Unique gene expression profiles in infants vaccinated with different strains of Mycobacterium bovis bacille Calmette-Guerin

Abstract

Vaccination with Mycobacterium bovis bacille Calmette-Guérin (BCG) has variable efficacy in preventing tuberculosis. We hypothesized that some of this variation might be due to differences among BCG strains. To test this, neonates in Orizaba, Mexico, were vaccinated with one of three different BCG strains (BCG-Brazil [BBCG], BCG-Denmark [DBCG], or BCG-Japan [JBCG]). One year after vaccination, peripheral blood mononuclear cells (PBMC) were obtained and recall immune responses to culture filtrate proteins (CFP) of Mycobacterium tuberculosis were evaluated using quantitative real-time PCR. CFP-activated PBMC from BBCG- and DBCG-immunized children expressed high levels of cytokines characteristic of an adaptive immune response (gamma interferon, interleukin-2beta [IL-12beta], and IL-27), while those from children immunized with JBCG did not. In contrast, vaccination with JBCG resulted in significantly greater expression of cytokines characteristic of a proinflammatory immune response (IL-1alpha, IL-1beta, IL-6, and IL-24) in PBMC activated with CFP compared to PBMC from children vaccinated with BBCG or DBCG. Thus, different strains of BCG can activate different immune pathways, which may affect long-term vaccine efficacy.

Figures

FIG. 1.

Expression of IFN-γ, IL-12β, and IL-27 mRNA in PBMC from infants vaccinated with BBCG, DBCG, or JBCG. Median increases are represented by horizontal bars.

FIG. 2.

Expression of IL-1α, IL-1β, IL-6, and IL-24 in PBMC from infants vaccinated with BBCG, DBCG, or JBCG. Median increases are represented by horizontal bars.

FIG. 3.

Expression of FOXP3, IL-2, IL-5, IL-8, IL-9, IL-10, IL-12α, IL-23α, TGF-β1, and TNF-α in PBMC from infants vaccinated with BBCG, DBCG, or JBCG. Median increases are represented by horizontal bars.

FIG. 4.

Hierarchical clustering of expression of IFN-γ, IL-27, IL-12β, IL-1α, IL-1β, IL-24, and IL-6. The color intensity reflects the magnitude of high (red rectangle) or low (blue rectangle) mRNA expression. Each row represents the mRNA expression profile of one infant, and each column represents one cytokine. (A) Hierarchical clustering of mRNA expression. Cytokines with similar immune functions are grouped. (B) Distribution of high and low responders among BCG-vaccinated infants. The chi-square test was performed (P > 0.05). (C) Cytokine responses in high responders among BBCG- or DBCG-vaccinated and JBCG-vaccinated infants. Type I, IL-1α/IL-1β/IL-24/IL-6; type II, IFN-γ/IL-27/IL-12β; type III, IFN-γ/IL-27/IL-12β/IL-1α/IL-1β/IL-24/IL-6. Fisher's exact test was performed (P < 0.0001).