New Anti-Tuberculosis Vaccines
Dendritic cell-based anti-tuberculosis vaccines
Tech Area / Field
- BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
8 Project completed
Senior Project Manager
Gremyakova T A
Central Tuberculosis Research Institute, Russia, Moscow
- Institute of Immunological Engineering, Russia, Moscow reg., Lyubuchany
- Med Micro & Immuno, Texas A&M University, USA, TX, College Station\nUS Department of Health & Human Services / Food and Drug Administration / Center for Biologics Evaluation and Research, USA, MD, Bethesda
Project summaryThere is a well-defined public health requirment for improved vaccines against TB. First, the protective efficacy of BCG, the only anti-TB vaccine presently available, is controversial. Being able to confer some protection against initial challenge and thus against childhood TB, vaccination with BCG is insufficient to control pulmonary TB in adults. Second, BCG can cause a disseminated infection in immunocompromised inpiduals and its use is not recommended when there is evidence of HIV-positivity. Third, among immunogenic components of BCG vaccine some are able to abrogate protective host responses.
There is no clear rationale at this stage for design of the most appropriate TB vaccine candidates, hence, virtually all possible types of vaccines are being tested: modified BCG vaccines, attenuated strains of M. tuberculosis, non-pathogenic mycobacteria transfected with genes encoding defined mycobacterial proteins, non-mycobacterial living vaccines, subunit vaccines, naked DNA vaccines. Considerations related to safety, manufacture and distribution all point to a preference for non-living subunit vaccines eliciting protective response which can be immunologically characterized in order to define correlates of protection. For good performance subunit protein vaccines must be given with potent adjuvants that are strictly prohibited for the use in humans because of their high reactogenicity. One of the most attractive alternative approaches to induce anti-TB immunity in the absence of harmful adjuvants is immunization with dendritic cells (DCs), enriched and activated in in vitro cultures in the presence of GM-CSF,G-CSF,IL-4,TNF-б and pulsed with mycobacterial antigens.
The goal of this project is to develop and to test in our experimental murine TB model a novel type of anti-TB vaccines, namely, dendritic cell-based vaccines. DCs will be obtained by the well-defined cultural approaches. Mycobacterial antigens will be chosen from the set of short-term cultural filtrate proteins, some of which (e. g., MPT59 and ESAT6) in our preliminary experiments have shown an exceptionally good protective efficacy being injected into murine host as mixtures with an adjuvant. To obtain new knowledge concerning dependence of vaccination efficacy upon genetically determined susceptibility to TB, we intend to use in vaccination experiments inbred mouse strains which differ prominently either by the level of resistance to TB-triggerred disease or by the ability to elicite protective response following BCG vaccination. Mouse strains representing polar extremes in TB susceptibility and BCG-non-protected strains were previously discovered in our lab among a wide panel of inbred mouse strains tested. Parameters of anti-TB immunity and efficacy of DC-based vaccines will be assessed after injecting antigen-loaded DC into syngenic recipient followed by M. tuberculosis H37Rv intratracheal challenge. We intend to assess several parameters of antigen-specific immune response following vaccination with DCs: serum IgG subclasses, as well as IFN-g, TNF-a, IL-4, IL-5, IL-10 and IL-12 production in vitro by lymphoid cells in response to PPD. Following M. tuberculosis H37Rv challenge, "DC + antigen"-vaccinated and control mice will be studied with respect to dynamics of mycobacterial multiplication in lungs and spleens, mean survival time, DTH response to PPD and cytokine profiles. Animals "vaccinated" with non-loaded DCs and BCG-vaccinated animals will serve as negative and positive controls, respectively.
The aim of the project: To develop dendritic cell-based protective vaccines in the murine model of tuberculosis, to assess parameters of antimycobacterial immune responses elicited by these vaccines and to compare the degree of protection conferred by these vaccines in mouse strains displaying prominent genetic differences in response to mycobacteria.