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Clinical Trial
. 2017 Apr 6;2(7):e91963.
doi: 10.1172/jci.insight.91963.

BCG Vaccination Induces HIV Target Cell Activation in HIV-exposed Infants in a Randomized Trial

Free PMC article
Clinical Trial

BCG Vaccination Induces HIV Target Cell Activation in HIV-exposed Infants in a Randomized Trial

Melanie A Gasper et al. JCI Insight. .
Free PMC article


BACKGROUND. Bacillus Calmette-Guérin (BCG) vaccine is administered at birth to protect infants against tuberculosis throughout Africa, where most perinatal HIV-1 transmission occurs. We examined whether BCG vaccination alters the levels of activated HIV target T cells in HIV-exposed South African infants. METHODS. HIV-exposed infants were randomized to receive routine (at birth) or delayed (at 8 weeks) BCG vaccination. Activated and CCR5-expressing peripheral blood CD4+ T cell, monocyte, and NK cell frequencies were evaluated by flow cytometry and immune gene expression via PCR using Biomark (Fluidigm). RESULTS. Of 149 infants randomized, 92% (n = 137) were retained at 6 weeks: 71 in the routine BCG arm and 66 in the delayed arm. Routine BCG vaccination led to a 3-fold increase in systemic activation of HIV target CD4+CCR5+ T cells (HLA-DR+CD38+) at 6 weeks (0.25% at birth versus 0.08% in delayed vaccination groups; P = 0.029), which persisted until 8 weeks of age when the delayed arm was vaccinated. Vaccination of the infants in the delayed arm at 8 weeks resulted in a similar increase in activated CD4+CCR5+ T cells. The increase in activated T cells was associated with increased levels of MHC class II transactivator (CIITA), IL12RB1, and IFN-α1 transcripts within peripheral blood mononuclear cells but minimal changes in innate cells. CONCLUSION. BCG vaccination induces immune changes in HIV-exposed infants, including an increase in the proportion of activated CCR5+CD4+ HIV target cells. These findings provide insight into optimal BCG vaccine timing to minimize the risks of HIV transmissions to exposed infants while preserving potential benefits conferred by BCG vaccination. TRIAL REGISTRATION. NCT02062580. FUNDING. This trial was sponsored by the Elizabeth Glaser Pediatric AIDS Foundation (MV-00-9-900-01871-0-00) and the Thrasher Foundation (NR-0095); for details, see Acknowledgments.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.


Figure 1
Figure 1. Consort diagram of the intent-to-treat population.
Figure 2
Figure 2. BCG vaccination of HIV-exposed infants is associated with an increase in activated CD4+ T cells.
(A) Representative flow plot depicting gating strategy for determining the frequency of CD4+HLADR+ cells of total (B) CD4+ and (C) CD8+ T cells in routine (circles; n = 45) or delayed (squares; n = 49) BCG-vaccinated infants at 6 weeks of age, when only the “routine” arm had received vaccination, while the “delayed” arm was unvaccinated. Only samples with >1,000 live CD3+ cells were included in the analysis. Lines depict medians; whiskers depict interquartile ranges.
Figure 3
Figure 3. BCG vaccination of HIV-exposed infants is associated with an increase of activated CD4+CCR5+ HIV target cells.
(A) Longitudinal frequency of activated CD4+CCR5+HLA-DR+CD38+ T cells from birth through 14 weeks in routine (gray circles) versus delayed (black squares) BCG-vaccinated infants. Syringe graphics indicate the time of vaccination in the routine arm (gray) or the delayed arm (black). (B) Plots depicting the increase in activated CCR5+CD4+ target cells in the routine or delayed groups 6 weeks after vaccination in each group (routine: n = 37 at 0 weeks, n = 44 at 6 weeks; delayed: n = 24 at 8 weeks, n = 21 at 14 weeks; only samples with >1,000 live CD3+ cells were included in the analysis. Lines depict the medians; whiskers represent the interquartile ranges. **P < 0.01; ***P < 0.001; ****P < 0.0001.
Figure 4
Figure 4. Fluidigm immune gene expression analysis in routine and delayed BCG-vaccinated HIV-exposed infants at 2 weeks of age.
Expression of 48 genes (including 2 housekeeping genes) was measured via Biomark (Fluidigm) quantitative real-time PCR analysis at 2 weeks of age when only the “routine” arm had received vaccination. (A) Fold change of gene expression between the routine versus delayed BCG-vaccinated groups. (B) –ΔCt (calculated by Ctgene of interest – CtGAPDH) of genes that demonstrated significantly differential expression between the groups. Lines depict the median; whiskers depict interquartile range. (C) Linear regression of gene expression of CIITA, CD8A, IL12RB1, IFNA1, and IL1A as determined at 2 weeks of age (–dCt expression value is shown on the x axis) and subsequent activation of activated CD4+CCR5+HLA-DR+CD38+ HIV target cells at 6 weeks in all infants combined (shown on the y axis).
Figure 5
Figure 5. NK cell phenotype and activation in routine and delayed BCG-vaccinated HIV-exposed infants at 8 weeks of age.
(A) Representative flow plot depicting CD56+ and CD16+ NK cells in PBMCs, which were previously gated on singlets, live, and Lin populations (CD3CD19CD14). (B) Graphs depicting the overall NK cell phenotypic distribution in routine (white triangles; n = 26) or delayed (gray inverted triangles; n = 25) BCG-vaccinated infants at 8 weeks of age and (C) activation status of each subset, as measured by the percentage of HLA-DR–expressing NK cells. Only infants in the routine arm received vaccination at this point, while the delayed arm was unvaccinated. Lines depict the median of each group; whiskers represent the interquartile range. Statistics were generated using a Mann-Whitney test for nonparametric data.

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