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.

Conditions

• Tuberculosis

Interventions

DRUG

etoricoxib

cyclooxygenase-2 inhibitor. Anti-inflammatory

BIOLOGICAL

H56:IC31

Therapeutic and prophylactic TB vaccine

Sponsors & Collaborators

• University of Oslo

  collaborator OTHER

• Statens Serum Institut

  collaborator OTHER

• Haukeland University Hospital

  collaborator OTHER

• Anne Margarita Dyrhol Riise

  lead OTHER

Principal Investigators

• Anne Margarita Dyrhol-Riise, PhD · Oslo University Hospital

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-11-30

Primary Completion

2019-09-30

Completion

2020-03-23

Countries

• Norway

Study Locations