Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals
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 a...
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| Format: | Article |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.747594/full |
| _version_ | 1818394439718010880 |
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| author | Emma Ispasanie Emma Ispasanie Lukas Muri Lukas Muri Anna Schubart Christine Thorburn Natasa Zamurovic Thomas Holbro Michael Kammüller Gerd Pluschke Gerd Pluschke |
| author_facet | Emma Ispasanie Emma Ispasanie Lukas Muri Lukas Muri Anna Schubart Christine Thorburn Natasa Zamurovic Thomas Holbro Michael Kammüller Gerd Pluschke Gerd Pluschke |
| author_sort | Emma Ispasanie |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T06:01:14Z |
| format | Article |
| id | doaj.art-738a9b24a2a8447095dcef2b7ca6d73f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T06:01:14Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-738a9b24a2a8447095dcef2b7ca6d73f2022-12-21T23:14:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.747594747594Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated IndividualsEmma Ispasanie0Emma Ispasanie1Lukas Muri2Lukas Muri3Anna Schubart4Christine Thorburn5Natasa Zamurovic6Thomas Holbro7Michael Kammüller8Gerd Pluschke9Gerd Pluschke10Molecular Immunology Unit, Swiss Tropical and Public Health Institute, Basel, SwitzerlandUniversity of Basel, Basel, SwitzerlandMolecular Immunology Unit, Swiss Tropical and Public Health Institute, Basel, SwitzerlandUniversity of Basel, Basel, SwitzerlandTranslational Medicine-Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, SwitzerlandGlobal Drug Development, Novartis Pharma AG, London, United KingdomTranslational Medicine-Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, SwitzerlandGlobal Drug Development, Novartis Pharma AG, Basel, SwitzerlandTranslational Medicine-Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, SwitzerlandMolecular Immunology Unit, Swiss Tropical and Public Health Institute, Basel, SwitzerlandUniversity of Basel, Basel, SwitzerlandDysregulation 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.747594/fullNeisseria meningitidisalternative pathwayvaccinationimmunotherapycomplement inhibitor |
| spellingShingle | Emma Ispasanie Emma Ispasanie Lukas Muri Lukas Muri Anna Schubart Christine Thorburn Natasa Zamurovic Thomas Holbro Michael Kammüller Gerd Pluschke Gerd Pluschke Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals Frontiers in Immunology Neisseria meningitidis alternative pathway vaccination immunotherapy complement inhibitor |
| title | Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals |
| title_full | Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals |
| title_fullStr | Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals |
| title_full_unstemmed | Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals |
| title_short | Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals |
| title_sort | alternative complement pathway inhibition does not abrogate meningococcal killing by serum of vaccinated individuals |
| topic | Neisseria meningitidis alternative pathway vaccination immunotherapy complement inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.747594/full |
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