title: Bacillus Calmette-Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses.
abstract: One third of the global population is estimated to be latently infected with Mycobacterium tuberculosis We performed a phase I randomized controlled trial of isoniazid preventive therapy (IPT) before revaccination with bacillus Calmette-Guérin (BCG) in healthy, tuberculin skin test-positive (≥15-mm induration), HIV-negative South African adults. We hypothesized that preclearance of latent bacilli with IPT modulates BCG immunogenicity following revaccination. Frequencies and coexpression of IFN-γ, TNF-α, IL-2, IL-17, and/or IL-22 in CD4 T cells and IFN-γ-expressing CD8 T, γδ T, CD3(+)CD56(+) NKT-like, and NK cells in response to BCG were measured using whole blood intracellular cytokine staining and flow cytometry. We analyzed 72 participants who were revaccinated with BCG after IPT (n = 33) or without prior IPT (n = 39). IPT had little effect on frequencies or cytokine coexpression patterns of M. tuberculosis- or BCG-specific responses. Revaccination transiently boosted BCG-specific Th1 cytokine-expressing CD4, CD8, and γδ T cells. Despite high frequencies of IFN-γ-expressing BCG-reactive CD3(+)CD56(+) NKT-like cells and CD3(-)CD56(dim) and CD3(-)CD56(hi) NK cells at baseline, BCG revaccination boosted these responses, which remained elevated up to 1 y after revaccination. Such BCG-reactive memory NK cells were induced by BCG vaccination in infants, whereas in vitro IFN-γ expression by NK cells upon BCG stimulation was dependent on IL-12 and IL-18. Our data suggest that isoniazid preclearance of M. tuberculosis bacilli has little effect on the magnitude, persistence, or functional attributes of lymphocyte responses boosted by BCG revaccination. Our study highlights the surprising durability of BCG-boosted memory NKT-like and NK cells expressing antimycobacterial effector molecules, which may be novel targets for tuberculosis vaccines.
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Sara
authors.initials: S
authors.lastname: Suliman
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Hennie
authors.initials: H
authors.lastname: Geldenhuys
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH, U.S.A.
authors.forename: John L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Hughes
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Erica
authors.initials: E
authors.lastname: Smit
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Melissa
authors.initials: M
authors.lastname: Murphy
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Asma
authors.initials: A
authors.lastname: Toefy
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Lesedi
authors.initials: L
authors.lastname: Lerumo
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Christiaan
authors.initials: C
authors.lastname: Hopley
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pienaar
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH, U.S.A.
authors.forename: Phalkun
authors.initials: P
authors.lastname: Chheng
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nemes
authors.affiliation: Division of Immunobiology, Departments of Internal Medicine and Molecular Biology, Saint Louis University Medical Center, and Center for Vaccine Development, Saint Louis, MO, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH, U.S.A.
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Mark
authors.initials: M
authors.lastname: Hatherill
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage*; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods*; D007538:Isoniazid / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000276:immunology*; D055985:Latent Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001500:BCG Vaccine; D007538:Isoniazid