Effect of BCG vaccination at birth on innate and adaptive immunity
A PhD project using an in vitro assay and a randomized trial in HIV-exposed infants to assess trained immunity induced by BCG vaccine.
About the research project
The Bacillus Calmette鈥揋u茅rin (BCG) vaccine is routinely given at birth in tuberculosis-endemic countries to prevent severe forms of the disease. However, it has been shown that BCG vaccine can induce long-term enhancement of the innate immune system, thereby protecting the vaccinated individual not just against tuberculosis. However, the mechanisms by which BCG vaccine may cause this non-specific protective effect is not yet clear.
Newborns don't have a mature adaptive immunity since they are not yet exposed to external pathogens. This makes them more vulnerable to infections than adults are and more dependent on their innate immunity for defense against microbes. Monocytes are innate immune cells and an important source of cytokine production during microbial infections.
The first part of the project aims to investigate how monocytes from Norwegian newborns and adults are able to adapt and respond to stimuli, and how they may 鈥渞emember鈥 these responses over time.
Results show that stimulation with BCG or beta-glucan induces similar cytokine production responses in both infant and adult monocytes in culture. This in vitro response is similar to trained immunity in vivo and indicates that BCG vaccination at birth modulates the development of the neonatal immune system and plays a role in the non-specific effects of BCG observed in epidemiological studies.
Innate and adaptive immunity substudy in the 鈥淓arly versus late BCG vaccination in HIV-1 exposed infants鈥 (BCGI)
The second part of the project is performed in infants of HIV infected mothers in Uganda.
Globally, about 1.2 million children are born each year to women living with HIV鈥1. HIV鈥慹xposed (HE) infants experience far higher morbidity and mortality than HIV鈥憉nexposed infants, with a particularly elevated risk of infectious diseases. Strengthening early鈥憀ife immunity is therefore essential and vaccination is a central strategy.
The Bacillus Calmette鈥慓u茅rin (BCG) vaccine is the only licensed tuberculosis vaccine and is typically given at birth. Several studies suggest that BCG may have non鈥憇pecific effects (NSEs), offering protection beyond tuberculosis. These NSEs are thought to arise from 鈥渢rained immunity,鈥 in which innate immune cells鈥攅specially monocytes and natural killer cells鈥攄evelop enhanced functional responses. In HE infants prenatal exposure to HIV and possibly maternal or perinatal antiretroviral therapy may disrupt normal immune maturation, raising the question of whether they can mount trained immunity after BCG vaccination.
Studies from low鈥慽ncome settings have reported non-specific effects of BCG vaccine in infants, supported by increased cytokine production after stimulation with pathogen extracts or toll鈥憀ike receptor agonists. However, similar findings have not been replicated in high鈥慽ncome countries such as Denmark, suggesting that the benefits of BCG vaccine may be most pronounced where infectious pressures are high. No studies to date have examined trained immunity responses to BCG vaccine in HE infants.
This randomized controlled trial is the first to do so. We will enroll 182 newborns, randomly assigning them to receive BCG either at birth or at 14 weeks, and follow them for one year with venous blood sampling at birth, week 6, week 14 and week 52.
Collaborating institutions
The Centre for Intervention Science in Maternal and Child Health (CISMAC) is performing a large randomized controlled trial of the effect of deferring BCG vaccination to 14 weeks of age in HIV-1 exposed infants in Uganda. BCGI is a substudy within this study, aiming to examine trained immunity readouts.
The project is undertaken in collaboration with:
- Centre for Intervention Science in Maternal and Child Health (international consortium CISMAC),聽
- (Kampara, Uganda), and聽
- (Entebbe, Uganda).
Publications
Relevant publications
Three publications are planned based on the data collected in this PhD project. One is published, two are being prepared.
- Namakula R, de Bree LCJ, A Tvedt TH, Netea MG, Cose S, Hanevik K.
PLoS One. 2020
People
Project manager
Project members
Halvor Sommerfelt Department of Global Public Health and Primary Care, University of Bergen, Norway
Hans Steinsland Department of Global Public Health and Primary Care, University of Bergen, Norway
Rhoda Namakula PhD candidate, Department of Global Public Health and Primary Care, and Department of Clinical Science, University of Bergen, Norway
L Charlotte J de Bree Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
Tor Henrik A. Tvedt Department of Medicine, Section for Hematology, Haukeland University Hospital, Bergen, Norway
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
London School of Hygiene and Tropical Medicine, United Kingdom | MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda