Failure of first meningococcal vaccination in patients with atypical haemolytic uraemic syndrome treated with eculizumab

Gäckler, Anja; Kaulfuß, Meike; Rohn, Hana; Vogel, Ulrich; Claus, Heike; Feldkamp, Thorsten; Kribben, Andreas; Witzke, Oliver

doi:10.1093/ndt/gfy225

Cited by 22 publications

(17 citation statements)

References 25 publications

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“…Interestingly, a question arises for the terminal pathway deficiencies: if the pathogenic strain is serum-sensitive, will the vaccine work if the response depends on C5b-9 formation only? The answer is most likely not, since the C5 is inactive; thus, the response will depend on the Fc-mediated phagocytosis (Jodele et al, 2016;Reher et al, 2018;Gäckler et al, 2020).…”

Section: E Therapeutic Approach To Treat Complementmentioning

confidence: 99%

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

2021

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The complement system was discovered at the end of the 19th century as a heat-labile plasma component that “complemented” the antibodies in killing microbes, hence the name “complement.” Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. Significance Statement The complement system is the host’s defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host’s enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.

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Section: E Therapeutic Approach To Treat Complementmentioning

confidence: 99%

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

2021

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“…Antibiotic prophylaxis should be administered in all patients with non-protective or unknown antibody titers against MenB analogous to the procedure after vaccination with the quadrivalent conjugate vaccine against serogroups A, C, W, and Y [19]. There is controversy about the sense of elimination of Neisseria sp.…”

Section: Protective Titers 50%mentioning

confidence: 99%

“…Previous studies have reported general reduced immunogenicity to vaccinations in patients with end-stage renal disease and kidney transplant recipients [17,18]. Immunogenicity of one vaccination with quadrivalent meningococcal polysaccharide conjugate vaccine was insufficient in patients with aHUS [19]. Due to the use of human complement in the bactericidal assay it is currently not possible to analyze serum from patients with ongoing eculizumab treatment, because the complement cascade is blocked by eculizumab [20].…”

Section: Introductionmentioning

confidence: 99%

Low efficacy of vaccination against serogroup B meningococci in patients with atypical hemolytic uremic syndrome

et al. 2020

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Background: The C5 complement inhibitor eculizumab is first-line treatment in atypical hemolytic uremic syndrome (aHUS) going along with a highly increased risk of meningococcal infections. Serogroup B meningococci (MenB) are the most frequently encountered cause for meningococcal infections in Europe. Efficacy of the protein-based MenB-vaccine Bexsero in aHUS has not been determined and testing is only possible in patients off-treatment with eculizumab as a human complement source is required. Methods: Patients with aHUS were vaccinated with two doses of the protein-based MenB-vaccine Bexsero. Serum bactericidal antibody (SBA) titers against factor H binding protein (fHbp) of MenB were determined in 14 patients with aHUS off-treatment with eculizumab. Results: Only 50% of patients showed protective human serum bactericidal antibody (hSBA) titers (≥1:4) against MenB following two vaccinations. Bactericidal antibody titers were relatively low (≤1:8) in three of seven patients with protective titers. While 71% of patients were on immunosuppressive treatment for either thrombotic microangiopathy or renal transplantation at either first or second vaccination, all four patients not receiving any immunosuppressive treatment showed protective bactericidal antibody response. Time between second vaccination and titer measurement was not significantly different between patients with protective titers compared with those with non-protective titers, while time between first and second vaccination was significantly longer in patients with protective titers going along with a tendency for reduction in immunosuppressive treatment. Conclusions: Efficacy of vaccination against MenB is insufficient in patients with aHUS. Response to vaccination seems to be hampered by immunosuppression. Therefore, implementation of adequate antibiotic prophylaxis seems pivotal.

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“…In general, patients need to be vaccinated against Neisseria meningitides serogroups A, C, W, Y and B prior to therapy initiation or, alternatively, prophylactically treated with antibiotics until 2 weeks after the vaccination. Notably, failure of the first vaccination to provide sufficient immunization has been reported and therefore antibiotic prophylaxis seems pivotal, as fatal infections with the germ have been reported even after vaccination [20, 21].…”

Section: Treatment Of Ctmamentioning

confidence: 99%

An updated classification of thrombotic microangiopathies and treatment of complement gene variant-mediated thrombotic microangiopathy

Aigner

Schmidt

Gaggl

et al. 2019

Clinical Kidney Journal

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Conditions presenting with signs of thrombotic microangiopathies (TMAs) comprise a wide spectrum of different diseases. While pathological hallmarks are thrombosis of arterioles and capillaries, clinical signs are mechanical haemolysis, thrombocytopenia and acute renal injury or neurological manifestations. The current classification of various syndromes of TMA is heterogeneous and often does not take the underlying pathophysiology into consideration. Therefore we propose a simplified classification based on the aetiology of different syndromes leading to TMA. We propose to categorize different TMA syndromes in hereditary and acquired forms and classify them based on the genetic background or underlying conditions. Of course, this classification is not always distinctly applicable in each case and from time to time reassessment of the established diagnosis is strongly recommended. The recommended treatment of TMA in the past was plasma exchange (PE). However, recently, the terminal complement inhibitor eculizumab became commercially available and has shown promising results in different open-label studies and case series. In our centre, first-line therapy is PE; however, patients are instantly switched to complement inhibitory therapy in case of treatment failure or intolerance.

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Failure of first meningococcal vaccination in patients with atypical haemolytic uraemic syndrome treated with eculizumab

Abstract: Immunogenicity of first quadrivalent meninongococcal vaccination is insufficient in patients with aHUS. Booster response is promising, but incomplete. Therefore, establishing antibiotic prophylaxes seems pivotal.

Cited by 22 publications

References 25 publications

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Low efficacy of vaccination against serogroup B meningococci in patients with atypical hemolytic uremic syndrome

An updated classification of thrombotic microangiopathies and treatment of complement gene variant-mediated thrombotic microangiopathy

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