TB Vaccine Candidates: How to Optimise Clinical Trials to Predict their Impact on the Population

Clinical trials of new TB vaccines could be optimised to assess the indirect protection conferred by such vaccines. This would help predict the impact of vaccine introduction at the population level and guide decision making. This is the main message of an opinion article published in The Lancet Microbe by a group of international experts in the field, led by Kristin Nelson (Emory University), Leo Martínez (Boston University) and Alberto García-Basteiro, researcher at ISGlobal. 

Tuberculosis remains the leading infectious killer. In 2021, it caused 1.6 million deaths and 10.6 million cases (up from 10.1 million cases the previous year, according to the WHO). New tools, including new vaccines, are needed to reverse this trend and achieve the goals of the END TB strategy. Seven vaccine candidates are currently in advanced clinical trials for use in adolescents and adults. Some are being tested to protect against infection, others to protect an infected person from developing the disease. 

"Clinical trials are typically designed to measure the individual benefit of vaccination, but they could be optimised to measure indirect effects at the population level. It would be a missed opportunity not to maximise the knowledge we can generate through vaccine efficacy trials," explains García-Basteiro. In addition to protecting the vaccinated, vaccination could indirectly protect the unvaccinated, either by reducing the number of people who become infected and can transmit the disease, or by reducing the infectiousness of those who are infected.

Knowing the effect of a new vaccine on disease transmission would help to guide decision making. Which vaccine to introduce? Which population should be vaccinated in priority? What is the expected impact on the population? What is the cost-benefit ratio?

Three possible approaches

The authors suggest three ways to optimise clinical trials to measure the potential indirect effect of a TB vaccine candidate:

1. Directly measure the infectivity of vaccinated or unvaccinated people who develop the disease. Although there are not yet reliable methods to measure the bacterial burden in TB patients, some proxy indicators can be used.
2. Measure the risk of transmission to close contacts in a subset of participants who develop the disease. For example, compare how many people in the household become infected depending on whether the patient is vaccinated or not.
3. Evaluate subclinical forms of infection that may contribute to transmission.

The authors also identify the knowledge gaps that need to be filled for such studies, such as developing reliable tests to measure infectiousness, or better understanding the risk of transmission by people with subclinical infections.

"The indirect protection conferred by a vaccine has enormous implications for estimating the overall impact of a vaccination programme," says García-Basteiro. "Having this information from the clinical phases will provide policy makers with the necessary evidence to make informed decisions about the introduction of new TB vaccines, at global and national levels," he adds.

Reference

Kristin N Nelson, Gavin Churchyard, Frank Cobelens, Willem A Hanekom, Philip G Hill, Benjamin Lopman, Vidya Mave, Molebogeng X Rangaka, Johan Vekemans, Richard G White, Emily B Wong, Leonardo Martinez, Alberto L García-Basteiro. Measuring indirect transmission-reducing effects in tuberculosis vaccine efficacy trials: why and how? The Lancet Microbe. 2023.  DOI:https://doi.org/10.1016/S2666-5247(23)00112-X