Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the MDR Tuberculosis Pandemic

Summary

Tuberculosis (TB) is a global challenge and for the increasing epidemic of multi-drug resistant (MDR)-TB there is restricted treatment options. This calls for research of new immune-modulating treatment strategies that can strengthen the patients immune system to better fight the TB bacteria. The pro-inflammatory, but still immunosuppressive mediator prostaglandin E2 (PGE2) is produced by cyclooxygenase-2 (COX-2) in inflamed infected tissue. Studies from both human and animal models show that COX-2 inhibitors (COX-2i) can improve the immune system and strengthen vaccines responses. Hypothesis 1. A hyperactive COX-2/PGE2 signal system in active TB causes down-regulated immune responses that favour TB survival, but this can be abrogated by COX-2i. 2. TB-specific immunisation with targeted antigens presented as a therapeutic TB vaccine and enhanced by COX-2i will improve immune-mediated host clearance of TB. 3. Combinations of COX-2i and a therapeutic TB vaccine to conventional anti-TB chemotherapy offer new treatment modalities for TB, including MDR/XDR-TB. Approach to test the hypothesis 1. Study design: 4-arm, open and randomized clinical intervention trial of patients starting treatment for active TB in specialized Norwegian TB centres and where two arms will receive the COX-2i etoricoxib with and without a TB vaccine, one arm vaccine only and the last arm serve as control receiving only standard anti-TB therapy. For safety precautions, only patients bearing sensitive TB strains are included and study arms will be sequentially introduced. 2. In a mouse model examine in more detail the effects of reversion of chronic inflammation with COX-2i locally in tissue and the interplay with TB vaccine responses, immune regulation, correlates of protection and survival in a well-characterized model for TB-exposed mice.

Timeline

Start

2015-11

Primary completion

2019-09

Completion

2020-03-23

Publications

• Nore KG, Louet C, Bugge M, Gidon A, Jorgensen MJ, Jenum S, Dyrhol-Riise AM, Tonby K, Flo TH. The Cyclooxygenase 2 Inhibitor Etoricoxib as Adjunctive Therapy in Tuberculosis Impairs Macrophage Control of Mycobacterial Growth. J Infect Dis. 2024 Mar 14;229(3):888-897. doi: 10.1093/infdis/jiad390.
• Jenum S, Tonby K, Rueegg CS, Ruhwald M, Kristiansen MP, Bang P, Olsen IC, Sellaeg K, Rostad K, Mustafa T, Tasken K, Kvale D, Mortensen R, Dyrhol-Riise AM. A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients. Nat Commun. 2021 Nov 22;12(1):6774. doi: 10.1038/s41467-021-27029-6.
• Tonby K, Mortensen R, Ruhwald M, Dyrhol-Riise AM, Jenum S. KLRG1-Expressing CD4 T Cells Are Reduced in Tuberculosis Patients Compared to Healthy Mycobacterium tuberculosis-Infected Subjects, but Increase With Treatment. J Infect Dis. 2019 Jun 5;220(1):174-176. doi: 10.1093/infdis/jiz056. No abstract available.

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Indications