In recent years, complement-mediated diseases have garnered increasing interest in medicine due to their impact on health and the complexity of their management. Among them, aHUS and PNH stand out due to their severity and the need for specific treatments to modulate complement response. The development of targeted therapies has revolutionized the prognosis of these patients, reducing morbidity and improving quality of life.

aHUS is a rare and severe disease, characterized by thrombotic microangiopathy (TMA), which predominantly affects the kidneys but can also involve other organs, such as the central nervous system, cardiovascular system, or gastrointestinal tract, among others.1 This condition is associated with alternative complement system pathway dysfunction due to genetic mutations in regulatory factors such as factor H (CFH), factor I (CFI), or CD46 (MCP), leading to uncontrolled complement activation and endothelial damage.2 Complement dysfunction induces a proinflammatory and prothrombotic state, resulting in hemolysis, thrombocytopenia, endothelial damage and acute kidney injury, which, if not promptly treated, may progress to chronic kidney failure, requiring renal replacement therapy or transplantation.3

Similarly, PNH is an acquired clonal hematopoietic disorder characterized by a deficiency of complement regulatory proteins on the surface of erythrocytes due to mutations in the PIGA gene.4 This deficiency renders erythrocytes susceptible to complement-mediated lysis, resulting in chronic intravascular hemolysis, anemia, thrombosis, and bone marrow dysfunction. Thrombosis, one of the leading causes of morbidity and mortality in PNH, can affect hepatic, cerebral, and pulmonary veins, significantly increasing the risk of severe thromboembolic events.5

The treatment of both diseases has been significantly transformed with the introduction of eculizumab, a monoclonal antibody targeting the C5 complement fraction.6 This drug blocks terminal complement activation and prevents the formation of the membrane attack complex, proving highly effective in reducing hemolysis in PNH and controlling TMA activity in aHUS, thereby preventing progressive organ damage. Eculizumab not only decreases the need for transfusions and improves patients’ quality of life but also reduces the progression of kidney damage and the risk of end-stage renal disease in aHUS. However, terminal complement inhibition also compromises immune defense against certain encapsulated pathogens, particularly Neisseria meningitidis, significantly increasing the risk of invasive infections.7

Recent studies have reported that patients treated with eculizumab have a 1000–2000-fold higher risk of developing invasive meningococcal meningitis compared to the general population, even after receiving the recommended meningococcal vaccines.8 This finding suggests that antibody-mediated immune responses may not be sufficient to compensate for the loss of complement activity in these patients.9,10 Given the high risk of meningococcal meningitis in patients receiving eculizumab, clinical guidelines recommend systematic meningococcal vaccination (serogroups A, C, W, Y, and B) before initiating treatment (but without delaying its start), along with antibiotic prophylaxis in selected cases.9,11 However, despite immunization, some patients continue to develop severe infections, raising concerns about the efficacy and duration of vaccine-induced protection, as well as the need for additional strategies to prevent meningococcal infections.

This article describes two clinical cases of aHUS patients receiving eculizumab who developed meningococcal meningitis. Their baseline characteristics, clinical presentation, microbiological findings, therapeutic management, and outcomes are detailed to provide a comprehensive clinical picture of these events in the context of long-term complement inhibition. These cases underscore the complexity of preventing invasive meningococcal meningitis in patients treated with complement inhibitors, even in the presence of prior vaccination and established preventive measures. Particular attention is given to vaccination history and timing in relation to therapy, acknowledging the variability that exists in real-world practice. Based on the experience gathered from these two cases, the findings are framed as descriptive clinical insights. The discussion outlines practical considerations that may arise in similar scenarios, acknowledging that broader evidence will be necessary to more clearly inform future strategies in this setting.

The primary objective of this study is to analyze the clinical presentation and progression of two patients diagnosed with aHUS who, despite having received the recommended vaccination, developed meningococcal meningitis while undergoing treatment with eculizumab. This phenomenon highlights the need to further investigate the relationship between vaccination status and the incidence of meningococcal infections in immunocompromised patients treated with complement inhibitors such as eculizumab. Additionally, the study aims to assess the relevance of periodic immunological monitoring in these patients and the necessity of implementing revaccination strategies, given that the immunosuppression induced by this treatment may affect the effectiveness of vaccine-induced protection.

This study seeks to establish a temporal relationship between the duration of eculizumab therapy and the progressive loss of vaccine-conferred protection, particularly against meningococcal infections through a detailed analysis of two clinical cases. This phenomenon could result from prolonged complement system inhibition, which may impair the body's ability to control infections caused by encapsulated pathogens. Furthermore, the study examines the efficacy of therapeutic interventions, such as plasmapheresis and antibiotic therapy, in the context of pharmacologically induced immunosuppression by eculizumab.

Based on these findings, the study outlines a possible framework for integrated immunological monitoring with the aim of contributing to the discussion on infection prevention strategies against N. meningitidis in this high-risk population.

A retrospective observational study was conducted on two patients diagnosed with aHUS treated with eculizumab who were admitted with suspected meningococcal meningitis at a tertiary hospital in Spain between 2016 and 2024. Data were obtained through a review of electronic medical records, hospital pharmacy registries, and microbiology and immunology laboratory reports from the center.

Detailed information on the nephrological history of the patients was collected, including family and genetic background, the initiation of eculizumab therapy, and clinical evolution prior to the infectious episode. Previous vaccination schedules against N. meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, and other relevant pathogens were analyzed to determine whether booster doses had been administered in accordance with established guidelines.

Additionally, the clinical presentation of meningococcal meningitis in both patients was reviewed, including initial symptoms, physical examination findings, and laboratory parameters at hospital admission. The therapeutic response was evaluated, considering the use of antibiotics, plasmapheresis, and supportive measures. These findings were compared with existing literature on meningococcal meningitis in patients treated with eculizumab. Potential deficiencies in vaccine-induced protection were compared.

Quantification of anti-meningococcal IgG antibodies was performed using a quantitative enzyme-linked immunosorbent assay (ELISA). An IgG concentration≥2μg/mL was used as an operational threshold to indicate measurable humoral response, based on previously reported immunogenicity criteria in immunocompetent populations.12 Serum IgG antibodies were quantified at Reference Laboratory S.A. (Barcelona, Spain), an ISO-certified clinical reference laboratory operating under standardized internal quality assurance procedures. Quantitative determination of vaccine-specific IgG was performed using commercially available ELISA kits (VaccZyme™ ELISA kits), validated for clinical application. Each analytical run incorporated manufacturer-provided calibrators and internal quality controls, including positive and negative control sera to verify assay performance and reproducibility. Calibration curves were generated using multipoint standards provided with the kits, and sample concentrations were interpolated from these curves according to the manufacturer's validated procedures. In addition, routine internal laboratory quality control measures were applied, including verification of control ranges and assay validity criteria prior to result validation. Pre-analytical handling was also standardized.

In addition to quantitative IgG assessment, functional serum bactericidal activity (SBA) assays were performed to evaluate complement-mediated bactericidal capacity against N. meningitidis. The SBA assays were conducted following standardized procedures using target meningococcal strains representative of the relevant serogroups.

Serological and functional determinations were obtained during the acute phase, after clinical stabilization of the infectious episode. In both patients, samples were collected within a comparable post-infection interval (16±2 days). All analyses for both patients were performed in the same reference laboratory, using identical analytical platforms and standardized procedures.

Additionally, a systematic review was conducted in PubMed/Clinical Key databases using the terms “eculizumab vaccine failure,” “complement inhibitor meningitis,” and “antibiotic prophylaxis meningococcus,” selecting 14 studies published between 2015 and 2025 that met level I–II evidence criteria according to the Oxford classification, aiming to compare our results with the available scientific evidence.

The first case is that of a 38-year-old woman with aHUS and CFHR1:CFH mutation, on treatment with eculizumab since 2016. She started eculizumab treatment in March 2016 with a loading regimen (900mg every 7 days IV for 4 weeks) followed by a maintenance regimen (1200mg every 15 days IV). Complete meningococcal vaccination (Nimenrix® (ACWY): 03/2016; Bexsero® (B): 04/2016) (see details in Table 1). In January 2020 (approx. 4 years post-initiation), she was admitted in critical condition due to septic shock secondary to meningococcal dissemination with multiorgan failure, requiring ICU admission. Upon admission, the patient presented with acute onset of severe, diffuse headache associated with high-grade fever and progressive neurological deterioration. Neurological examination revealed marked nuchal rigidity and significant photophobia. Meningeal irritation signs were positive, including both Kernig's and Brudzinski's signs. Lumbar puncture revealed turbid cerebrospinal fluid with 1300leukocytes/μL, protein 137mg/dL, glucose 28mg/dL (serum glucose 110mg/dL), and positive PCR for N. meningitidis, confirming bacterial meningitis. Cultures confirmed the presence of N. meningitidis serogroup B. Anti-MenB antibody titers were undetectable (<0.3μg/mL) at admission. Functional serum bactericidal activity (hSBA) against N. meningitidis was undetectable (<1:4), confirming the absence of functional immunity despite prior vaccination. Her clinical course was complicated by the development of ischemic acral necrosis secondary to aminergic support, requiring amputation of distal phalanges. She received intensive antibiotic treatment (ceftriaxone 2g every 12h IV), hemodynamic, and ventilatory support, achieving progressive recovery. The temporary discontinuation of eculizumab and the use of third-generation cephalosporins allowed control of the infection, although hematological and renal relapse were observed after 8 weeks, requiring reinstitution of the drug.

The second case is that of a 20-year-old man with aHUS secondary to a pathogenic heterozygous mutation in exon 23 of CFH (CFH-H3 variant), on treatment with eculizumab since 2020. He started eculizumab treatment in November 2020 with a loading regimen (900mg every 7 days IV for 4 weeks) followed by a maintenance regimen (1200mg every 15 days IV). Complete vaccination against meningococcus B (11/2020, Bexsero®) and ACWY (02/2021, Nimenrix®), following the recommended intervals (see details in Table 1). In May 2024 (approx. 4 years post-initiation), he presented to the emergency room with sudden onset of severe headache, fever (38.8°C), and neck stiffness. A lumbar puncture revealed turbid cerebrospinal fluid with elevated protein levels and decreased glucose, with PCR positive for N. meningitidis (serogroup not identified). Intravenous antibiotic treatment (ceftriaxone 2g every 12h IV) was started, and a session of plasmapheresis (150% plasma volume exchange with fresh frozen plasma and 5% albumin replacement) was performed to eliminate eculizumab and allow recovery of complement activity (CH50 at admission: 23U/mL (normal: 30–75), indicating residual drug activity). Anti-MenB IgG titers were <0.5μg/mL at diagnosis. Functional serum bactericidal activity (hSBA) against N. meningitidis was undetectable (<1:4), confirming the absence of functional immunity despite prior vaccination. He progressed favorably, achieving clinical resolution of the infection without neurological sequelae after 9 days, with ulterior reactivation of the aHUS, where hematological and renal relapse were also observed, requiring eculizumab reinstitution.

Both patients developed meningococcal infection almost four years after starting eculizumab treatment, despite receiving the complete recommended vaccination schedule against N. meningitidis (see details in Table 1). A post-infection immunological evaluation showed low or undetectable serological response against meningococcus, suggesting a possible decline in antibody levels over time or a suboptimal vaccine-induced response in the context of complement inhibition. Attenuated inflammatory response (max CRP: 197.5mg/L vs 350–500mg/L in immunocompetent individuals, measured during the acute infectious episode) and slow recovery of memory B-lymphocytes (CD19+/CD27+: 2.1% vs 8–15% normal) post-infection were also noticed. Despite this, both patients restarted eculizumab treatment after resolution of the infectious episode and as a consequence of their hematologic and renal relapse, remaining under close monitoring for signs of aHUS relapse and possible immune deficits. Despite the significant risk of meningococcal infections associated with complement inhibition, the potential consequences of aHUS progression outweighed the risks of reinfection. Given the life-threatening nature of aHUS relapses and the lack of alternative targeted therapies offering comparable efficacy, eculizumab remained the cornerstone of disease management.

Eculizumab treatment significantly increases the risk of meningococcal infections due to the inhibition of terminal complement, a key mechanism in defense against N. meningitidis.13 Although vaccination is mandatory before starting treatment, the protection provided may be insufficient or decrease over time, especially in patients with humoral immunity abnormalities or complement activation deficits. Studies have reported that the efficacy of conjugate vaccines may decrease over the years, suggesting the need for more frequent boosters in these patients. Specifically, these results align with evidence published by Crew et al. (2020),14 where 62% of meningococcal infections in vaccinated patients occurred more than 3 years after starting eculizumab. The loss of humoral immunity may be explained by the interdependence between complement and immune memory due to: (I) the blockade of the serum bactericidal activity (SBA),8,13 which requires functional complement for opsonization, and (II) the alteration of immune memory, where several in vivo studies have shown that signaling through C5aR on dendritic cells is crucial for the survival of memory B lymphocytes. In murine models, chronic inhibition of C5 reduces CD27+ memory B cell populations by 70% after 2 years of anti-C5 therapy. Plasmapheresis has demonstrated dual utility: (I) rapid elimination of eculizumab (an 89% reduction in serum levels after one session, with a shortened half-life from 11 to 2.5 days), and (II) replenishment of complement factors. However, its use should be balanced with the risk of hematological relapse in aHUS, as the abrupt restoration of complement activity can precipitate relapses of microangiopathy, as seen in the second case.

Regarding vaccination strategies, available data on antibody kinetics suggest that shorter revaccination intervals with tetravalent conjugate vaccines (MenACWY-TT, Nimenrix®) and periodic MenB-4C (Bexsero®) boosters may help sustain antibody levels in a proportion of patients.15,16 However, the optimal schedule in individuals receiving long-term eculizumab remains uncertain and should be individualized according to immunological response, clinical context, and evolving evidence. In previously published cohorts,15,16 more intensive revaccination strategies were associated with a higher proportion of patients (78%) maintaining operational titers (>2μg/mL) at 36 months compared with standard schedules (31%), although these data are limited.

These observations also emphasize the importance of close clinical surveillance and timely management of suspected infections in this population. In selected severe scenarios,8,17 adjunctive measures such as plasmapheresis have been described as potential considerations, given their capacity to remove circulating drug and partially restore complement activity. Nevertheless, their role should be carefully weighed on an individual basis. Overall, preventive and therapeutic decisions in patients receiving complement inhibitors require a tailored approach, balancing infection risk, underlying disease control, and the limitations of currently available evidence.

Additionally, several reports indicate that prophylaxis with penicillin V (250mg every 12h orally) or ciprofloxacin (500mg every 24h orally) can reduce the risk of encapsulated infections by up to 89%.8,17 Furthermore, some authors have proposed prolonged antibiotic prophylaxis with penicillin or rifampicin as an additional strategy to reduce the risk of meningococcal meningitis in patients treated with eculizumab.17,18 However, prolonged use of antibiotics may promote bacterial resistance, requiring an individualized risk-benefit assessment in each case. This aligns with recently published results, which reveal a concerning resistance pattern: 83% of isolates from patients under prophylaxis showed resistance to penicillin (MIC≥0.12mg/L), compared to 22% in non-prophylaxed patients.19,20 This suggests that selective antibiotic pressure could modulate the local epidemiology of N. meningitidis.

The duration of eculizumab therapy has been associated in some studies with a higher likelihood of reduced functional vaccine response, although the strength and clinical implications of this relationship remain to be fully clarified. Eculizumab, a complement inhibitor, significantly impairs the terminal complement pathway, which is crucial for the immune response against pathogens, including N. meningitidis, the causative agent of meningococcal infections. This inhibition leads to a heightened susceptibility to infections despite vaccination. This risk persists even in patients who have received the standard pre-treatment vaccination regimen (MenACWY and MenB), which has been shown to provide suboptimal long-term protection in some individuals. In fact, evidence indicates that the effectiveness of these vaccines may diminish over time, especially in patients on eculizumab therapy, as the inhibition of complement interferes with the immune system's ability to maintain memory responses. These observations suggest that periodic assessment of immune status and antibody titers may be a relevant consideration in patients receiving eculizumab, particularly in those undergoing long-term therapy.

In this context, some authors have proposed annual or biennial serological evaluation of anti-MenB and anti-MenACWY IgG antibodies to better characterize the persistence of vaccine-induced protection. Such monitoring could inform individualized clinical decisions, including the potential need for revaccination when antibody levels decline below commonly used operational thresholds (e.g., 2μg/mL). However, the optimal frequency of monitoring and revaccination has not been definitively established, and available data indicate that these IgG concentrations may not be consistently sustained over time in all patients.

Beyond vaccination strategies, antibiotic prophylaxis has been described as a complementary preventive measure in patients receiving eculizumab, particularly in those considered at increased risk. Agents such as penicillin or ciprofloxacin have been associated in some reports with a reduced incidence of invasive meningococcal disease. Nevertheless, the decision to implement long-term prophylaxis remains complex. Prolonged antibiotic exposure may contribute to the emergence of resistant strains through sustained selective pressure, and breakthrough infections have also been reported despite prophylaxis. Therefore, the potential benefits and limitations of this approach should be carefully weighed on an individual basis, taking into account patient-specific risk factors and local epidemiological considerations.

Beyond resistance, prolonged antibiotic therapy carries significant risks for individual patients, including: (I) gastrointestinal toxicity, which may compromise treatment adherence and quality of life, (II) infection by Clostridioides difficile, where the antibiotic-induced disruption of the gut microbiota predisposes patients to colonization, leading to potentially severe colitis, particularly in immunocompromised individuals, and (III) other secondary infections, since broad-spectrum antibiotics may increase susceptibility to fungal or other bacterial infections due to microbial dysbiosis.

In severe infectious scenarios, plasmapheresis has been described as a potential adjunctive measure to reduce circulating eculizumab levels and partially restore complement activity, thereby potentially enhancing host defense. However, its role in this setting is not well defined and should be balanced against the risk of precipitating aHUS relapse.

Finally, patient education plays an essential role in the prevention and early detection of infections in this vulnerable population. Given the atypical presentation of infections in patients on eculizumab, where signs may be subtle or delayed, it is vital for patients and healthcare providers to be well informed about the symptoms of meningococcal meningitis and other serious infections. Early recognition and prompt treatment are critical for improving outcomes and preventing severe complications, including sepsis and organ failure.

In conclusion, the available evidence and the clinical experience described herein highlight the complexity of managing infection risk in patients receiving eculizumab. Elements such as clinical surveillance, assessment of vaccine response, consideration of prophylactic measures, and, in selected situations, adjunctive interventions like plasmapheresis may all play a role within an individualized care plan. However, optimal strategies remain to be clearly defined, and further data are needed to better inform long-term management in this population.

This study has been conducted in strict compliance with Organic Law 3/2018, of December 5, on the Protection of Personal Data and the Guarantee of Digital Rights, as well as with Regulation (EU) 2016/679 of the European Parliament and the Council, of April 27, 2016 (General Data Protection Regulation, GDPR).

The data used in this study corresponds to information from previously anonymized patients, which prevents their direct or indirect identification, ensuring the elimination of any data that could allow for the re-identification of the subjects. Furthermore, the principle of data minimization has been applied, using exclusively the information strictly necessary for the purposes of the study. No biometric or sensitive data that could compromise individuals’ privacy has been used. Genetic information, when included, was handled in a fully anonymized and non-identifiable manner.

The research protocol has been approved by the corresponding Clinical Research Ethics Committee, ensuring that the data processing complies with the current ethical and legal principles. Additionally, the recommendations of the Code of Good Practice in Data Protection in Health Research, promoted by the Spanish Agency for the Protection of Data, have been followed. In the case of an audit or request by the competent authorities, the data processing records will be available for review, in compliance with the principles of transparency and proactive responsibility established by the current regulations.

During the preparation of this work, the authors may have used AI-assisted technologies to improve the writing and enhance the clarity of the language. The authors carefully reviewed and edited the content as needed and take full responsibility for the content of the publication.

This work has been developed independently, without receiving direct funding from private entities with commercial interests in the study's outcomes. Furthermore, no author has personal, professional, or financial relationships with pharmaceutical, biotechnology companies, government entities, or private organizations that could have influenced the development or conclusions of the study.

In compliance with transparency and ethics standards in scientific publishing, the authors guarantee that: (I) the authors have not received fees, grants, or financial compensation that could introduce bias into the study, (II) the authors do not have advisory roles or shareholding in companies that could benefit from the results, and (III) the data, methodologies, and conclusions solely reflect the scientific findings obtained objectively.

The authors of this study declare that there are no conflicts of interest that could have influenced the conduct of the research, the interpretation of the data, or the preparation of this article. In the event that potential conflicts of interest arise in the future, they will be duly communicated to the scientific community and the relevant editorial entity.