Novel Mechanisms of Mycobacterium tuberculosis-based vaccines
Sangeeta Tiwaria 1, ¶, Taru S. Duttd,¶, Bing Chenb, Mei Chenb, John Kimb, Annie Zhi Daib, Regy Lukoseb, Crystal Shanleyd, Amy Foxd, Burton R. Kargerd, Steven A. Porcellib,c, John Chanc, Brendan K. Podelld, Andres Obregon-Henaod, Ian M. Ormed, William R. Jacobs, Jr.b,1,& and Marcela Henao-Tamayod,1,
a Department of Biological Sciences & Border Biomedical Research Center, University of Texas at El Paso, El Paso, Texas 79968.; b Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
c Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; d Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523;
BCG, only FDA-approved prevents disseminated forms of childhood tuberculosis (TB), but it does not protect against adult pulmonary infection. BCG contains a deletion in the Esx-1 region, a type seven secretion system (T7SS), involved in pathogenesis of mycobacteria by secretion of virulence effectors thus a major cause of attenuation of BCG. Mtb encodes five specialized T7SS, Esx1-5 and interestingly, Esx-5 is exclusively found in slow growing, pathogenic mycobacteria including clinical strains of Mtb. In fish pathogen M. marinum, Esx-5 is involved in secretion of the majority of the three large families of effector proteins Pro- Glu (PE), Pro-Pro-Glu (PPE) and PGRS proteins that have immunogenic T and B cell epitopes and have been implicated in immune evasion and virulence, immune suppression of the host.Therefore, we have generated a complete deletion mutant (encompassing 17 genes) of the Mtb Esx-5 type VII secretion system (Mtb Δesx-5) to enhance safety and inhibit the revertant’s of Mtb. We have demonstrated that Mtb Δesx-5 was highly attenuated and safe in immunocompromised mice. As most of the people in the world already are immunized with BCG we furthertested Mtb Δesx-5 as a vaccine candidate to boost BCG-primed immunity. Interestingly, boosting with MtbΔesx-5 showed improved protection against highly virulent Mtb strains in the murine and guinea pig models of TB. Furthermore, enhanced protection provided by heterologous BCG-prime plus Mtb Δesx-5 boost regimenwas associated with increased pulmonary influx of central memory T cells (TCM), follicular helper T cells (TFH) and activated monocytes. Conversely, we have observed lower numbers of T cells expressing exhaustion markers in vaccinated animals. Our results suggest that boosting BCG-primed immunity with Mtb Δesx-5 is a potential approach to improve protective immunity against Mtb. Additionally; we are looking into the mechanism of action of this novel prime-boost approach and role of Mtb Δesx-5 in pathogenesis of Mtb.