TB: How to Accelerate the Development of New Vaccines against Old Diseases

[This article has been written by Adelaida Sarukhan, scientific writer at ISGlobal, with the collaboration of Alberto García-Basteiro, Associate Research Professor at ISGlobal and coordinator of the TB research unit at the CISM]

The COVID-19 pandemic has been a major setback in the fight against tuberculosis (TB) and other infectious diseases that mainly affect low-income countries: in 2020, the number of TB deaths increased for the first time in more than a decade. Therefore, if the international community is to reach the 2030 targets (reduce the number of new TB cases by 80% and the number of deaths by 90%), new tools are urgently needed, including more effective vaccines for children and adults.

There are currently several candidate TB vaccines in development, but the clinical trials needed to test their safety and efficacy are expensive, and the available resources are limited (in 2020, 113 times more money was spent on COVID-19 research than on TB research, even though the latter caused around 1.5 million deaths in that year alone). To make the best use of available resources it is therefore important to design clinical trials in a more intelligent and efficient manner. This is precisely what Alberto García-Basteiro and colleagues, as part of a group of experts, argue in a recent review in which they analyse the pros and cons of different possible strategies, and identify areas that require further research.

There are basically three strategies for testing the efficacy of a TB vaccine, depending at what moment of the disease’s natural history they are administered and the outcome they are intended to prevent:

1. Ability to prevent infection. Given that Mycobacterium tuberculosis infections are more frequent than disease episodes, this strategy has the advantage of requiring a smaller sample of participants and a shorter follow-up time to have results. By avoiding infection, potential disease would be avoided (it is estimated that 10% of those infected will develop disease in their lifetime). The difficulty lies in diagnosing the presence of viable bacteria in apparently healthy people. Infection is currently diagnosed by indirect methods that detect immune responses to the bacterium. The most specific test detects the production of a mediator (gamma interferon) by T-lymphocytes, but it does not detect all infections, and the result may vary over time, perhaps reflecting non-persistent infections.
2. Ability to prevent disease. In this case, the vaccine is administered to people exposed to the pathogen or already diagnosed with the infection, and the trial assesses how many of them go on to develop the disease. It is important to determine the type of samples and tests used to diagnose the disease (some are more sensitive but more laborious to perform in the field or at a large scale, some do not allow characterisation of the bacterial strain, some need to be performed more than once, and some do not allow diagnosis of extra-pulmonary forms of the disease). It is also important to define the objectives: to prevent disease in patients with clinical symptoms at an individual level or also to prevent subclinical disease (which occurs in patients who do not report symptoms, but present radiological and/or microbiological evidence of disease). Several studies (here and here) suggest that subclinical disease is prevalent and also plays an important role in transmission. Therefore, preventing subclinical TB may be something to consider in future clinical trials.
3. Ability to prevent disease recurrence. This type of trial, in which people are vaccinated during treatment, evaluates the efficacy of the vaccine in enhancing treatment efficacy and/or preventing disease recurrence or reinfections. This strategy allows for smaller and therefore less costly trials (it is common for treated patients to have new episodes of TB in the years following treatment). But it is important to define the optimal time to vaccinate (at the beginning or at the end of treatment) and to perform the necessary tests to differentiate recurrence (reactivation of the original TB episode that had not been fully cured) from reinfections.

We are entering a promising era with regard to the development of new vaccines against old diseases. However, making them a reality will depend on our ability to design more cost-effective and informative clinical trials, identifying the most relevant criteria/outcomes, and using the most appropriate diagnostic techniques.  

Reference

Alberto L. Garcia-Basteiro, Richard G. White, Dereck Tait, et al. End-point definition and trial design to advance tuberculosis vaccine development. Eur Respir Rev 2022; 31: 220044.