Abstract
This systematic review critically evaluates the efficacy and safety of monoclonal (mAb) and polyclonal (pAb) antibody therapies in adult sepsis and septic shock by synthesizing data from 29 randomized controlled trials (RCTs) encompassing over 10,000 patients. Sepsis and septic shock continue to be major critical-care mortality causes worldwide because of simultaneous hyperinflammatory and immunosuppressive responses. The clinical results from using targeted antibody therapies to manage this dysregulated response have shown inconsistent results. We conducted a comprehensive search of MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Google Scholar (through February 2025) to identify RCTs that compared mAb and pAb treatments to placebo or standard care in adult patients with sepsis or septic shock. Monoclonal antibodies against single cytokines e.g., Tumor Necrosis Factor-alpha (TNF-α) and endotoxin, did not significantly reduce 28-day mortality in unselected cohorts, though subgroup analyses of patients with elevated Interleukin-6 (IL-6) or early septic shock showed trends toward benefit. Intravenous Immunoglobulin (IVIG) enriched for Immunoglobulin M (IgM) demonstrated the most consistent mortality reduction when administered early in hyperinflammatory phases. Emerging precision strategies-including checkpoint inhibitors targeting Programmed Cell Death Protein 1/Programmed Death-Ligand 1 inhibitors (anti-PD-1/PD-L1), complement component 5a inhibitors (anti-C5a), and anti-adrenomedullin-were safe and improved organ-support-free days and Sequential Organ Failure Assessment (SOFA) scores. According to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, evidence showed moderate confidence for mortality, high certainty for safety and low to moderate certainty for secondary outcomes. The use of broad single-target monoclonal treatments has failed to deliver significant improvements in sepsis patient outcomes. The most promising approaches for sepsis treatment involve biomarker-guided precision strategies and polyclonal IgM-enriched IVIG. Future sepsis trials need to implement rapid immune profiling and adaptive designs and combination regimens to achieve optimal efficacy and establish personalized guideline-based sepsis management.