STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

Erik Van Dis; Kimberly M Sogi; Chris S Rae; Kelsey E Sivick; Natalie H Surh; Meredith L Leong; David B Kanne; Ken Metchette; Justin J Leong; Jacob R Bruml; Vivian Chen; Kartoosh Heydari; Nathalie Cadieux; Tom Evans; Sarah M McWhirter; Thomas W Dubensky Jr; Daniel A Portnoy; Sarah A Stanley

doi:10.1016/j.celrep.2018.04.003

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

Cell Rep. 2018 May 1;23(5):1435-1447. doi: 10.1016/j.celrep.2018.04.003.

Authors

Erik Van Dis¹, Kimberly M Sogi², Chris S Rae³, Kelsey E Sivick³, Natalie H Surh³, Meredith L Leong³, David B Kanne³, Ken Metchette³, Justin J Leong³, Jacob R Bruml³, Vivian Chen², Kartoosh Heydari⁴, Nathalie Cadieux⁵, Tom Evans⁶, Sarah M McWhirter³, Thomas W Dubensky Jr³, Daniel A Portnoy⁷, Sarah A Stanley⁸

Affiliations

¹ Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, CA 94720, USA.
² School of Public Health, Division of Infectious Disease and Vaccinology, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Aduro Biotech, Inc., 740 Heinz Avenue, Berkeley, CA 94710, USA.
⁴ LKS Flow Cytometry Core, Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Aeras, 1405 Research Blvd., Rockville, MD 20850, USA.
⁶ Vaccitech Limited, King Charles House, Park End Street, Oxford OX1 1JD, UK.
⁷ Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, CA 94720, USA; School of Public Health, Division of Infectious Disease and Vaccinology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁸ Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, CA 94720, USA; School of Public Health, Division of Infectious Disease and Vaccinology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: sastanley@berkeley.edu.

Abstract

There are a limited number of adjuvants that elicit effective cell-based immunity required for protection against intracellular bacterial pathogens. Here, we report that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. Subcutaneous administration of this vaccine provides equivalent protection to that of the live attenuated vaccine strain Bacille Calmette-Guérin (BCG). Protection is STING dependent but type I IFN independent and correlates with an increased frequency of a recently described subset of CXCR3-expressing T cells that localize to the lung parenchyma. Intranasal delivery results in superior protection compared with BCG, significantly boosts BCG-based immunity, and elicits both Th1 and Th17 immune responses, the latter of which correlates with enhanced protection. Thus, a CDN-adjuvanted protein subunit vaccine has the capability of eliciting a multi-faceted immune response that results in protection from infection by an intracellular pathogen.

Keywords: Mycobacterium tuberculosis; Th17; cyclic dinucleotides; vaccine adjuvant.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adjuvants, Immunologic / pharmacology*
Animals
BCG Vaccine / immunology
BCG Vaccine / pharmacology*
Disease Models, Animal
Immunity, Cellular / drug effects
Membrane Proteins / immunology*
Mice
Mice, Knockout
Mycobacterium tuberculosis / immunology*
Th1 Cells / immunology
Th1 Cells / pathology
Th17 Cells / immunology*
Th17 Cells / pathology
Tuberculosis, Pulmonary / immunology
Tuberculosis, Pulmonary / pathology
Tuberculosis, Pulmonary / prevention & control*
Vaccines, Subunit / immunology
Vaccines, Subunit / pharmacokinetics

Substances

Adjuvants, Immunologic
BCG Vaccine
Membrane Proteins
Sting1 protein, mouse
Vaccines, Subunit

Abstract

Publication types

MeSH terms

Substances

Grants and funding