Generation of an innovative Tuberculosis therapeutic vaccine – DC-TBVac

With an estimated 1.5 million deaths in 2020 according to the WHO Report 2021, Tuberculosis (TB) remains a major public health issue. On average, 5-10% of individuals exposed to Mycobacterium tuberculosis (Mtb) develop active TB disease, but the emergence of antibiotic resistance has made TB increasingly difficult to treat. Most Mtb-infected individuals remains asymptomatic, although displaying immune reactivity to Mtb, and either clears the pathogen or maintains a latent infection (LTBI). Therefore, there is an urgent need for an efficient therapeutic vaccine. Current “classic” strategies under development failed or are not optimal, and to reach the World Health Organization’s 2035 End TB Strategy, more efficacious vaccines and innovative strategies are needed.
The DC-TBVac project is based on the hypothesis that targeting selected Mtb protective antigens to dendritic cells (DC), key cells for antigen presentation playing a key role in inducing and regulating antigen-specific immunity, represents a potent and innovative therapeutic vaccine strategy to cure TB by inducing enhanced protective cellular immunity against Mtb.
We have already generated a first post-exposure/therapeutic TB vaccine candidate by targeting 3 pertinent Mtb antigens to a DC-specific receptor, namely CD40 (?CD40.TB), prone to induce strong anti-TB cellular immunity.
Thus, in the DC-TBVac project, we propose: i) to assess Mtb recall responses in different cohorts of TB patients after in vitro stimulation with the ?CD40.TB construct; ii) to evaluate and characterize ?CD40.TB vaccine immunogenicity in transgenic mice harboring human CD40 (hCD40Tg); and iii) to assess the efficacy of the therapeutic ?CD40.TB vaccine in vivo in mice and non-human primates.
The rationale behind this innovative vaccine development is strongly supported by a large set of data accumulated by our consortium and the long-standing experience of the teams gathered for this program in i) the best knowledge on the mechanisms of induction of specific immune responses centered on the targeting of DC; ii) our strong expertise and development of DC-based vaccines for other pathogens, including HIV in phase I clinical trial; iii) the expertise on preclinical models of pathogenic TB infection allowing the evaluation of the efficacy of our vaccine using the most appropriate and innovative tools such as in vivo imaging.
This project is highly feasible and all the tools are already available, including hCD40Tg mice which are actually in breeding at Inserm. The implementation of this project is made possible by bringing together 4 teams with complementary expertise and platforms (DC-targeting vaccine platform and transcriptomic at Inserm, mouse facilities at Inserm, mouse model of Mtb infection at Institut Pasteur, NHP facilities/in vivo imaging at IDMIT, availability of cohorts of TB patients and LTBI subjects at Inserm and at the National Center of Infectious and Parasitic Diseases in Bulgaria), as well as advice from a recognized expert in TB vaccination influent in several international TB consortia and member of the Research and Innovation panel of the TuBerculosis Vaccine Initiative.
Overall, this 3 year DC-TBVac project will deliver a new anti-TB therapeutic vaccine with the potential to improve TB patients’ health care. We are confident that the ?CD40.TB therapeutic vaccine will be a promising and safe alternative approach to help limiting both the risk of secondary transmission during treatment and anti-TB drug toxicity through a reduction in treatment duration, and overall, to prevent reactivation of TB disease in LTBI individuals. This vaccine strategy is totally in line with the attributes recommended by the WHO for new innovative TB vaccines.