Clinical and Proteomic Associations of SARS-CoV-2 Infection and COVID-19 Vaccination in Multimorbid Patients: A Cross-Sectional Observational Study.

Vaccines played a crucial role in the COVID-19 pandemic, but their long-term biological effects and efficacy in vulnerable populations remain under intensive investigation. This study assessed clinical outcomes, comorbidities, and systemic biomarker and proteomic profiles in 366 multimorbid patients, stratified into four groups based on SARS-CoV-2 infection and vaccination status (COV+ vac+, COV+ vac-, COV- vac+, COV- vac-). Clinical and laboratory data, including comorbidities and relevant biomarkers, were collected. Proteomic analysis using mass spectrometry was performed to identify molecular changes associated with infection and vaccination. Statistical analyses examined associations between clinical status, biomarkers, and patient outcomes. As most participants received mRNA-based vaccines, the results primarily reflect responses to spike protein-expressing platforms. Biomarkers of cardiac and renal stress-namely proBNP and carbamide-were elevated in vaccinated individuals. Five deaths occurred in the COV+ vac+ group and two in the COV+ vac- group, most of which were attributed to exacerbations of pre-existing chronic diseases rather than to COVID-19 pneumonia. Protection against breakthrough infections waned over time, particularly beyond 200 days post-vaccination. Mass spectrometry identified proteins such as actin, fibrinogen chains, and SAA2 as potential diagnostic targets. Although the cross-sectional observational design limits the ability to draw causal inferences, the observed waning immunity and potential systemic alterations in vaccinated multimorbid patients highlight the importance of longitudinal follow-up to guide tailored immunization strategies and post-vaccination monitoring in high-risk groups.