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.

Highlights

  • Neisseria meningitidis is a Gram-negative bacterium, called meningococcus, which asymptomatically colonizes the nasopharyngeal mucosa of 5-10% of the adult population

  • The aim of the study was to investigate the effect of complement inhibitors on serum bactericidal antibody activity (SBA) against meningococci in naïve and vaccinated individuals

  • We analyzed the correlation between serum anti-capsular antibody concentrations and SBA titers

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Summary

Introduction

Neisseria meningitidis is a Gram-negative bacterium, called meningococcus, which asymptomatically colonizes the nasopharyngeal mucosa of 5-10% of the adult population. Colonization mostly induces immunity with protective antibody response, but in rare cases the meningococci can gain access to the circulation and may cause systemic disease such as sepsis and meningitis [1,2,3]. Killing of N. meningitidis by the complement system membrane attack complex (MAC)-induced bacteriolysis represents a key element of host immune defense against meningococci. Determination of the serum bactericidal antibody activity (SBA) serves as surrogate of meningococcal vaccine efficacy as it measures the MAC-induced killing [9]. Binding of the C1 complex to the Fc region of the antibodies, which are bound to their target antigen on the bacterial cell surface, initiates CP activation by cleavage of C4 and covalent C4b deposition on the meningococcal cell surface. Subsequent interactions between C5b and the other terminal components C6, C7, C8, and C9 form the MAC (C5b-9), which lyses the meningococcal cell by forming pores on the membranes [15, 16]

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