Complement Inhibition in the Clinic: Are We Doing Enough to Protect Patients From Infection?

Discovered in the late 19th century as a heat-sensitive plasma factor called "alexin", complement was first identified for its ability to work with antibodies to destroy microorganisms. Over the past two centuries, research advances have firmly established the complement system as a fundamental component of the immune system, with broader roles in immune surveillance, inflammation, and clearing immune complexes and apoptotic debris, while also bridging innate and adaptive immunity. Due to complement playing a central role in modulating biological processes on a system-wide scale, dysregulation or excessive activation can drive harmful inflammation and self-tissue damage. Despite some initial safety concerns and biological complexity, therapeutic targeting of the complement system has, over the past decade, emerged as a key strategy for controlling disorders in which its unregulated activation becomes pathogenic. However, inhibition of complement, particularly at the level of C3 or C5, predisposes patients to infections, most notably by encapsulated bacteria. These include a markedly increased risk of invasive infections caused by Neisseria meningitidis, as well as susceptibility to Streptococcus pneumoniae, Haemophilus influenzae, and other opportunistic viral and fungal pathogens. In this review, we aim to describe the infection risks associated with therapeutic complement inhibition and outline emerging approaches to mitigate their complications. These include optimised vaccination protocols, antimicrobial prophylaxis, patient education, and surveillance programs, as well as next-generation approaches such as pathway-selective inhibitors, personalised risk stratification, and adjunctive immune support. Enhancing these protective measures will be vital to optimising the therapeutic benefit of complement inhibition while reducing infectious morbidity and mortality.