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Review
. 2022 Jun 7;31(164):220044.
doi: 10.1183/16000617.0044-2022. Print 2022 Jun 30.

End-point definition and trial design to advance tuberculosis vaccine development

Alberto L Garcia-Basteiro  1   2   3 , Richard G White  4 , Dereck Tait  5 , Alexander C Schmidt  6 , Molebogeng X Rangaka  7   8 , Matthew Quaife  4 , Elisa Nemes  9 , Robin Mogg  10 , Philip C Hill  11 , Rebecca C Harris  4   12 , Willem A Hanekom  13   14 , Mike Frick  15 , Andrew Fiore-Gartland  16 , Tom Evans  17 , Alemnew F Dagnew  6 , Gavin Churchyard  18   19   20 , Frank Cobelens  21 , Marcel A Behr  22 , Mark Hatherill  9
Affiliations
Review

End-point definition and trial design to advance tuberculosis vaccine development

Alberto L Garcia-Basteiro et al. Eur Respir Rev. .

Abstract

Tuberculosis (TB) remains a leading infectious cause of death worldwide and the coronavirus disease 2019 pandemic has negatively impacted the global TB burden of disease indicators. If the targets of TB mortality and incidence reduction set by the international community are to be met, new more effective adult and adolescent TB vaccines are urgently needed. There are several new vaccine candidates at different stages of clinical development. Given the limited funding for vaccine development, it is crucial that trial designs are as efficient as possible. Prevention of infection (POI) approaches offer an attractive opportunity to accelerate new candidate vaccines to advance into large and expensive prevention of disease (POD) efficacy trials. However, POI approaches are limited by imperfect current tools to measure Mycobacterium tuberculosis infection end-points. POD trials need to carefully consider the type and number of microbiological tests that define TB disease and, if efficacy against subclinical (asymptomatic) TB disease is to be tested, POD trials need to explore how best to define and measure this form of TB. Prevention of recurrence trials are an alternative approach to generate proof of concept for efficacy, but optimal timing of vaccination relative to treatment must still be explored. Novel and efficient approaches to efficacy trial design, in addition to an increasing number of candidates entering phase 2-3 trials, would accelerate the long-standing quest for a new TB vaccine.

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Conflict of interest statement

Conflict of interest: D. Tait is a salaried employee IAVI NPC. E. Nemes has received grants or contracts from US National Institutes of Health, Bill and Melinda Gates Foundation and Gates Medical Research Institute, outside the submitted work. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: “TB immune correlates” Leadership Team. Conflict of interest: R. Mogg advises that support for the present manuscript has been received from Bill and Melinda Gates, for which they are currently an employee. Consulting fees received from PMV Pharma, Autobahn Therapeutics, Asher Biotherapeutics, Inc., and Bill and Melinda Gates Foundation, outside the submitted work. Unpaid participation on a Data Safety Monitoring Board or Advisory Board for COnV-ert DSMB, outside the submitted work. Stock or stock options held for Takeda, outside the submitted work. Conflict of interest: R.C. Harris is current employee of Sanofi Pasteur. Shares held for Sanofi Pasteur, outside the submitted work. Conflict of interest: A. Fiore-Gartland reports support for the present manuscript received from Bill and Melinda Gates Foundation, grant-based funding for Vaccines and Immunology Statistical Center. Conflict of interest: T. Evans has received consulting fees from Vir Biotechnology, outside the submitted work. Participation on an advisory board to GHIF on a recombinant BCG project run by Serum Institute of India, outside the submitted work. Conflict of interest: A.F Dagnew is a current employee of the Bill and Melinda Gates Medical Research Institute. Conflict of interest: F. Cobelens has received grants or contracts from EDCTP and the Bill and Melinda Gates Foundation, outside the submitted work. Support for attending meetings and/or travel received from Tuberculosis Vaccine Initiative, outside the submitted work. Participation on a Data Safety Monitoring Board or Advisory Board for Tuberculosis Vaccine Initiative and EDCTP Tuberculosis Vaccine Oversight Committee, outside the submitted work. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Coalition for TB Vaccine Discovery, Bill and Melinda Gates Foundation. Conflict of interest: M.A. Behr has received grants or contracts from Canadian Institutes for Health Research (Foundation Grant) and Canada Research Chair, outside the submitted work. Patents planned, issued or pending: Molecular differences between species of the M. tuberculosis complex Grant US-7364740-B2. Priority date 1998/08/25. Participated on the Endpoint Committee of RCT comparing 9 INH to 4 Rif (Menzies, NEJM, 2018). Conflict of interest: M. Hatherill reports institutional clinical trial grants to University of Cape Town, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Vaccine strategies along the natural history of tuberculosis (TB), according to the expected effect. Vaccines developed with the strategy to prevent infection (POI) are mostly targeted for populations not yet exposed to Mycobacterium tuberculosis (i.e. pre-infection). Vaccines developed for prevention of disease (POD) could be useful if administered post- or pre-TB infection to prevent development of symptomatic disease. Therapeutic vaccines could have effects both in treatment-shortening and/or prevention of recurrence. Vaccines primarily developed for a prevention of recurrence (POR) strategy could be given with the aim of prevention of either re-infection or recurrence of disease (true relapse).
FIGURE 2
FIGURE 2
Hypothesised interferon gamma (IFN-γ) release assay (IGRA) dynamics after vaccination with a prevention of infection candidate. QuantiFERON-TB (QFT) negative participants receiving vaccine or placebo. Rates of acquisition of Mycobacterium tuberculosis infection (QFT conversion), established infection (sustained QFT conversion through 6 months post conversion) and transient infection (QFT reversion within 6 months post conversion) are compared between the study arms. Participants with sustained QFT conversion and QFT >4 IU·mL−1 are considered at higher risk of tuberculosis compared to non-converters and reverters. The dotted line represents the standard QFT cut-off at 0.35 IU·mL−1.
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References

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