Dissociation between humoral and multi-omic immune responses to inactivated COVID-19 vaccination in patients with pulmonary tuberculosis

Introduction Patients with pulmonary tuberculosis (PTB) may experience persistent immune dysregulation during anti-tuberculosis treatment, yet vaccine evaluation in this population has largely relied on humoral endpoints. Whether preserved antibody responses reflect coordinated systems-level immune activation after inactivated COVID-19 vaccination remains unclear. This study used systems vaccinology to identify multi-omic immune signatures induced by vaccination in PTB patients. Methods We compared PTB patients who had completed at least 3 months of anti-tuberculosis therapy with healthy controls. This nested subcohort analysis was derived from a phase IV multicenter randomized controlled trial that evaluated vaccine safety and immunogenicity in PTB patients and healthy participants. Paired plasma samples for proteomic profiling using the Olink Explore 3072 platform and peripheral blood mononuclear cells (PBMCs) for transcriptomic sequencing were collected at baseline (Day 0, pre-vaccination) and Day 56 (28 days post-second dose). Proteomic analysis included 38 PTB patients and 38 healthy controls, while transcriptomic profiling was performed on a subset of 20 participants per group. We compared neutralizing antibody responses, differential molecular signatures, inferred immune-cell fractions, and antibody-protein correlations between the two cohorts. Within each group, we further characterized longitudinal molecular alterations from Day 0 to Day 56. Results After two doses of inactivated COVID-19 vaccine, PTB patients and healthy controls achieved comparable neutralizing antibody titers and similar seroconversion rates. However, the two cohorts exhibited markedly distinct baseline immune landscapes. Prior to vaccination, PTB patients had widespread depletion of plasma proteins enriched in vesicle transport and phagocytosis pathways, accompanied by pro-inflammatory transcriptional reprogramming. After vaccination, healthy controls showed broad proteomic and transcriptomic remodeling, whereas PTB patients displayed minimal molecular perturbation and limited inferred immune-cell changes. Exploratory covariate-adjusted partial Spearman protein-antibody correlation analyses suggested a predominance of nominal negative associations in PTB patients, involving proteins related to inflammatory regulation, intracellular trafficking, and phagocytosis; no individual association survived false-discovery-rate correction. Conclusion Despite comparable short-term neutralizing antibody responses, PTB patients receiving anti-tuberculosis treatment exhibited attenuated and distinct systems-level proteomic and transcriptomic remodeling after inactivated COVID-19 vaccination compared with healthy controls. Clinical Trial Registration https://clinicaltrials.gov/study/NCT05148949 , identifier NCT05148949.