Neonatal BCG vaccination: screening for genetic factors that influence host-pathogen interactions and reducing and replacing the requirement for animal infection models in immune mechanism discovery

Aims

This research aims demonstrate the use of human samples and cells to screen for genetic factors which influence tuberculosis infection and immunity, potentially reducing reliance on animal models of infection.

Background

Tuberculosis (TB) kills two million people annually, a problem compounded by rising levels of multi-drug resistant TB and the fact that BCG, the TB vaccine, does not protect against TB in countries where prevalence of the infection is high. The development of therapeutics currently relies extensively on the use of animals.

Genetics are important to a person’s susceptibility to TB, and identifying the genes involved could lead to new targets for treatments and vaccines. However, such data derived from animals do not always extrapolate accurately to humans.

This study uses vaccination responses in infants, as they are more likely to have never been exposed to TB, to identify the relevant genes involved in infection. This will avoid animal use and could be adapted to study human interactions with other pathogens for which vaccines are, or will be, given in early life.

Research details and methods

Five candidate genes have been identified previously that encode key molecules known to play a role in regulating the production of a critical cytokine needed for TB immunity, interferon-gamma (IFNγ). These genes will be sequenced in existing samples from 30 BCG-vaccinated infants to identify variations which could potentially have a functional impact.

The variants will be used to identify which molecules are linked to a poor inflammatory response to TB and how they control inflammation. This is an important first step for identifying new methods of treatment.

Related content

Tuberculosis (TB) kills 2 million people each year. Multidrug resistant TB is on the rise globally and BCG, the TB vaccine does not protect against TB in high-prevalence countries. New therapies are urgently required. It is well documented that host genetic factors are important determinants of susceptibility to TB – identification of the specific genes involved could identify critical pathways that control TB infection which could in turn be targets for new treatments and vaccines. Studies aimed at identifying human TB susceptibility genes have been disappointing due to the complexity of the gene-environment interaction that lead to disease. Meanwhile data derived from animals do not extrapolate to humans. Alternative models are required. We have developed a novel human model in which we have identified interferon-gamma (IFN-y) regulatory genes that are significantly linked to immune responses to mycobacterial antigens following BCG vaccination at birth. This project will use a range of laboratory techniques in human samples to further characterise the functional effects of these genes and provide proof of principle that studies on vaccination responses in early life can identify relevant genes and pathways involved in host-pathogen interactions.

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PhD Studentship

Grant reference number

NC/K500537/1

Award date:

Oct 2011 - Sep 2014

Grant amount

£90,000