Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals

Abstract

Dysregulation of complement activation causes a number of diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. These conditions can be treated with monoclonal antibodies (mAbs) that bind to the complement component C5 and prevent formation of the membrane attack complex (MAC). While MAC is involved in uncontrolled lysis of erythrocytes in these patients, it is also required for serum bactericidal activity (SBA), i.e. clearance of encapsulated bacteria. Therefore, terminal complement blockage in these patients increases the risk of invasive disease by Neisseria meningitidis more than 1000-fold compared to the general population, despite obligatory vaccination. It is assumed that alternative instead of terminal pathway inhibition reduces the risk of meningococcal disease in vaccinated individuals. To address this, we investigated the SBA with alternative pathway inhibitors. Serum was collected from adults before and after vaccination with a meningococcal serogroup A, C, W, Y capsule conjugate vaccine and tested for meningococcal killing in the presence of factor B and D, C3, C5 and MASP-2 inhibitors. B meningococci were not included in this study since the immune response against protein-based vaccines is more complex. Unsurprisingly, inhibition of C5 abrogated killing of meningococci by all sera. In contrast, both factor B and D inhibitors affected meningococcal killing in sera from individuals with low, but not with high bactericidal anti-capsular titers. While the anti-MASP-2 mAb did not impair SBA, inhibition of C3 impeded meningococcal killing in most, but not in all sera. These data provide evidence that vaccination can provide protection against invasive meningococcal disease in patients treated with alternative pathway inhibitors.

Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study

“…It also blocks the amplification of classical and lectin pathway-dependent–C5 activation, although it does not impact amplification-independent complement activation via these pathways, which may potentially lead to lower infection risk in vaccinated patients as compared with other proximal complement inhibitors. 1, 16, 22, 23 Based on data from nonclinical and phase 1 studies, the pharmacokinetics of iptacopan is characterized by high absorption and moderate clearance (data on file). The main clearance pathway is hepatic metabolism (cytochrome P450 2C8-mediated oxidation, direct glucuronidation), followed by direct renal excretion (∼25%).…”

Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial

“…This may be important in immunized individuals such that membrane attack complex-dependent killing of bacteria, such as Neisseria meningitidis, is maintained. 28 , 29 , 30 …”

“…In contrast, iptacopan, does not fully block the generation of MAC initiated by the C5 convertases of the classical and lectin pathways (C4b2aC3b) and therefore infection risk is theoretically lower. This may be important in immunized individuals such that MAC-dependent killing of bacteria, such as Neisseria meningitidis, is maintained [27][28][29] .…”

Inhibition of the different complement pathways has varying impacts on the serum bactericidal activity and opsonophagocytosis against Haemophilus influenzae type b

“…Serum bactericidal titers were measured as previously described ( 34 ), but with modifications. Each reaction mixture contained approximately 400 CFUs of mid-log phase Hib bacteria and 20% human serum with internal complement preserved ( 35 ).…”

“…Neisseria meningitidis infections dominate ( 31 , 32 ), but it is recommended that children treated with eculizumab also receive vaccinations to prevent Streptococcus pneumoniae and Hib infections. As potential alternatives to C3 and C5 inhibitors, AP inhibitors are being developed and we have previously shown that AP inhibition abrogates meningococcal SBA and pneumococcal opsonophagocytosis in vaccine-naïve, but not in vaccinated individuals ( 33 , 34 ). Here we assessed the impact of complement inhibitors targeting C3, the AP (fB, fD), the lectin pathway (LP) (MASP-2) and the terminal pathway (C5) on both SBA and opsonophagocytic killing of Hib isolates by serum or reconstituted blood from individuals before and after vaccination with a capsule conjugate vaccine.…”