Eculizumab impairs Neisseria meningitidis serogroup B killing in whole blood despite 4CMenB vaccination of PNH patients

Abstract

Complement C5 inhibitor eculizumab has a great impact on the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). However, this treatment success has a major drawback: a substantially increased susceptibility for life-threatening Neisseria meningitidis infections. Therefore, N meningitidis vaccination is strongly advised before initiating complement C5-blocking therapy. In this study, we show that the multicomponent N meningitidis serogroup B (4CMenB) vaccination of PNH patients treated with eculizumab results in a significant increase in anti-N meningitidis serogroup B (MenB) plasma immunoglobulin G (IgG) levels. Anti-MenB IgG was able to bind to the bacterial surface and initiate complement activation; however, inhibition of the membrane attack complex formation completely blocked whole blood-mediated killing of MenB. This would suggest that, despite 4CMenB vaccination, PNH patients taking C5 inhibitors are not sufficiently protected against MenB infection, which is in line with the fact that vaccinated PNH patients still experience meningococcal infections.

Graphical abstract

Figure 1.

Characterization of functional antibody responses induced by 4CMenB vaccination. (A) Schematic representation of vaccinations and blood draws. MenB IgG level (B), IgG binding to the bacterial surface of MenB (C), and complement C3 binding to the bacterial surface of MenB (D) using PNH patient plasma from before and after the first and second 4CMenB vaccinations and immune plasma from healthy individuals. Figures show boxplots with minimum/maximum whiskers; horizontal lines and values indicated in the figures are medians. Spearman correlation for IgG binding to the bacterial surface with MenB IgG concentration in serum (r = +0.5865; P < .0001) (E) and C3 binding to the bacterial surface (r = +0.7217; P < .0001) (F). Statistical analyses were performed with Prism version 5.03 for Windows (GraphPad Software, La Jolla, CA). Repeated measures analysis of variance with Tukey’s posttest was used to determine statistical significance. **P < .01, ***P < .001. AU, arbitrary unit; MFI, median fluorescence intensity.

Figure 2.

Determining opsonophagocytic response induced by 4CMenB vaccination. (A) Whole blood-mediated killing of MenB using PNH patient plasma from before and after the first and second 4CMenB vaccinations and immune plasma from healthy individuals. Figure shows boxplots with minimum/maximum whiskers; horizontal lines and values indicated in the figure are medians. Statistical analyses were performed with Prism version 5.03 for Windows. Repeated measures analysis of variance with Tukey’s posttest was used to determine statistical significance. No statistically significant differences were found. The filled circles represent killing of MenB with plasma from patient 1 and patient 54. Complement survival of MenB in HI plasma and normal plasma taken before and after the first and second 4CMenB vaccinations: Patient 1 (B) and Patient 54 (C).