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Eculizumab blocks vaccine-induced opsonophagocytic killing of meningococci by whole blood from immunized adults

Monica Konar and Dan M. Granoff

Key points

  • Eculizumab, an anti-complement C5 mAb, blocked killing of meningococci by whole blood from healthy immunized adults.

  • Blocking the alternative pathway with ACH-4471, a small molecule in development for PNH, had much less effect on meningococcal killing.

Abstract

Eculizumab, a humanized anti-complement C5 monoclonal antibody for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended, but whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A,C,W,Y vaccines. Bacterial survival was measured after 3 hours incubation in the presence of eculizumab or, a control complement factor D inhibitor, ACH-4471, that blocks the alternative complement pathway (AP) and is in phase 2 development for treatment of PNH. In the absence of inhibitors, CFU/ml in blood from all 12 immunized subjects decreased from ~4000 at time 0 to sterile cultures at 3 hours. In the presence of eculizumab, there was a >22-fold increase in geometric mean CFU/ml (90,596 and 114,683, for serogroup B and C strains, respectively; P<0.0001 compared to time 0). In the presence of ACH-4471, there was a >12-fold decrease (23 and 331 CFU/ml, respectively; P<0.0001). The lack of meningococci killing by blood containing eculizumab resulted from inhibition of release of C5a, a C5 split product needed for up-regulation of phagocytosis. The results provide an explanation for the large number cases of meningococcal disease in immunized patients being treated with eculizumab and suggest that vaccination may provide better protection against meningococcal disease in patients treated with an AP-specific inhibitor.

  • Submitted May 5, 2017.
  • Accepted June 18, 2017.