High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation

Laura Sibley; Andrew White; Karen Gooch; Lisa M. Stevens; Rachel Tanner; Ashley Jacobs; Owen Daykin-Pont; Fergus Gleeson; Anthony McIntyre; Randall Basaraba; Simon Clark; Graham Hall; Geoff Pearson; Emma Rayner; Helen McShane; Ann Williams; Mike Dennis; Phillip Marsh; Sally Sharpe

doi:10.1038/s41598-021-90913-0

High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation

Laura Sibley^*, Andrew White, Karen Gooch, Lisa M. Stevens, Rachel Tanner, Ashley Jacobs, Owen Daykin-Pont, Fergus Gleeson, Anthony McIntyre, Randall Basaraba, Simon Clark, Graham Hall, Geoff Pearson, Emma Rayner, Helen McShane, Ann Williams, Mike Dennis, Phillip Marsh, Sally Sharpe

^*Corresponding author for this work

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

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Abstract

This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

Original language	English
Article number	12274
Number of pages	14
Journal	Scientific Reports
Volume	11
Issue number	1
Early online date	10 Jun 2021
DOIs	https://doi.org/10.1038/s41598-021-90913-0
Publication status	Published - 10 Jun 2021

Bibliographical note

Funding Information: This work was supported by the Department of Health, UK. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. We thank the staff of the Biological Investigations Group at PHE Porton and the PHE macaque colonies for assistance in conducting studies; Dominic Kelly for bacteriology and aerobiology support and Kim Hatch and Laura Hunter for histology support.

Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Publisher Copyright: © 2021, The Author(s).

Citation: Sibley, L., White, A.D., Gooch, K.E. et al. High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation. Sci Rep 11, 12274 (2021).

DOI: https://doi.org/10.1038/s41598-021-90913-0

Keywords

NONHUMAN PRIMATE MODEL
T-CELLS CORRELATE
RHESUS MACAQUES
INFECTION
MEMORY
PREVENTION
METAANALYSIS
LYMPHOCYTES
RESEMBLES
DELIVERY

UN SDGs

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

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Sibley2021High-DoseMycobacteriumTuberculosisAerosolSciRepFinal published version, 2.22 MBLicence: CC BY

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Sibley, L., White, A., Gooch, K., Stevens, L. M., Tanner, R., Jacobs, A., Daykin-Pont, O., Gleeson, F., McIntyre, A., Basaraba, R., Clark, S., Hall, G., Pearson, G., Rayner, E., McShane, H., Williams, A., Dennis, M., Marsh, P., & Sharpe, S. (2021). High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation. Scientific Reports, 11(1), Article 12274. https://doi.org/10.1038/s41598-021-90913-0

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abstract = "This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.",

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author = "Laura Sibley and Andrew White and Karen Gooch and Stevens, {Lisa M.} and Rachel Tanner and Ashley Jacobs and Owen Daykin-Pont and Fergus Gleeson and Anthony McIntyre and Randall Basaraba and Simon Clark and Graham Hall and Geoff Pearson and Emma Rayner and Helen McShane and Ann Williams and Mike Dennis and Phillip Marsh and Sally Sharpe",

note = "Funding Information: This work was supported by the Department of Health, UK. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. We thank the staff of the Biological Investigations Group at PHE Porton and the PHE macaque colonies for assistance in conducting studies; Dominic Kelly for bacteriology and aerobiology support and Kim Hatch and Laura Hunter for histology support. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Publisher Copyright: {\textcopyright} 2021, The Author(s). Citation: Sibley, L., White, A.D., Gooch, K.E. et al. High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation. Sci Rep 11, 12274 (2021). DOI: https://doi.org/10.1038/s41598-021-90913-0",

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Sibley, L, White, A , Gooch, K, Stevens, LM, Tanner, R, Jacobs, A, Daykin-Pont, O, Gleeson, F, McIntyre, A, Basaraba, R, Clark, S, Hall, G, Pearson, G, Rayner, E, McShane, H, Williams, A, Dennis, M, Marsh, P & Sharpe, S 2021, 'High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation', Scientific Reports, vol. 11, no. 1, 12274. https://doi.org/10.1038/s41598-021-90913-0

High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation. / Sibley, Laura; White, Andrew ; Gooch, Karen et al.
In: Scientific Reports, Vol. 11, No. 1, 12274, 10.06.2021.

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

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KW - LYMPHOCYTES

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High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation

Abstract

Bibliographical note

Keywords

UN SDGs

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