The international team describe in the August 2023 Lancet Microbe1 the benefits for introducing measures to determine transmission-reducing effects of new vaccines, but also the limitations of current technologies.
Little information about tuberculosis transmission
Seven promising tuberculosis candidates are currently in late-stage clinical trials. Although vaccine trials rightly establish the individual benefit, the standard design of these trials collect little information on the ability of the vaccines to prevent tuberculosis transmission. This is critical for understanding the indirect population-level impact of a vaccine programme on the future burden of disease.
The authors give the example of mRNA SARS-CoV-2 vaccines, which, although having similar efficacy in severe disease, vary widely in reducing viral loads and preventing transmission. Given two TB vaccines with similar efficacy, the one that reduces infectiousness would have a greater benefit.
Knowing this information would support decision-making, particularly in lower incidence countries where cost-effectiveness of a TB vaccine programme is uncertain. It would also support decisions over how to prioritise populations for vaccination and inform effective strategies to reduce the incidence quickly.
However, the authors point out significant limitations in conducting such assessments using current techniques. Specifically, they suggest that vaccine studies would need to evaluate either the infectiousness of cases that arise or determine the proportion of potentially infectious cases that are prevented. Methods for reliably measuring disease infectiousness are yet to be established, with techniques such as cough aerosol sampling, which measures expelled bacterial load, being resource intensive with limited background evidence to support policy development.
Actiphage offers a potential solution
A potential solution is to use a phage-based blood test that could identify disease progression at an early stage. This would create the opportunity to detect active infection within an unvaccinated population, such as household contacts before they develop transmissible disease.
M.tuberculosis (Mtb), the bacteria that causes TB, is controlled by the immune system within granulomas in the lungs that contain the infection. However, if the immune response is compromised the granulomas break down and bacteria can escape into the blood system and out of the lungs. Detecting low-level bacteraemia may therefore identify the first stages of disease progression and this is achievable using a bacteriophage specific to Mtb2.
Clinical trials with the phage-based diagnostic Actiphage have demonstrated efficacy detecting the presence of live Mtb in the blood of household contacts of pulmonary tuberculosis patients3. Using clinical, microbiological and imaging methods to confirm the endpoint, Actiphage was shown to identify those with active infection, and without treatment, at increased risk of developing potentially infectious active TB.
This demonstrates the potential for using phage-based diagnostics to assess the transmission-reducing effects of new vaccines.
A further clinical trial of Actiphage started on the 4th September 2023.
1 Measuring indirect transmission-reducing effects in tuberculosis vaccine efficacy trials: why and how? Lancet Microbe, Vol 4, August 2023. Kristin N Nelson, Gavin Churchyard, Frank Cobelens, Willem A Hanekom, Philip C Hill, Benjamin Lopman, Vidya Mave, Molebogeng X Rangaka, Johan Vekemans, Richard G White, Emily B Wong, Leonardo Martinez, Alberto L. García-Basteiro. https://doi.org/10.1016/S2666-5247(23)00112-X
2 Verma, R. et al, ‘A novel high sensitivity bacteriophage-based assay identifies low level M. tuberculosis bacteraemia in immunocompetent patients with active and incipient TB’, Clinical Infectious Diseases, ciz548
3 Jee Whang Kim et al, A novel bacteriophage-based assay stratifies tuberculosis risk in recent household contacts of pulmonary tuberculosis: A prospective observational cohort study
