BCG and Adverse Events in the Context of Leprosy

Abstract

Background: Notwithstanding its beneficial immunoprophylactic outcomes regarding leprosy and childhood TB, BCG vaccination may cause adverse events, particularly of the skin. However, this local hyper-immune reactivity cannot be predicted before vaccination, nor is its association with protection against leprosy known. In this study we investigated the occurrence of adverse events after BCG (re)vaccination in contacts of leprosy patients and analyzed whether the concomitant systemic anti-mycobacterial immunity was associated with these skin manifestations.

Methods: Within a randomized controlled BCG vaccination trial in Bangladesh, 14,828 contacts of newly diagnosed leprosy patients received BCG vaccination between 2012 and 2017 and were examined for adverse events 8 to 12 weeks post-vaccination. From a selection of vaccinated contacts, venous blood was obtained at follow-up examination and stimulated with Mycobacterium leprae (M. leprae) antigens in overnight whole-blood assays (WBA). M. leprae phenolic glycolipid-I-specific antibodies and 32 cytokines were determined in WBAs of 13 individuals with and 13 individuals without adverse events after vaccination.

Results: Out of the 14,828 contacts who received BCG vaccination, 50 (0.34%) presented with adverse events, mainly (80%) consisting of skin ulcers. Based on the presence of BCG scars, 30 of these contacts (60%) had received BCG in this study as a booster vaccination. Similar to the pathological T-cell immunity observed for tuberculoid leprosy patients, contacts with adverse events at the site of BCG vaccination showed elevated IFN-γ levels in response to M. leprae-specific proteins in WBA. However, decreased levels of sCD40L in serum and GRO (CXCL1) in response to M. leprae simultaneously indicated less T-cell regulation in these individuals, potentially causing uncontrolled T-cell immunity damaging the skin.

Conclusion: Skin complications after BCG vaccination present surrogate markers for protective immunity against leprosy, but also indicate a higher risk of developing tuberculoid leprosy.

Clinical trial registration: Netherlands Trial Register: NTR3087.

Keywords: BCG (re)vaccination; Mycobacterium leprae; adverse events; biomarker profiles; household contacts; leprosy; protective immunity.

Figure 1

Representative examples of skin complications after BCG vaccination. (A) Three contacts with big ulcers (>10 mm). (B) A contact with keloid (picture taken before operation). (C) A contact with an ulcer and lymphadenitis who developed leprosy at follow-up.

Figure 2

Mycobacterium leprae phenolic glycolipid-I (PGL-I)-specific antibodies in contacts of leprosy patients with or without BCG-induced skin complications. IgG and IgM antibodies directed against synthetic PGL-I (ND–O–HSA) were determined by ELISA. Samples with OD₄₅₀ (corrected for background OD) >0.2 were considered seropositive. No statistically different levels of IgG and IgM antibodies were observed between the contacts with (+ ; gray dots) or without (−; black squares) complications.

Figure 3

Cytokine concentrations in 24-h whole-blood assays (WBA) with or without stimulation with Mycobacterium leprae (M. leprae) unique proteins (Mlep) or M. leprae whole cell sonicate (WCS) in contacts with and without BCG complications (left panels). The global test (26) indicated that sCD40Lmed, GROwcs, and IFN-γ_Mlep were significantly different between BCG-vaccinated contacts of leprosy patients with BCG-related complications and those without. This was confirmed by a Mann–Whitney U test. *p < 0.05–0.01. Receiver operating characteristic curves (ROCs) were computed and the area under the curve (AUC) is indicated for each analyte (right panels). The limits of detections for sCD40Lmed were 1.5–10,000, for GROwcs were 12.5–9,600. and IFN-γ_Mlep were 2–10,000.

Figure 4

Results of whole-blood assays (WBAs) in contacts with and without BCG complications in (A) medium (designated NIL). (B) Mycobacterium leprae whole cell sonicate (designated WCS). (C) ML2478/ML0840 recombinant proteins (designated Mlep) (C).