Abstract
Background
TB vaccine development is hampered by the natural history of M. tuberculosis: most infected people rarely progress to disease, so trials must be very large and long to accrue sufficient disease endpoints. Current trials enrol IGRA-positive participants (IGRA: Interferon-Gamma Release Assays), but IGRAs remain positive for many years and cannot distinguish recent from remote infection. Tests for recent infection are now in development, and we argue they could make trials substantially more efficient. Here, we investigate how screening participants prior to enrolment with a test for recent M.tb infection could impact the total number of enrollees required for an adequately-powered TB vaccine trial.
Methods
Using a statistical model of vaccine trial recruitment, we estimated the number needed to contact, test, and enrol to achieve an ‘effective’ trial (defined as 50 disease endpoints), under IGRA-gated enrolment (life-long duration of positivity) vs. enrolment with a test for recent infection. We considered five recruitment strategies: non-test-based enrolment for ages 15-49, ages 12-34, and household contacts of recent cases; and test-based enrolment using IGRA, and a test for recent infection with two-year duration of positivity. The model explored trial recruitment in South Africa, Kenya, and India.
Results
Compared with an extended-positivity test, a test for recent infection reduced the median number needed to enrol by 4.2- to 6-fold under favourable conditions. It also outperformed non-test-based strategies, including enrolling household contacts. This comes at the cost of substantially more testing, but crude estimates suggest recency-based enrolment would still be cheaper overall provided the new test does not cost more than roughly 5-10 times an IGRA.
Conclusions
Diagnostics for recent M.tb infection have the potential to improve vaccine trial efficiency, but more research is now needed to understand test characteristics and to evaluate their use in this setting. Our Viewpoint sets out the test attributes that would need to be established, such as time to positivity, duration of positivity, sensitivity, and specificity, before such tests could be used in vaccine trials.
Full Text
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