expressing fHBP variant (v.) 2 or 3. Each fHBP phenotype had 6–13 isolates. A, Percentage of strains giving a titer ≥1:8; B, Reciprocal geometric mean titers (GMTs). Error bars indicate 95% confidence intervals. Shaded bars, anti–fHBP v.1 antiserum; hatched bars, anti–fHBP v.2; white bars, anti–fHBP v.3.

Figure 5

Percentage of isolates giving a titer ≥1:8 to anti–5-component (5C) vaccine antiserum. Also shown are data for the respective percentages susceptible to the anti–factor H–binding protein (fHBP) variant (v.) 1 antiserum tested alone. A, fHBP v.1 isolates; B, fHBP v.2 or v.3 isolates. Error bars indicate 95% confidence intervals. Stippled bars, anti-5C antiserum; shaded bars, anti-fHBP v.1.