Therapeutic vaccination and immune modulation -
new treatment strategies for the multidrug-resistant tuberculosis pandemic (TBCOX2 study)
Tuberculosis (TB) is a global challenge and for the increasing epidemic of multi-drug resistant (MDR)-TB there is restricted treatment options. The pro-inflammatory, but still immunosuppressive mediator prostaglandin E2 (PGE2) produced by cyclooxygenase-2 (COX-2) is increased in inflamed TB infected tissue. Mouse studies of acute intravenous TB infection have suggested a potential benefit of COX-inhibition as host-directed therapy (HDT). Therapeutic TB vaccines may also have potential as HDT and thus strengthen the immune response. We have tested the hypothesis that TB vaccines and COX-2 inhibiting drugs given separately and together to patients receiving standard TB therapy will improve the immune system and boost responses. This strategy can make the patient able to better fight the TB bacteria.
As part of this project, we published in 2019 data from a mouse model study of respiratory TB infection, performed in collaboration with our Danish partners (SSI). In contrast to our hypothesis, we show that COX-inhibiting treatment (ibuprofen and celecoxib) could be detrimental to TB control in the mice linked to impairments of the Type-1 helper T-cell responses. This could imply that the route of TB infection has relevance for the COX effect.
We finalised in 2019 a human phase 1 clinical intervention trial on the safety and immunogenicity of the therapeutic TB vaccine candidate H56:IC31 and a COX-2 inhibitor (etoricoxib) given to TB patients during 26-weeks of standard anti-TB chemotherapy in the period 2015-2019. A total of 40 TB patients were included from Oslo University Hospital, other hospitals in the region and from Haukeland University Hospital and randomized into four study arms (1. H56:IC31, 2. etoricoxib, 3. H56:IC31 + etoricoxib and 4. controls). Overall, safety was good for all interventions. Detailed laboratory analyses on stored blood samples from the patients show that the H56:IC31 vaccine administrated at two doses in active TB induced beneficial TB specific Type-1 helper T-cell responses. In contrast, COX-2 inhibitors din not seem to influence cellular immune regulation in human TB. Still, exploratory studies performed on material from the TBCOX2 project in collaboration with our South-African partners at Stellenbosch University show that COX-2 inhibitors may influence upon innate immunity presented by monocytes and myeloid derived suppressor cells. We report the first clinical data on therapeutic vaccination with H56:IC31 showing an good safety profile and vaccine responses, supporting development of this therapy. Although COX-2i appears to be safe in active TB, our data do not support COX-2i as adjunctive HDT or to improve TB vaccine responses.
We have ongoing in-depth studies of immune profiles and biosignatures for efficacy of treatment. These studies will be performed in collaboration with national and international partners, included in EU-funded Projects where OUS is partner (SU, IGTP, LUMC). The results will make us able to further optimize HDT strategies and prepare for larger clinical trials in collaboration with our partners. Thus, this project may contribute to new treatment options for MDR-TB.
Principal investigator: Anne Ma Dyrhol-Riise, Oslo University Hospital (OUS) and University of Oslo (UIO), Norway
Institutional partners:
Department for Infectious Diseases,OUS, Norway.
Institute of Clinical Medicine,UiO, Norway.
Statens Serum Institut (SSI),Copenhagen, Denmark.
Haukeland University Hospital,Bergen, Norway.
University of Bergen, Norway.
Stellenbosch University, immunology research group (SU), South Africa.
INSTITUT DINVESTIGACIÓ EN CIÈNCIES DE LA SALUT GERMANS TRIAS I PUJOL (IGTP), Barcelona, Spain.
ACADEMISCH ZIEKENHUIS LEIDEN (LUMC), Leiden, Netherlands.
This is the first-in-man clinical trial exploring the safety and immunogenicity of the therapeutic TB vaccine candidate H56:IC31 and COX-2i administrated to patients under standard therapy for active TB disease. Our results demonstrating a good safety profile and a therapeutic potential of the H56:IC31-vaccine will provide essential information for strategic decisions within vaccine development and clinical studies on HDT. The study also prepare the grounds for treatment shortening in both sensitive and multidrug resistant TB important for resource-poor countries. Although no evident safety issues were observed for etoricoxib we cant based on the immunogenicity data conclude if COX-2i has a role as HDT adjunctive to standard TB treatment. The collaboration in this project have led to local competence building, student exchange, technology transfer, and a new research network resulting in EU Horizon 2020 funding with Oslo University Hospital as partner.
Tuberculosis (TB) is a global challenge and for the increasing epidemic of multidrug-resistant (MDR)-TB there are restricted treatment options. This calls for research for new treatment strategies. This proposal is based on our translational research incl uding; (i) establishment of the prostaglandin E2 (PGE2)-cyclic AMP (cAMP)-pathway as a major inhibitor of antigen-specific activation causing T cell dysfunction in HIV-infection; (ii) three clinical trials demonstrating that cyclooxygenase-2 inhibitor (CO X-2i) reverses PGE2-cAMP mediated T cell dysfunction and improves vaccine responses in HIV-infected patients; (iii) pilot in vitro data indicating that COX-2i could block regulatory T cells in active TB patients and (iv) extensive preclinical, animal and clinical research on therapeutic TB vaccine candidates. These promising data open up for therapeutic TB vaccines and COX-2i in combination as new immune-modulating strategies to boost immunity in TB infection. Our hypothesis is that the increased producti on of PGE2 by COX-2 in TB-infected tissue seen in mice is a major contributor to the elevated cAMP with subsequent T cell dysfunction and immunosuppression also in human active TB. Thus, addition of COX-2i to anti-TB chemotherapy may improve immune-mediat ed eradication of TB and boost TB vaccine responses and thus offering new treatment modalities for patients with MDR-TB as well as open for shorter duration of standard TB treatment. The project will provide safety and efficacy data from a randomized clin ical trial of the therapeutic TB vaccine H56:IC and COX-2i alone and in combinations during conventional treatment of active TB. With clinical data and exploratory in-depth studies of immune regulatory mechanisms and correlates of protection in a parallel animal mouse model we will be able to further optimize the therapeutic strategy and prepare for future larger clinical efficacy trials in collaboration with our partners i low-middle income countries.