Complement Inhibitors and the Risk of (Breakthrough) Infections—Critical Analysis and Preventive Strategies

Abstract

The complement system is a key component of innate immunity, responsible for mediating the rapid clearance of pathogens and coordinating adaptive immune responses. Although complement activation is essential for effective infection control and prevention, its excessive or dysregulated function contributes to the pathogenesis of various immune-mediated disorders. Therefore, therapeutic inhibition of the overactive complement cascade, in which specific components are selectively blocked to suppress pathological activation, plays an important role in the treatment of various complement (immune)-mediated diseases. This article provides an overview of complement inhibition as a therapeutic strategy, highlighting the infectious risks associated with its use. Disruption of complement-dependent host defence mechanisms increases the risk of invasive infections (caused by encapsulated pathogens, e.g., Neisseria spp., Streptococcus pneumoniae and Haemophilus influenzae type B), which represent a significant clinical challenge. Therefore, the use of complement inhibition should not only be effective but also safe in combination with the application of all possible tools to prevent infections. Strategies, such as vaccination and antibiotic prophylaxis, are crucial to minimise these complications, despite the persistence of the risk of breakthrough infections. Furthermore, this review examines advancements in patient risk stratification, evaluates alternative preventive measures, and identifies key gaps in current clinical practice. Future directions include improving monitoring protocols, creating more selective or locally acting complement inhibitors, and implementing biomarker-driven personalised therapies that maximise benefits while reducing side effects.

1. The Complement System and Its Role in Infection Prevention

The complement system is a key component of innate immunity and plays an essential role in protecting the host against pathogens [1,2,3,4]. It consists of more than 50 plasma and membrane-associated proteins, including soluble effectors (C1–C9), regulatory molecules, and cell-surface complement receptors [3,4]. Although most complement proteins are produced in the liver and circulate in the blood and lymphatic system, they can also be activated on cellular membranes or within intracellular compartments [1,3,5,6].

Complement activation is triggered by carefully regulated proteolytic cascade that interacts with antibodies and other immune components. Activation may occur in response to immune complexes (IC), microbial surfaces, or apoptotic and necrotic cells. The three main pathways of complement activation—classical, lectin, and alternative—all converge at the central component C3. Cleavage of C3 serves as a pivotal point in the cascade, directly leading to the formation of the membrane attack complex (MAC) (Figure 1) [1,2,4].

The complement system performs multiple critical functions, including the lysis of target cells and bacteria, the opsonisation of pathogens through fragments such as C3b to facilitate phagocytosis and the release of the anaphylatoxins C3a and C5a, which recruit and activate inflammatory cells [3,6]. Beyond its antimicrobial role, complement contributes to the removal of ICs and modulates inflammatory responses [4,7].

Complement also serves as a cross-link between innate and adaptive immunity. Activated complement components enhance B-cell responses, support antibody production and regulate T-cell activity, thereby promoting a coordinated immune response [3,4]. A comprehensive overview of complement functions is presented in

Table 1. Overview of the complement system pathways and their principal components and functions.

Complement Function	Molecular/Mechanistic Basis	Immunological Consequence	References
Pathogen lysis	Formation of MAC/C5b-9	Lysis of bacteria and target cells	[1,2]
Opsonisation	Deposition of C3b/iC3b and C4b on pathogens	Enhancement of phagocytosis via CR1/CR3	[1,3,5]
Anaphylatoxin generation	Release of C3a and C5a	Chemotaxis, activation of neutrophils and monocytes, oxidative burst	[1,3,4]
Clearance of ICs and apoptotic cells	C1q binding; CR1/CR3-mediated uptake	Removal of ICs and apoptotic cells; prevention of autoimmunity	[4,5,7]
Modulation of adaptive immunity	C3d–CR2 signalling; intracellular complement (complosome)	Activation of B-cells, antibody affinity maturation, and T-cell regulation	[3,4,6]
Crosstalk with innate immunity	Complement–TLR interactions; C5a–C5aR1 axis	Amplification of cytokine responses; activation of NK cells and neutrophils	[3,4,6,8]
Antiviral activity	Opsonisation of viral particles (C3b, C4b); enhancement of phagocytic uptake; modulation of inflammatory responses (C3a, C5a)	Promotion of early viral clearance	[3,6,9,10,11]
Antifungal defence	Recognition of fungal PAMPs via MBL/ficolins; opsonophagocytosis	Recruitment of phagocytes and fungal killing	[8,12]
Intracellular complement (complosome)	Noncanonical roles of C3 and C5 inside cells	Regulation of cell metabolism, survival, gene expression, and modulation of immune responses	[3]
Tissue homeostasis and repair	Clearance of apoptotic cells, angiogenesis, and regulation of regeneration	Maintenance of tolerance, tissue integrity, and immune homeostasis	[6,11]
Tumour immunity modulation	C5a–C5aR1 signalling; complement interactions within TME	Modulation of T-cell and myeloid responses within tumours	[3]

Abbreviations: C1q—complement component 1q; C3—complement component 3; C3a—complement component 3a; C3b/iC3b—complement component 3b/inactivated C3b; C3d—complement component 3d; C4b—complement component 4b; C5—complement component 5; C5a—complement component 5a; C5aR1—C5a receptor 1; C5b-9—terminal complement complex; CR1—complement receptor 1; CR2—complement receptor 2; CR3—complement receptor 3; ICs—immune complexes; MAC—membrane attack complex; MBL—mannose-binding lectin; NK—natural killer; PAMPs—pathogen-associated molecular patterns; TLR—toll-like receptor; TME—tumour microenvironment.

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Deficiencies in complement proteins, whether congenital (rare, affecting approximately 0.03% of the population) or acquired (i.e., due to therapeutic complement inhibition), are associated with increased susceptibility to infections, particularly from encapsulated bacteria such as Neisseria spp., Streptococcus pneumoniae and Haemophilus influenzae type B [7,13,14,15,16,17]. These deficiencies are also linked to higher rates of autoimmune and inflammatory conditions [5,7]. Similarly, pharmacologic inhibition of complement pathways, including C3 or C5 blockade, leads to a comparable increase in susceptibility to invasive infections [4,8,16,18,19,20].

2. Complement Inhibition as a Therapeutic Strategy

Excessive activation of the complement system contributes to various immune-mediated and inflammatory diseases. Current therapeutic strategies use complement inhibitors (CI) to target specific components of the complement cascade [4,5,7,14,21]. The most established approach involves inhibiting the terminal pathway in the complement component C5. The monoclonal antibody Eculizumab, approved for paroxysmal nocturnal haemoglobinuria (PNH), demonstrates that C5 blockade prevents intravascular haemolysis, stabilises haemoglobin levels, reduces transfusion requirements and reduces the risk of thromboembolic complications. Registry analyses and clinical trials in Europe and North America confirm these clinical benefits [12,22,23,24]. Eculizumab has also been approved for atypical haemolytic uraemic syndrome (aHUS), generalised myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD), resulting in improved functional outcomes, fewer relapses and increased survival. Moreover, several biosimilars of eculizumab have recently been introduced in selected regions [22,23,24,25].

Ravulizumab, an engineered derivative of Eculizumab with an extended half-life, provides equivalent efficacy while requiring infusions only every 8 weeks (compared to Eculizumab, which requires infusions every 2 weeks), thereby reducing the treatment burden without compromising disease control. These two C5 inhibitors remain the cornerstone of therapy in complement-driven haemolytic and neuroinflammatory diseases [22,23,24].

Beyond terminal pathway blockade, proximal inhibition has also entered clinical practice. Pegcetacoplan, a cyclic peptide inhibitor of complement component C3, is approved for the treatment of PNH in adults, including patients with persistent anaemia despite stable C5 inhibition, depending on regional regulatory labelling [12,23,26]. By targeting C3, it prevents both intravascular and extravascular haemolysis. Pegcetacoplan is administered subcutaneously, allowing self-application and improving adherence and accessibility [12,24].

The therapeutic landscape has expanded with the approval of new agents across multiple regulatory regions. Crovalimab, a humanised monoclonal antibody against C5 with a recycling mechanism, is approved for PNH and offers monthly subcutaneous administration with efficacy comparable to Eculizumab [12,24,26]. Zilucoplan, a synthetic peptide C5 inhibitor, is approved for gMG [12,24,27]. Oral small-molecule inhibitors include Danicopan (a factor D inhibitor), which is approved as add-on therapy to C5 inhibition in patients with PNH and residual extravascular haemolysis, and Iptacopan (a factor B inhibitor), which is approved for PNH and C3 glomerulopathy (C3G) and, in the United States (US), for IgA nephropathy [12,24,26].

Therapeutic expansion has also reached the classical pathway. Sutimlimab, a monoclonal antibody targeting C1s, is approved for the treatment of cold agglutinin disease (CAD), effectively preventing complement-mediated haemolysis, normalising haemoglobin levels and reducing transfusion dependence [24].

An overview of currently available CIs, their key characteristics and approved indications across major regulatory regions is summarised in

Table 2. Currently approved complement inhibitors: molecular targets, mechanisms of action, and principal clinical indications.

Molecule	Brand Name	Approved Region(s)	Characteristics	Indications	Age
Eculizumab	Soliris®	US, EU/EEA, other*	Humanised monoclonal anti-C5 antibody	PNH, aHUS	US: adults and children ≥ 1 month and ≥5 kg; EU/EEA: adults and children ≥ 5 kg
				gMG (anti-AChR positive)	≥6 years
				NMOSD (anti-AQP4 positive)	≥18 years
Eculizumab-aeeb	Bkemv®	US	Biosimilar to Eculizumab	PNH, aHUS	same as for Soliris®
				gMG (anti-AChR positive)	≥18 years
Eculizumab-aagh	Epysqli®	US	Biosimilar to Eculizumab	PNH, aHUS	same as for Soliris®
				gMG (anti-AChR positive)	≥18 years
ABP959/Elizaria®	Elizaria® (ABP959)	Russia and selected Eastern European countries	Biosimilar to Eculizumab	PNH, aHUS	≥18 years
Ravulizumab	Ultomiris®	US, EU/EEA, other*	Humanised monoclonal anti-C5 antibody	PNH, aHUS	US: adults and children ≥ 1 month and ≥5 kg; EU/EEA: adults and children ≥ 10 kg
				gMG (anti-AChR positive)	≥18 years
				NMOSD (anti-AQP4 positive)	≥18 years
Pegcetacoplan	Aspaveli®	EU/EEA, CH, other*	PEGylated peptide targeting C3	PNH	≥18 years
	Empaveli®	US		PNH	≥18 years
				C3G, primary IC-MPGN (to reduce proteinuria)	Adults and children ≥ 12 years
Zilucoplan	Zilbrysq®	US, EU/EEA	Cyclic peptide targeting C5	gMG (anti-AChR positive)	≥18 years
Danicopan	Voydeya®	JP, US, EU/EEA, other*	Factor D inhibitor	PNH (add-on to C5 inhibition; extravascular haemolysis)	≥18 years
Iptacopan	Fabhalta®	US; EU/EEA	Factor B inhibitor	US: PNH; IgA nephropathy (accelerated approval based on reduction of proteinuria), C3G (to reduce proteinuria) EU/EEA: PNH, C3G (to reduce proteinuria)	≥18 years
Crovalimab	Piasky®	US, EU/EEA, CH, other*	Humanised monoclonal anti-C5 antibody	PNH	US: adults and children ≥ 13 years and ≥40 kg; EU/EEA/CH: adults and children ≥ 12 years and ≥40 kg
Sutimlimab	Enjaymo®	US, EU/EEA, JP, other*	Humanised monoclonal anti-C1s antibody	CAD	≥18 years

Abbreviations: aHUS—atypical haemolytic uraemic syndrome; AChR—acetylcholine receptor; AQP4—aquaporin-4; CAD—cold agglutinin disease; C3G—C3 glomerulopathy; CH—Switzerland; EEA—European Economic Area; EU—European Union; gMG—generalised myasthenia gravis; IC-MPGN—immune-complex–mediated membranoproliferative glomerulonephritis; JP—Japan; NMOSD—neuromyelitis optica spectrum disorder; other*—additional non-EU/EEA regions where an agent is approved (e.g., Canada, Australia, Brazil, South Korea, Israel); PNH—paroxysmal nocturnal haemoglobinuria; US—United States.

, with approval status based on labelling from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and other regional authorities as of September 2025 [24].

2.1. Risk of Infections During Complement Inhibitor Therapy

The complement system is crucial for host immunity as it integrates innate and adaptive responses. It supports the recognition, opsonisation, clearance and activation of T- and B-cells [2,4,6]. Proper regulation provides an effective defence, while dysregulation can lead to tissue injury, coagulation abnormalities, chronic inflammation and a predisposition to bacterial, viral and fungal infections [2,3,4].

Complement inhibitors (CIs), especially those targeting C3 or C5, increase infection risk by impairing key effector functions that facilitate pathogen clearance. Complement-mediated opsonisation is particularly critical for encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type B. Their polysaccharide capsules mask surface antigens, making direct phagocytosis inefficient and highlighting the essential role of complement in early immune recognition and clearance [7,28]. Additionally, complement receptor-mediated transport of ICs via CR1 on erythrocytes and CR3/CR4 on macrophages facilitates hepatic and splenic clearance. Complement inhibition slows this process, potentially leading to transient accumulation of ICs [5,8,29].

Beyond bacterial susceptibility, complement inhibition may also affect host defence against viral and fungal pathogens. Pharmacovigilance analyses from the FDA Adverse Event Reporting System indicate that viral infections are reported more frequently than fungal infections during therapy with CIs, most commonly influenza, herpes zoster, and viral gastroenteritis [9]. Although fatal viral infections are rare, reported cases have predominantly occurred early after treatment initiation, typically within the first two weeks [9]. Fungal infections remain uncommon and have been reported mainly in immunocompromised individuals, including cases of disseminated candidiasis and invasive aspergillosis [8,12].

Proximal Versus Distal Complement Inhibition

The infection risk associated with complement inhibition therapy is influenced by which component is targeted. Clarifying these mechanisms helps illustrate key differences in immune outcomes. Additional risk factors include young age, incomplete vaccination, increased exposure to pathogens, comorbidities, and the use of immunosuppressive therapy [4,28,30,31]. These age-dependent risk profiles reflect different clinical contexts: young children (<2 years) are particularly vulnerable to invasive infections with encapsulated bacteria due to their reliance on innate immunity, whereas in adults receiving CIs, factors such as older age, chronic kidney disease, prolonged therapy, and concurrent immunosuppression predominantly increase the risk of viral infections, reactivation events, and severe outcomes [9,22,32].

C3 inhibitors: block the entire cascade, preventing both early opsonisation and terminal lysis. In contrast to distal inhibition, this also eliminates co-stimulation of C3d–CR2, altering germinal centre responses and memory B-cell formation, which may reduce vaccine efficacy. By inhibiting C3b deposition, opsonophagocytosis, and immune complex clearance, C3 blockade broadly compromises host defence against bacteria, fungi, and viruses by abrogating complement-mediated opsonisation and early inflammatory signalling [8,9,12,30,31]. Proximal inhibition also suppresses activation of the classical and lectin pathways, potentially attenuating early antiviral responses, delaying antigen presentation, and modifying B-cell responses. These effects may contribute to increased vulnerability to viral reactivation or severe infection (e.g., herpes zoster, cytomegalovirus (CMV), influenza, hepatitis B, SARS-CoV-2). However, current clinical evidence is largely limited to pharmacovigilance data and case-based reports [9,24]. Furthermore, impaired recognition of fungal pathogen-associated molecular patterns, such as mannans and β-glucans, may diminish neutrophil-mediated antifungal responses and has been associated with rare cases of invasive Candida and Aspergillus infections, mainly in immunocompromised individuals [8,12].

C5 inhibitors: act further downstream, selectively blocking activation of the terminal pathway and C5a-mediated inflammation, while preserving C3-dependent opsonisation. Reduced C5a-mediated activation of neutrophils and macrophages, including chemotaxis and oxidative burst, limits pathogen clearance. Despite preserved C3b deposition, the lack of C5a-driven phagocyte activation and MAC formation can permit breakthrough infections, especially with encapsulated bacteria [8,33,34]. Distal inhibition may modestly slow viral clearance and fungal elimination, although the overall risk of severe infections appears lower than with C3 blockade. Rare cases of invasive fungal infections have been reported in patients receiving C5 inhibitors [8,12]. However, prospective data to accurately quantify this risk are lacking [24,33].

Beyond immediate effector mechanisms, an emerging and clinically relevant aspect of complement inhibition is its impact on other components of the immune system, particularly on long-term innate immune adaptation. Inhibition at the level of C3 alters the generation of C3a and C3b, which are essential for the metabolic and epigenetic reprogramming of monocytes. C3a receptor signalling has been implicated in the induction of “trained” immunity in innate immune cells, including monocytes and myeloid progenitors, thereby supporting enhanced secondary responses to heterologous infections [35]. Disruption of these pathways may attenuate the development of such trained responses. In contrast, although C5a is a potent chemoattractant and activator of myeloid cells, its contribution to the induction of trained immunity appears to be less prominent than that of C3-derived signals [36]. Collectively, these observations suggest that therapeutic complement inhibition may not only impair immediate antimicrobial defence but also modulate the long-term functional readiness of the innate immune system by interfering with mechanisms underlying trained immunity.

Selective alternative pathway inhibition with factor B and factor D inhibitors: reduces alternative pathway amplification while preserving initiation of the classical and lectin pathways and maintaining terminal complement activity [30,31,34]. In contrast to broad C3 inhibition, antibody-dependent opsonisation and MAC formation remain largely intact. Phase 3 clinical trials and extension studies of factor B inhibition across PNH, C3G, and IgA nephropathy demonstrate overall infection rates comparable to placebo or standard therapy, with most reported events being mild to moderate respiratory or viral infections. Serious infections with encapsulated bacteria have been rare, resolved with standard antimicrobial therapy, and no cases of meningococcal sepsis or infection-related mortality have been reported to date [37]. By comparison, factor D inhibition has been associated with a more modest impact on complement-mediated bacterial killing. In vitro data indicate that factor D blockade affects meningococcal killing to a lesser extent than C3 or C5 inhibition, consistent with its more selective attenuation of alternative pathway amplification [30,31,34]. Taken together, these data suggest that selective alternative pathway inhibition is associated with a more restricted infectious risk profile than broad C3 blockade, although longer-term post-marketing surveillance remains warranted.

C1s inhibitors: selectively inhibit activation of the classical pathway while preserving both the lectin and alternative pathways. With Sutimlimab as the approved agent, C3b-mediated opsonisation and terminal complement activity remain largely intact, resulting in a substantially lower infection risk than that observed with C3 or C5 inhibition. Across clinical trials, infections were predominantly mild respiratory or gastrointestinal events, with no cases of invasive meningococcal disease reported [24,38,39].

The key infection risk profiles associated with different classes of complement inhibitors, including underlying immunological mechanisms and clinical implications, are summarised in

Table 3. Infection risk profiles associated with different classes of complement inhibitors, including key pathogens, proposed mechanisms, and available clinical evidence.

Immunological Mechanism (Molecular Target)	Associated Inhibitor Class	Primary Consequence	Immediate Functional Effect	Clinical Implications	References
Reduced opsonophagocytosis (C3b/iC3b) and reduced C5a-mediated neutrophil/macrophage activation (via C5aR1, chemotaxis, oxidative burst, NETosis)	C3 inhibitors; C5 inhibitors; factor B inhibitors and factor D inhibitors (attenuated effects)	Impaired pathogen tagging and uptake by neutrophils/macrophages; impaired NETosis	Delayed pathogen clearance; reduced extracellular trapping	Increased susceptibility to encapsulated bacteria (N. meningitidis, S. pneumoniae, H. influenzae type B)	[11,29,33,34]
Blunted chemotaxis and cytokine signalling	C3 inhibitors; C5 inhibitors	Delayed early inflammatory responses	Slower recruitment of immune cells	Broader susceptibility to bacterial and viral infections	[8,9,34]
Compromised adaptive immunity (C3d–CR2)	C3 inhibitors	Reduced T-/B-cell activation; altered germinal centre responses	Reduced antibody affinity and memory B-cell formation	Lower vaccine efficacy and broad-spectrum susceptibility	[3,18,30]
MAC (C5b-9) formation abolished	C5 inhibitors	Loss of SBA	Inability to lyse bacteria directly	Predominant risk of invasive meningococcal infections	[16,29]
Impaired IC clearance (CR1/CR3)	C3 inhibitors (primary); factor B inhibitors (partial); factor D inhibitors (minimal)	Delayed IC removal	Persistence of circulating ICs	Secondary bacterial/viral risk, potential inflammation	[5,33]
Impaired antiviral defence	C3 inhibitors (primary); C5 inhibitors (partial)	Reduced complement-mediated opsonisation of viral particles; attenuated early inflammatory signalling	Slower early viral clearance	Reported viral infections and reactivation (influenza, HSV, HBV, CMV, SARS-CoV-2)	[9,10,24,33]
Impaired fungal clearance	C3 inhibitors (primary); C5 inhibitors (partial)	Reduced opsonophagocytosis and neutrophil recruitment; impaired recognition of fungal PAMPs (mannans, β-glucans)	Delayed fungal elimination	Rare reported cases of invasive Candida and Aspergillus infections	[8,12]
Selective blockade of the classical pathway (C1s)	C1s inhibitors	Loss of classical-pathway activation with intact lectin and alternative pathway function	Preserved opsonisation and MAC formation via non-classical pathways	Mild increase in susceptibility to encapsulated bacteria, lower than with C3/C5 inhibition	[24,38,39]

Abbreviations: C3b/iC3b—complement component 3b/inactivated C3b; C3d—complement component 3d; C5a—complement component 5a; C5aR1—C5a receptor 1; CMV—cytomegalovirus; CR1—complement receptor 1; CR2—complement receptor 2; CR3—complement receptor 3; HBV—hepatitis B virus; HSV—herpes simplex virus; IC—immune complex; MAC/C5b-9—membrane attack complex/terminal complement complex; NETosis—neutrophil extracellular trap formation; PAMPs—pathogen-associated molecular patterns; SBA—serum bactericidal activity.

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2.2. Prevention of Infections—Vaccination and Antibiotic Prophylaxis

Individuals receiving CIs are at a substantially increased risk of serious bacterial infections, particularly invasive meningococcal disease [18,19,29]. Vaccination is therefore a central component of infection prevention in this population [7,8,26]. Although vaccination and antibiotic prophylaxis are widely used during therapy with CIs, substantial heterogeneity exists among international guidelines with respect to their timing, duration, and the scope of recommended vaccines and prophylactic strategies. Moreover, the availability of specific vaccines varies considerably across countries and continents.

All patients who begin complement inhibition therapy should receive immunisation against meningococci, including quadrivalent conjugate vaccines that cover serogroups A, C, W and Y, as well as protein-based vaccines against serogroup B. Compared to the standard vaccination schedule, booster doses are recommended for both vaccines if the risk of infection persists due to ongoing treatment with CI [13,15,40]. Additional vaccination against other encapsulated bacteria, such as S. pneumoniae and H. influenzae type B, is recommended due to increased susceptibility during complement inhibition [7].

A single dose of the 20-valent pneumococcal conjugate vaccine (PCV20, Prevenar-20^®) is recommended to prevent invasive pneumococcal infections. The 21-valent pneumococcal conjugate vaccine (PCV21) has recently been approved for adult use in both the US and the European Union, with the European Commission granting marketing authorisation in March 2025 [41,42]. For adults requiring broad serotype coverage, sequential administration of both PCV20 and PCV21 is advised, with the order determined by clinical judgment [7]. Although no formal revaccination schedule has been established, the introduction of higher-valent vaccines may necessitate future booster doses [7,40]. Infants in their first year of life should follow the vaccination schedule outlined in their national immunisation program [7,13]. Annual influenza and COVID-19 vaccination or booster doses are also strongly recommended, regardless of ongoing therapy [43,44].

All vaccines in this context are inactivated and can generally be administered simultaneously by intramuscular injection [40]. Vaccination should be deferred during acute disease flares or high-dose immunosuppressive therapy (≥20 mg/day prednisone or equivalent). When appropriate, vaccination can be scheduled around intravenous immunoglobulin (IVIG) administration or CI dosing cycles to minimise potential adverse effects [7,18]. Currently, there is no universal and generally accepted international consensus on the standardisation of vaccination schedules or antibiotic prophylaxis, and recommendations can vary by region and national guidelines [7]. Whenever possible, the entire vaccination series should be completed at least 2 weeks before starting CIs [7,8]. In specific clinical scenarios, such as the acute onset of aHUS or NMOSD, the initiation of complement inhibition may be essential and cannot be delayed, requiring vaccination to be postponed until the disease reaches a stable phase. In such cases, antibiotic prophylaxis should be maintained for at least 2 weeks following completion of the vaccination schedule. If the series is not complete at the time the therapy begins, prophylactic antibiotics should be used until all doses of the basic vaccination schedule have been administered, usually for at least 2 weeks after the final vaccine. However, some guidelines recommend extending this period to 4 weeks to ensure adequate protection [21,26,45,46]. In selected high-risk patients, prophylaxis can be continued throughout the entire course of CI therapy [20,26].

The choice and duration of antibiotic prophylaxis should be individualised according to patient-specific factors, including age, history of drug allergies and underlying comorbidities. Oral penicillin V is the most commonly used treatment, while macrolides, such as erythromycin or azithromycin, are preferred by patients who are allergic to penicillin, with recommended regimens outlined in

Table 4. Options for oral antibiotic prophylaxis during treatment with CIs.

Drug	Adult Dose	Paediatric Dose	Notes
V-Penicillin	500 mg twice daily	≥3 years: 250 mg twice daily <3 years: 125 mg twice daily	Recommended as first-line prophylaxis
Azithromycin	250–500 mg once daily	5 mg/kg once daily (max. 500 mg)	For patients allergic to penicillin; higher dose (500 mg) may be used during the first 1–2 weeks in high-risk settings
Amoxicillin	500 mg twice daily	20 mg/kg/day	-
Ciprofloxacin	500 mg twice daily	Not recommended	-

[8,21].

Patients should also have ‘emergency’ antibiotics readily available to initiate at the first sign of symptoms, until a bacterial infection can be excluded. Recommended regimens include amoxicillin–clavulanic acid, ciprofloxacin, or moxifloxacin, which provide rapid coverage against invasive infections caused by encapsulated bacteria. When long-term antibiotic prophylaxis is required, monitoring for potential antimicrobial resistance is recommended [21,26,45].

In summary, infection prevention for patients receiving CIs should be individualised, with timely vaccination and antibiotic prophylaxis tailored to patient risk factors and local epidemiology.

2.3. Breakthrough Infections After Vaccination

Despite vaccination, patients receiving CIs remain at a persistent, although reduced, risk of invasive meningococcal infections. This residual risk also extends to other encapsulated bacteria, including Streptococcus pneumoniae and Haemophilus influenzae type B, although the strongest clinical evidence relates to Neisseria meningitidis [7,24]. Breakthrough infections have been reported even in fully immunised individuals, highlighting the limitations of vaccine-induced protection and underscoring the need for early recognition of suspected infections [18,19,20].

The immunological basis of this vulnerability is well established. Clinical observations indicate that the risk of invasive meningococcal disease is particularly pronounced during terminal complement inhibition at the level of C5, whereas inhibition upstream at the level of C3 or within the alternative complement pathway is associated with a broader and more heterogeneous infectious phenotype [24,28,29]. C5 inhibition disrupts the terminal complement pathway by preventing the cleavage of C5 into C5a and C5b, thereby blocking MAC assembly [4,31,47]. While C3b deposition and opsonophagocytosis are partially preserved, the absence of C5a markedly impairs phagocyte activation, chemotaxis and CR3 expression. This results in reduced efficiency of neutrophil- and macrophage-mediated bacterial clearance [29,33,34]. The combined deficiency of MAC-mediated lysis and impaired phagocytic function explains why vaccinated patients can still develop severe invasive infections despite high antibody titres [8,26].

This dissociation reflects that, for meningococcal disease, functional serum bactericidal activity (SBA), rather than antibody concentration, represents the primary correlate of protection following vaccination. Although meningococcal vaccines induce high levels of circulating antibodies, only antibodies capable of activating complement and mediating bactericidal killing confer effective protection against invasive disease. Fc-mediated effector functions contribute to bacterial clearance through opsonophagocytosis but are insufficient to compensate for the loss of complement-dependent bactericidal activity in invasive meningococcal infection [16,29,34].

Epidemiological data substantiate these mechanistic insights. Surveillance in the US between 2008 and 2016 identified 16 cases of meningococcal disease in patients treated with eculizumab, most of which occurred despite prior vaccination. Eleven cases involved nongroupable N. meningitidis strains, which are usually avirulent in immunocompetent hosts, while the remaining cases were caused by serogroup Y. All patients presented with meningococcemia; six developed meningitis and one patient died [19]. Although these early observations predate current vaccination and prophylaxis standards and are subject to reporting bias, they illustrate how strain-specific virulence and antigenic heterogeneity become clinically relevant in the context of profound terminal complement blockade [16,17,29,48].

More contemporary pharmacovigilance data provide a clearer estimate of residual risk under current preventive strategies. Across large cumulative exposures, meningococcal infection during long-term eculizumab therapy remains uncommon but clinically consequential, with reported infection rates of approximately 0.25 per 100 patient-years and meningococcal-related mortality of approximately 0.03 per 100 patient-years in paroxysmal nocturnal haemoglobinuria [23]. These data more accurately reflect current clinical practice than earlier surveillance reports. For newer long-acting or pathway-selective CIs, phase 3 trials and early post-approval safety experience reported to date have not suggested new safety concerns under current vaccination and monitoring practices; however, follow-up duration remains limited, and studies are not powered to detect rare invasive infections [49,50,51].

Experimental and clinical studies further support this vulnerability. Post-vaccination antibody titres in patients under C5 inhibition often approximate those of healthy controls; however, these antibodies alone fail to restore full bactericidal activity due to the absence of MAC function [47,52,53]. Early studies suggested that several-fold increases in antibody concentrations might partially compensate for the loss of C5 function. However, contemporary evidence shows that antibody titres alone are insufficient [18]. Recent functional studies confirmed that while inhibition of the alternative complement pathway preserves opsonophagocytic and bactericidal activity against encapsulated bacteria, C5 blockade abrogates serum bactericidal killing against meningococci even in vaccinated individuals [47,53].

A distinction must also be made between vaccine formulations. Conjugate vaccines induce a T-cell-dependent immune response and immunological memory, whereas polysaccharide vaccines do not [54]. However, even after the vaccination with conjugated polysaccharide vaccines, patients under complement inhibition remain at high risk of breakthrough infections because protection against encapsulated bacteria critically depends on terminal complement activity and MAC formation. Neither high antibody titres nor immunological memory can fully substitute for complement-dependent bactericidal activity. For this reason, conjugate vaccines are preferable, but it must be emphasised that they cannot completely eliminate the risk of breakthrough infections in the context of C5 blockade [47].

The introduction of tetravalent meningococcal conjugate vaccines, covering serogroups A, C, W, and Y, and protein-based serogroup B vaccines has nevertheless improved protection in this high-risk population. Protective antibody levels can only be achieved through vaccination, not through natural infection, because vaccination induces robust T-cell-dependent responses and high titres of functional antibodies. In contrast, natural infection in patients under complement inhibition often fails to generate sufficient bactericidal activity [18,19,40].

Host-related factors also modify susceptibility beyond complement inhibition itself. Younger age is associated with limited naturally acquired anti-meningococcal immunity and less mature T-cell-dependent immune responses, which may reduce the effectiveness of vaccine-induced protection [6,7,30]. In adults, comorbidities such as chronic kidney disease or haematological disorders, concomitant immunosuppressive therapies, and increased environmental exposure to pathogens can further attenuate post-vaccination immune responses and facilitate bacterial colonisation [13,15,16,17,26,32]. In addition, interindividual variability in mucosal immunity, microbiome composition, and genetic polymorphisms affecting complement components or Fcγ-receptor–mediated effector functions may influence the efficiency of antibody-dependent bacterial clearance [17,29,32]. Together, these host-related factors help explain the substantial clinical heterogeneity observed among patients receiving identical C5-inhibiting regimens.

Effective management requires heightened clinical awareness and consideration of prophylactic antibiotics for high-risk patients. Clear communication regarding the limitations of vaccination is essential. Cocoon strategies, including vaccination of household contacts and long-term antibiotic prophylaxis when appropriate, should be implemented to prevent the spread of infection. Prompt recognition of infection symptoms can help prevent rapid progression to sepsis and reduce morbidity and mortality [7,13,26].

3. Future Directions

The therapeutic landscape of systemic complement inhibition has evolved rapidly, with ongoing efforts to improve both safety and efficacy while minimising unintended side effects, including increased susceptibility to infections [22,24]. Researchers are increasingly focusing on the precise modulation of complement activity, shifting away from broad systemic inhibition toward approaches that are tissue-specific and tailored to individual patients [31,55].

Next-generation CIs are expanding treatment options beyond traditional C5 blockade. Agents targeting C3, factor B, or C1s are currently under clinical investigation or have recently entered clinical practice. Advances in protein engineering and medicinal chemistry have enabled the development of inhibitors with improved stability, bioavailability and safety profiles [56,57]. For example, Crovalimab offers longer dosing intervals, approximately once monthly, compared with every 8 weeks for Ravulizumab and every 2 weeks for Eculizumab, thereby improving convenience and quality of life for patients with PNH [58].

RNA and RNA-based approaches, such as RNA interference, have emerged as promising strategies for selectively regulating complement components. Sefaxersen^® (IONIS-FB-LRx) targets factor B of the alternative complement pathway, allowing precise control of complement activation in conditions such as IgA nephropathy and geographic atrophy associated with age-related macular degeneration [22,59].

Combination therapies that integrate CIs with agents that target non-complement pathways, such as CD14 blockade, can further improve inflammation control and protect organs in sepsis and other inflammatory conditions [60,61]. Conventional systemic CIs can produce off-target effects, which have motivated the development of tissue-targeted and intracellular strategies. Complement dysregulation often occurs locally at tissue injury sites. Therapies that focus on these areas while preserving systemic immune function can reduce infections and improve drug efficacy by avoiding the pharmacological ‘sink’ effect, in which high circulating complement proteins form a large and rapidly turning-over target pool that sequesters systemically administered inhibitors and reduces the amount of active drug available for local complement inhibition. The pharmacological sink effect is particularly relevant for complement inhibitors and, in part, can be overcome by the use of higher systemic doses [33,62,63].

Biomarker-guided approaches are increasingly being explored to monitor complement activity and may support more individualised dosing strategies in the future. Urinary C5b-9 reflects local complement activation in immune-mediated kidney diseases, but it is not used in routine clinical practice [64,65,66]. Available assays are largely restricted to research settings, exhibit substantial pre-analytical and analytical variability, and lack validated cut-off values [67,68]. The marker has also not been evaluated in clinical trials to guide treatment in patients receiving C3 or C5 inhibitors [24,28]. Clinically accessible markers therefore remain standard complement panels such as C3 and C4, functional assays of classical and alternative pathway haemolytic complement activity, as well as assays used to monitor complement blockade, including measurements of free and total C5 and serum eculizumab levels [69,70,71]. At present, urinary C5b-9 should thus be regarded as a promising research biomarker rather than a tool for individualised clinical decision-making.

Vaccination remains a key component of patient management. Although prophylactic immunisation is standard for patients receiving systemic complement inhibition, current vaccines offer only partial protection. Broader and more immunogenic meningococcal vaccines are expected to further enhance safety and complement general patient care [19,21].

In general, these developments illustrate a shift from broad systemic suppression toward precision complement modulation. By integrating tissue-targeted strategies, RNA-based therapeutics, next-generation inhibitors, biomarker-guided approaches, combination regimens and optimised vaccination, complement therapies can extend beyond rare, life-threatening disorders. This paradigm emphasises targeted, individualised interventions designed to maximise efficacy and patient safety while preserving essential immune function [22,24]. Importantly, continued studies are needed to assess long-term safety, identify patients most likely to benefit, and evaluate the effectiveness of these novel treatment strategies in various clinical contexts [24].

4. Conclusions

CIs have markedly advanced the treatment of complement-mediated disorders, providing effective control of haemolysis, inflammation and disease progression. Despite these benefits, inhibition of key innate immune mechanisms, particularly against encapsulated bacteria, continues to carry a risk of serious infection. Importantly, this risk persists despite vaccination and reflects an incomplete understanding of how different levels and targets of complement inhibition modify host defence and its complexity. Recommendations for vaccination and antibiotic prophylaxis in patients receiving CIs are not yet standardised internationally, underscoring the importance of individualised preventive strategies and highlighting ongoing uncertainty rather than simple gaps in implementation.

Effective infection prevention requires timely vaccination, targeted antibiotic prophylaxis when indicated, patient education, and immediate access to healthcare services. Multidisciplinary management, including haematology, immunology, infectious disease and primary care specialists, is crucial for the early recognition of infections and the implementation of customised interventions. However, the optimal scope and duration of these preventive measures remain debated and vary substantially across clinical settings and patient populations.

Emerging strategies, including tissue-targeted inhibitors, proximal pathway blockade and biomarker-guided therapy, may improve safety and precision. Whether these approaches can meaningfully reduce infectious risk while preserving therapeutic efficacy remains to be established. Ongoing research is needed to determine optimal approaches and validate their effectiveness in broader clinical practice. Integrating these advances with preventive measures is essential to maximise outcomes and maintain host defence.