BCG vaccination induces HIV target cell activation in HIV-exposed infants in a randomized trial

Abstract

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. 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). Of 149 infants randomized, 92% ( = 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 CD4CCR5 T cells (HLA-DRCD38) at 6 weeks (0.25% at birth versus 0.08% in delayed vaccination groups; = 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 CD4CCR5 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. BCG vaccination induces immune changes in HIV-exposed infants, including an increase in the proportion of activated CCR5CD4 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. ClinicalTrials.gov NCT02062580. 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.

Live attenuated varicella-zoster virus vaccine does not induce HIV target cell activation

“…While the rate of herpes simplex virus 2 (HSV-2) seropositivity was higher in the delayed than in the immediate group (P = 0.008), subsequent adjustment for HSV-2 status did not alter our findings. The median participant age was 26 years (IQR [21][22][23][24][25][26][27][28][29][30]. The majority of the participants were married (73%), and 58% used the progesterone-based injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA).…”

“…Additionally, genital inflammation measured by an increased level of proinflammatory cytokines was associated with elevated risk of HIV infection (10,11) and a quiescent state of immune activation (IA) linked to resistance to HIV acquisition in highly exposed HIV-1seronegative (HESN) individuals (9,12,13). Genital inflammation interfere with the efficacy of vaccines (28) and that vaccination may induce sustained CD4 + T cell activation, potentially increasing HIV susceptibility in certain populations (29), thus supporting the examination of the IA status in vaccinology.…”

T Cell Activation in South African HIV-Exposed Infants Correlates with Ochratoxin A Exposure

“…The low-income setting of this study resulted in difficulties with infant retention, and blood samples at some of the desired time points were not available. There were no demographic differences between infants that were retained in the study and those that were lost to follow-up ( 33 ). We acquired the largest number of samples at week 6, and a decreased number of samples at weeks 2 (28 infants), 8 (15 infants), and 14 (11 infants).…”

“…This study cohort has been previously described in Ref. ( 33 ). Inclusion criteria were term pregnancy (36 weeks gestational age or greater at birth), birth weight >2.4 kg, maternal age 18 years or older, known maternal HIV status, HIV DNA PCR negative at birth or at 6 weeks of age (where applicable), and no potential household tuberculosis contact.…”

“…Only infants who had not received BCG vaccination were included in these analyses, the influence of BCG vaccination on immune activation was assessed in a previous study ( 33 ). The focus on only non-BCG vaccinated infants enabled us to remove this potential immune stimulation as a confounder from the analysis, as BCG vaccination independently increases T cell activation ( 33 , 34 ). Each sample was stained with optimized volumes of antibodies to evaluate T cell activation as previously published in Ref.…”