BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis

Sangeeta Tiwari; Taru S. Dutt; Bing Chen; Mei Chen; John Kim; Annie Zhi Dai; Regy Lukose; Crystal Shanley; Amy Fox; Burton R. Karger; Steven A. Porcelli; John Chan; Brendan K. Podell; Andres Obregon-Henao; Ian M. Orme; William R. Jacobs; Marcela Henao-Tamayo

doi:10.1016/j.vaccine.2020.08.004

BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis

Sangeeta Tiwari, Taru S. Dutt, Bing Chen, Mei Chen, John Kim, Annie Zhi Dai, Regy Lukose, Crystal Shanley, Amy Fox, Burton R. Karger, Steven A. Porcelli, John Chan, Brendan K. Podell, Andres Obregon-Henao, Ian M. Orme, William R. Jacobs, Marcela Henao-Tamayo

Research output: Contribution to journal › Article › peer-review

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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 (T_CM), follicular helper T cells (T_FH) 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.

Original language	English (US)
Pages (from-to)	7156-7165
Number of pages	10
Journal	Vaccine
Volume	38
Issue number	45
DOIs	https://doi.org/10.1016/j.vaccine.2020.08.004
State	Published - Oct 21 2020

Keywords

Esx secretion system
Live-attenuated vaccine
Mycobacteria
Tuberculosis

ASJC Scopus subject areas

Molecular Medicine
General Immunology and Microbiology
General Veterinary
Public Health, Environmental and Occupational Health
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.vaccine.2020.08.004

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Tiwari, S., Dutt, T. S., Chen, B., Chen, M., Kim, J., Dai, A. Z., Lukose, R., Shanley, C., Fox, A., Karger, B. R., Porcelli, S. A., Chan, J., Podell, B. K., Obregon-Henao, A., Orme, I. M., Jacobs, W. R., & Henao-Tamayo, M. (2020). BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis. Vaccine, 38(45), 7156-7165. https://doi.org/10.1016/j.vaccine.2020.08.004

Tiwari, S, Dutt, TS, Chen, B, Chen, M, Kim, J, Dai, AZ, Lukose, R, Shanley, C, Fox, A, Karger, BR, Porcelli, SA, Chan, J, Podell, BK, Obregon-Henao, A, Orme, IM, Jacobs, WR & Henao-Tamayo, M 2020, 'BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis', Vaccine, vol. 38, no. 45, pp. 7156-7165. https://doi.org/10.1016/j.vaccine.2020.08.004

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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",

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doi = "10.1016/j.vaccine.2020.08.004",

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AU - Tiwari, Sangeeta

AU - Dutt, Taru S.

AU - Chen, Bing

AU - Chen, Mei

AU - Kim, John

AU - Dai, Annie Zhi

AU - Lukose, Regy

AU - Shanley, Crystal

AU - Fox, Amy

AU - Karger, Burton R.

AU - Porcelli, Steven A.

AU - Chan, John

AU - Podell, Brendan K.

AU - Obregon-Henao, Andres

AU - Orme, Ian M.

AU - Jacobs, William R.

AU - Henao-Tamayo, Marcela

PY - 2020/10/21

Y1 - 2020/10/21

N2 - 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.

AB - 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.

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KW - Mycobacteria

KW - Tuberculosis

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BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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