@article{954ce9be67f44198a10ec390e4a423ba,
title = "BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis",
abstract = "Although vaccination with BCG prevents disseminated forms of childhood tuberculosis (TB), it does not protect against pulmonary infection or Mycobacterium tuberculosis (Mtb) transmission. In this study, we generated a complete deletion mutant of the Mtb Esx-5 type VII secretion system (Mtb Δesx-5). Mtb Δesx-5 was highly attenuated and safe in immunocompromised mice. When tested as a vaccine candidate to boost BCG-primed immunity, Mtb Δesx-5 improved protection against highly virulent Mtb strains in the murine and guinea pig models of TB. Enhanced protection provided by heterologous BCG-prime plus Mtb Δesx-5 boost regimen was associated with increased pulmonary influx of central memory T cells (TCM), follicular helper T cells (TFH) and activated monocytes. Conversely, lower numbers of T cells expressing exhaustion markers were observed 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. Further insight into the mechanism of action of this novel prime-boost approach is warranted.",
keywords = "Esx secretion system, Live-attenuated vaccine, Mycobacteria, Tuberculosis",
author = "Sangeeta Tiwari and Dutt, {Taru S.} and Bing Chen and Mei Chen and John Kim and Dai, {Annie Zhi} and Regy Lukose and Crystal Shanley and Amy Fox and Karger, {Burton R.} and Porcelli, {Steven A.} and John Chan and Podell, {Brendan K.} and Andres Obregon-Henao and Orme, {Ian M.} and Jacobs, {William R.} and Marcela Henao-Tamayo",
note = "Funding Information: This study was funded by NIH fund numbers RO1AI127475-01A1 and 1R21AI121099-01A1, RO1AI026170, R21AI141088. Funding Information: We dedicate this work to the memory of Ian Orme, who played a major role in the initiation of these studies and provided a source of inspiration and leadership to a generation of TB researchers. We thank the Colorado State University Flow Cytometry Core Facility staff for expert technical guidance, Keely Redhage for her help with manuscript preparation and Brian Weinrick for assisting with Illumina sequencing. This study was funded by NIH fund numbers RO1AI127475-01A1 and 1R21AI121099-01A1, RO1AI026170, R21AI141088. ST, MHT and WRJ conceived and planned the study. ST, TSD, AOH, BC, MC, JK, AZD, RL, CS, IO, AF, BRK and BKP performed experiments. ST, MHT, SAP, JC, TSD, IO and WRJ analyzed and interpreted the data. BKP and IO obtained as well as analyzed histology and pathology results. ST, TSD, AOH, MHT, SAP, SP, JC and WRJ wrote and edited the paper. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = oct,
day = "21",
doi = "10.1016/j.vaccine.2020.08.004",
language = "English (US)",
volume = "38",
pages = "7156--7165",
journal = "Vaccine",
issn = "0264-410X",
publisher = "Elsevier BV",
number = "45",
}
