BCG Vaccination Modulates Long-Term TNF-α and sCD40L in COVID-19: An Exploratory Longitudinal Study

Background: Bacillus Calmette–Guérin (BCG) vaccination exerts non-specific immunomodulatory effects through trained immunity, potentially modulating inflammatory responses in COVID-19. Tumor necrosis factor-alpha (TNF-α) and soluble CD40 ligand (sCD40L) are key inflammatory and pro-thrombotic mediators implicated in COVID-19 pathogenesis. Methods: A randomized, placebo-controlled trial was conducted involving young, healthy adults with mild COVID-19 (BATTLE trial). Intradermal BCG vaccination or placebo was administered during the acute phase of infection. Plasma TNF-α and sCD40L levels were measured at days 7 and 45, and at 6 months post-intervention in a subset of participants, total n=13; BCG n=7; placebo n=6. The sCD40L/TNF-α ratio was calculated to explore the balance between adaptive immune activation and systemic inflammation. Results: At day 7, BCG-vaccinated individuals exhibited higher TNF-α (p=0.01) and sCD40L (p=0.018) levels compared with the placebo group. In the placebo group, TNF-α showed a transient decline by day 45 (p=0.040), whereas sCD40L remained stable throughout follow-up (all p> 0.05). In contrast, BCG recipients demonstrated a sustained reduction in both mediators from day 45 to 6 months (TNF-α: p=0.0012 at day 45 and p=0.0017 at 6 months; sCD40L: p=0.024 at day 45 and p=0.05 at 6 months). The sCD40L/TNF-α ratio increased transiently at day 45 in the BCG group (p=0.035), suggesting a temporary predominance of adaptive immune activation. Conclusion: BCG vaccination induced a distinct and durable modulation of TNF-α and sCD40L in mild COVID-19, consistent with the concept of trained immunity. This immune profile may support faster resolution of inflammation and potentially reduce the risk of inflammatory complications. Larger and more diverse controlled trials are needed to confirm these findings and clarify their clinical implications.