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Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination.

ABSTRACT: BCG vaccination can strengthen protection against pathogens through the induction of epigenetic and metabolic reprogramming of innate immune cells, a process called trained immunity. We and others recently demonstrated that mucosal or intravenous BCG better protects rhesus macaques from Mycobacterium tuberculosis infection and TB disease than standard intradermal vaccination, correlating with local adaptive immune signatures. In line with prior mouse data, here, we show in rhesus macaques that intravenous BCG enhances innate cytokine production associated with changes in H3K27 acetylation typical of trained immunity. Alternative delivery of BCG does not alter the cytokine production of unfractionated bronchial lavage cells. However, mucosal but not intradermal vaccination, either with BCG or the M. tuberculosis-derived candidate MTBVAC, enhances innate cytokine production by blood- and bone marrow-derived monocytes associated with metabolic rewiring, typical of trained immunity. These results provide support to strategies for improving TB vaccination and, more broadly, modulating innate immunity via mucosal surfaces.

SUBMITTER: Vierboom MPM

PROVIDER: S-EPMC7817864 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination.

Vierboom Michel P M MPM Dijkman Karin K Sombroek Claudia C CC Hofman Sam O SO Boot Charelle C Vervenne Richard A W RAW Haanstra Krista G KG van der Sande Maarten M van Emst Liesbeth L Domínguez-Andrés Jorge J Moorlag Simone J C F M SJCFM Kocken Clemens H M CHM Thole Jelle J Rodríguez Esteban E Puentes Eugenia E Martens Joost H A JHA van Crevel Reinout R Netea Mihai G MG Aguilo Nacho N Martin Carlos C Verreck Frank A W FAW

Cell reports. Medicine 20210119 1

BCG vaccination can strengthen protection against pathogens through the induction of epigenetic and metabolic reprogramming of innate immune cells, a process called trained immunity. We and others recently demonstrated that mucosal or intravenous BCG better protects rhesus macaques from <i>Mycobacterium tuberculosis</i> infection and TB disease than standard intradermal vaccination, correlating with local adaptive immune signatures. In line with prior mouse data, here, we show in rhesus macaques ...[more]

PMID: 33521699

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Project description:BACKGROUNDThe antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity.METHODSEighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age- and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG.RESULTSCompared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning- compared with evening-isolated monocytes.CONCLUSIONSBCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration.FUNDINGThe Netherlands Organization for Scientific Research, the European Research Council, and the Danish National Research Foundation.

Project description:Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies.ImportanceBCG remains the only licensed vaccine against TB. Parenterally administered BCG has variable efficacy against pulmonary TB, and thus, improved prevention strategies and a more refined understanding of correlates of vaccine protection are required. Induction of memory T cells has been shown to be essential for protective TB vaccines. Mimicking the natural infection route by mucosal vaccination has been known to generate superior protection against TB in animal models; however, the mechanisms of protection have remained elusive. Here we performed an in-depth analysis to dissect the immunological mechanisms associated with superior mucosal protection in the mouse model of TB. We found that mucosal, and not subcutaneous, BCG vaccination generates lung-resident memory T cell populations that confer protection against pulmonary TB. We establish a comprehensive phenotypic characterization of these populations, providing a framework for future vaccine development.

Dataset Information

Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination.

Publications

Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination.

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