Robert Krause, Stellenbosch University, South Africa - VALIDATE Fellow
Measuring the immunogenicity and efficacy of a novel DNA-launched therapeutic for tuberculosis in both murine and human models
Project Aims
Without a preventative vaccine, we rely on anti-TB drugs. Although TB is curable, treatments are lengthy and involve multiple drugs. About 2-10% of patients fail initial therapy or relapse, requiring re-treatment, which contributes to poor adherence and increasing drug resistance. While the primary goal of vaccination is preventative, there is great value in investigating therapeutic potential, especially in infected people.
This new DNA-launched tuberculosis vaccine candidate (DNA-construct) is plasmid-based and encodes TB antigens along with parts of the SARS-CoV-2 virus as an adjuvant. Designed to avoid producing any infectious virus, it also includes safety features to prevent the DNA from causing cancer. With a good safety profile in animal models, this DNA-construct was tested as a vaccine and reduced the bacterial burden in Kramnik mice, resulting in low histopathology.
To mimic real-world scenarios, our parent study tests two DNA-constructs as a therapeutic in mice infected with a drug-resistant clinical TB isolate and on drug treatment. The mice are divided into five groups: a control/placebo group, a BCG vaccinated group, two groups receiving different versions of the new DNA-construct, and a non-coding construct control group. The study measures survival rates and bacterial load in the mice.
I aim to understand immune responses in each group by measuring anti-SARS-CoV-2 and anti-TB antibody levels and examining immune cell activity in the lungs and circulation. I will also investigate how B-cells might prime T-cells to respond to the therapeutic. The effectiveness of the new therapeutic will be compared to the BCG and control groups by correlating immune responses with bacterial load in the lungs. Similar correlations will be made using the human 3D granuloma biomimetic model in which the best construct will be tested, adding value to the DNA-construct's efficacy and validating the granuloma model for pre-clinical testing.
Find out more about Dr Robert Krause here.
