Research: Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination

SATVI Associate Professor Tom Scriba has co-authored a research paper titled "Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination" appearing in the Scientific Reports journal.

Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB) and induces highly variable protection against pulmonary disease in different countries. We hypothesised that DNA methylation is one of the molecular mechanisms driving variability in BCG-induced immune responses. DNA methylation in peripheral blood mononuclear cells (PBMC) from BCG vaccinated infants was measured and comparisons made between low and high BCG-specific cytokine responders.

Study participants

We retrieved blood samples collected from a subset of 10 week old infants who were enrolled into a large study of BCG vaccination at the South African Vaccine Initiative (SATVI) field site in the Worcester area, near Cape Town, South Africa (Hawkridge et al., BMJ 2008¹⁸. Parents All participants were vaccinated with BCG at birth and samples were collected 10 weeks after birth. Participants were excluded from the study if any of the exclusion criteria were met: infant not immunised with BCG within 24 hours; mother infected with human immunodeficiency virus (HIV); chronic and acute disease in the infant at the time of enrolment; clinical anaemia in the infant; significant perinatal complications in the infant; and contact with any person with TB disease or anyone who was coughing. Participants were followed for two years to observe the development of TB disease. Only healthy infants who did not develop TB disease were selected for this study. Parents gave consent for their infants to participate in the study. The study was conducted according to the U.S. Department of Health and Human Services and Good Clinical Practice guidelines, and included protocol approval by the University of Cape Town Research Ethics Committee and written informed consent from the parent or legal guardian. The study also received ethical approval from the Ethics Committee of the London School of Hygiene and Tropical Medicine (LSHTM, #8720).

Table 1

We found 318 genes and 67 pathways with distinct patterns of DNA methylation, including immune pathways, e.g. for T cell activation, that are known to directly affect immune responses. We also highlight signalling pathways that could indirectly affect the BCG-induced immune response: potassium and calcium channel, muscarinic acetylcholine receptor, G Protein coupled receptor (GPCR), glutamate signalling and WNT pathways.

This study suggests that in addition to immune pathways, cellular processes drive vaccine-induced immune responses. Our results highlight mechanisms that require consideration when designing new TB vaccines.