M. smegmatis vaccination reveals the mycobacterial ribosome as a potential CD4+ Tcell enhancing vaccine target

Abstract

Abstract Mycobacterium tuberculosis(Mtb) is an airborne pathogen that infects one third of the world’s population. To date no vaccine has had major success in reducing the enormous global burden of disease from this infection. Critical to the control of Mtb is the ability of a vaccine to induce a strong CD4+ Tcell response. The currently available vaccine, M. bovis BCG, is of limited efficacy, potentially due to its retention of immune evasion mechanisms that actively inhibit the host presentation of critical antigens to CD4+ Tcells. Examining antigens that are hidden during a BCG immunization may lead to identification of novel vaccine targets. Our lab has previously identified an M. smegmatis based vaccine, IKEPLUS, which elicits a strong CD4+ Tcell response leading to significantly enhanced protection to Mtb over BCG vaccination. M. smegmatis is a non-pathogenic mycobacterium that has not retained the ability to disrupt antigen presentation to the host immune system. Examination of the CD4+ Tcell response to IKEPLUS and BCG has identified the mycobacterial ribosome as a major immunogenic target in the M. smegmatis based IKEPLUS, but not in BCG. This dichotomy in the immune response led us to further characterize the ribosome and evaluate its protein constituents as potential vaccine targets. The ribosome is composed of 57 individual proteins; of these 57 proteins, we have identified 20 as immunogenic, and identified minimal CD4+ Tcell epitopes for 10 of the 20 identified proteins. These findings have led us to begin development of a mycobacterial ribosome based vaccine to enhance the currently existing BCG regimen. This approach will allow us to complement what we believe is a critical flaw of BCG while retaining the widely used BCG vaccination regimen.