Background: Despite hybrid and vaccine-induced immunity, SARS-CoV-2 continues to cause disease. The characterization of humoral and cellular immune responses is essential for guiding prevention strategies and booster dose policies; Methods: A prospective cohort study was conducted with 131 hospitalized patients with confirmed COVID-19 in the Aburrá Metropolitan Valley, Colombia. Clinical and immunological data were evaluated on days 1–3, days 5–7, days 8–12, and 4–5 months after diagnosis. Humoral immunity was assessed by enzyme-linked immunosorbent assay (ELISA), chemiluminescent microparticle immunoassay (CMIA), and neutralization testing, and cellular immunity by CD4⁺/CD8 T-cell responses. Results: vaccinated patients had higher baseline levels of IgG and neutralizing antibody positivity than unvaccinated patients (ELISA 89.1% vs. 60.0%; CMIA 86.4% vs. 50.0%; neutralizing antibodies 88.2% vs. 65.0%), but cases of severe disease occurred in both groups. Adults aged ≥65 years had higher antibody positivity, but severe disease persisted. Mortality at 28 days was 7.6%, mainly among critically ill patients with comorbidities. Antibodies persisted at 4–5 months but were lower in those with severe acute disease. Those who received the booster dose showed stronger CD4⁺/CD8⁺ activation (notably against the Omicron variant) than unvaccinated/partially vaccinated patients. Conclusions: Vaccination improved humoral and cellular responses, but severe breakthrough infections still occurred, particularly in high-risk patients.

To evaluate the impact of early dynamic changes in immunological variables—IL-6, IL-10, CD4 + T cells, and CD8 + T cells—measured at days 1–3, 5–7, and 8–12 after diagnosis on 28-day mortality and organ dysfunction in hospitalized patients with COVID-19. This prospective observational study included 131 patients. Joint models for longitudinal data and time-to-event analysis were used to assess the relationship between immunological variables and 28-day mortality. A two-stage maximum likelihood estimation (2SMLE) method was applied to evaluate organ dysfunction. During the first 12 days of hospitalization, IL-6 levels and CD8 + T-cell counts were independently associated with 28-day mortality. After adjustment for confounders, higher log-transformed IL-6 levels were associated with a more than twofold increase in the hazard of 28-day mortality (adjusted HR = 2.36; 95% CI 1.11–5.03), whereas higher log-transformed CD8 + T-cell values were associated with an approximately 80% lower hazard of mortality (adjusted HR = 0.17; 95% CI 0.05–0.58). Elevated log-transformed IL-6 levels at admission were also associated with fewer ventilator-free days. In contrast, higher baseline log-transformed CD4 + and CD8 + T-cell levels, as well as increases in log-transformed CD4 + T cells over time, were associated with more ventilator-free days. This study highlights the critical role of immunological markers in determining outcomes for hospitalized COVID-19 patients. IL-6 and T-cell levels significantly influence mortality and clinical recovery, suggesting their potential as biomarkers for patient management and therapeutic strategies.