INTEGRATED BLOOD IMMUNOLOGY FROM VACCINATION TO CRITICAL ILLNESS: BIOMARKERS, MACHINE LEARNING, AND TRANSCRIPTOMIC PATHWAYS

Abstract

Infection-related critical illness remains a major cause of morbidity and mortality in intensive care units, where COVID-19, bacteremia, sepsis, and septic shock often converge on similar clinical trajectories despite distinct etiologic triggers. Peripheral blood offers a practical window into these systemic responses. However, the molecular programs that distinguish protective immunity from maladaptive inflammation, and early sensing from later tissue injury, remain incompletely resolved. This publication-format thesis investigates blood immune activity along a continuum from controlled antigen exposure in vaccination to dysregulated host response in critical illness, aiming to define shared and syndrome-specific signals that are relevant for risk stratification and treatment. A central challenge in the field is that current clinical labels and single-analyte biomarkers capture hemodynamic consequences of disease better than they capture underlying biology, leading to limited reproducibility and weak guidance on when to apply host-directed interventions. To address this, the thesis integrates complementary blood-based approaches that connect functional humoral immunity, interpretable multiplex biomarker patterns at ICU presentation, and whole-blood transcriptomic pathways measured side by side across major ICU syndromes. By organizing these data into a unified, pathway-centered, time-aware framework, the work tests which programs are conserved across pathogen classes, which are syndrome-specific, and how they evolve with increasing severity. Across the integrated studies, heterologous SARS-CoV-2 vaccination elicits strong binding and neutralizing antibody responses, providing a quantitative benchmark for later blood-signal interpretation. Interpretable machine-learning analyses of ICU biomarker panels identify a small set of stable severity drivers across clinically overlapping infections, with programmed death ligand-1 and myeloperoxidase emerging as conserved indicators linked to worsening multi-organ failure. Comparative whole-blood RNA sequencing of adults with COVID-19, bacteremia, sepsis, and septic shock reveals a shared early core of innate sensing and cytokine activity, with syndrome-specific modulation of complement–coagulation and progressive engagement of metabolic stress, proteostasis, and cytoskeletal remodelling modules as illness severity increases. Together, these findings support a phased model of critical-illness biology and provide a practical scaffold for endotype- and timing-aware biomarker development and therapeutic trials.