Understanding the non-specific effects of BCG vaccination in babies – the expansion of Th17 cells in early life

Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis. The bacteria typically infect the lungs but can affect other sites as well. TB continues to be a leading cause of morbidity and mortality, especially in developing countries. About one-third of the world’s population is infected with TB and TB is the second leading cause of death from an infectious disease worldwide.

The bacillus Calmette-Guérin (BCG) vaccine has existed for 100 years and is one of the most widely used of all current vaccines in developing countries, where it is part of the national childhood immunization programme. To date, more than 4 billion people have received BCG vaccine, which has a documented protective effect against cerebral TB and disseminated TB in children. The live germs used in the BCG vaccine have been weakened (attenuated) to induce an immune response without harming healthy individuals. However, those who are clinically immunosuppressed and HIV patients should not receive the vaccine. This is due to the possibility that the vaccination strain could overproduce and result in a severe infection. This applies to infants whose mothers had immunosuppressive therapy when they were expecting or nursing. When administered later in life to adults, BCG has only modest efficacy against pulmonary TB. The BCG vaccine protects against both infection and disease; for instance, there has been a correlation shown between having a BCG scar and reduced rates of interferon-gamma release assay positivity.

Aside from the specific protective effects against TB, a series of observational studies and randomized trials have shown that BCG has marked non-specific effects, which means that the vaccine induces a beneficial immune response which is protective against other infectious diseases. The potential immunological mechanisms contributing to BCG’s non-specific effects in neonates include ‘‘trained innate immunity”, induction of emergency granulopoiesis and/or induction of heterologous T-cell immunity. Previous studies has linked maternal BCG scars with an induction of a beneficial pro-inflammatory immune profile; however, the potential mechanistic immunological routes of parental priming with BCG in the kids are far from fully understood. Dr. Frederik Schaltz-Buchholzer from Uni. Southern Denmark has together with Dr. Gergely Toldi, affiliated with University of Birmingham in the UK, and University of Auckland in New Zealand, conducted an exploratory study in a small cohort of healthy newborns from the UK to look at the immunological profile and responses related to the triad of parental and offspring BCG vaccination. The new findings were published in the scientific journal Vaccine. “The non-specific effects of BCG have an enormous potential to improve morbidity and mortality in newborns and to positively influence the developing immune system of a baby. However, in order to harness these benefits, we need to establish a better understanding of the underlying cellular mechanisms” – says Dr. Toldi.

The researchers studied healthy newborns among which there were no severe infections requiring hospitalization; 11 were born to BCG-vaccinated parents, and 8 of these newborns received BCG themselves at birth. By contrast, BCG was not given to the 6 newborns born to unvaccinated parents. All parent pairings had either received the childhood BCG vaccine together or none had.. The authors evaluated the expression of intracellular cytokines and cell surface markers in T cells in neonates who had received the BCG vaccine and those who had not in samples withdrawn at 3 weeks of age. While the frequency of regulatory T cells (Tregs, CD4 + CD25hi FoxP3+) were comparable between groups, the prevalence of T helper 17 (Th17) CD4 + IL-17 + cells were increased to 4-fold greater levels in peripheral blood of newborns who had received the BCG vaccine, when compared to those who had not. As a result, the neonates that received the BCG vaccine had a greater Th17/Treg ratio than the control neonates. However, there was no difference between the two study groups regarding the intracellular expression of IL-17 (mean fluorescence intensity) in CD4 or CD8 cells. While the predominance of Th1 (CD4 + IFN-g +) cells did not differ between the two groups, there was a tendency for Th2 (CD4 + IL-4+) cells to be less common in newborns who had received the BCG vaccine compared to those who had not. Interestingly, among the neonates in the unvaccinated group, those whose parents had received a BCG vaccination had among the highest Th17 counts and a substantial increase over the neonates with no parental BCG. This finding might be of importance, given that Th17 cells are important in early-life immune responses against infectious diseases.

In summary, numerous studies have shown that infant BCG has positive non-specific effects, and that parental priming may enhance these effects, but the immunological pathways are yet unknown. The new study by Dr. Frederik Schaltz-Buchholzer and Dr. Gergely Toldi found for the first time that receiving neonatal BCG and/or having BCG-vaccinated parents was linked to a 4-fold growth of the Th17 cell subgroup by the time the child was 3 weeks old. Further studies are required to investigate the role of protective properties of offspring and maternal BCG against infectious diseases and early life development of the immune response.