title: Induction and regulation of T-cell immunity by the novel tuberculosis vaccine M72/AS01 in South African adults.
abstract: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines.
  
  
  
  We investigated a novel TB vaccine candidate, M72/AS01, in a phase IIa trial of bacille Calmette-Guérin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa.
  
  
  
  Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry.
  
  
  
  The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67(+) T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants.
  
  
  
  M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals.
  
  
  
  Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).
authors.affiliation: South African Tuberculosis Vaccine Initiative and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.forename: Michele
authors.initials: M
authors.lastname: Tameris
authors.forename: Nazma
authors.initials: N
authors.lastname: Mansoor
authors.forename: Michele
authors.initials: M
authors.lastname: van Rooyen
authors.forename: Marwou
authors.initials: M
authors.lastname: de Kock
authors.forename: Hennie
authors.initials: H
authors.lastname: Geldenhuys
authors.forename: Mzwandile
authors.initials: M
authors.lastname: Erasmus
authors.forename: Lebohang
authors.initials: L
authors.lastname: Makhethe
authors.forename: E Jane
authors.initials: EJ
authors.lastname: Hughes
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gelderbloem
authors.forename: Anne
authors.initials: A
authors.lastname: Bollaerts
authors.forename: Patricia
authors.initials: P
authors.lastname: Bourguignon
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Demoitié
authors.forename: Pascal
authors.initials: P
authors.lastname: Mettens
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Jerald C
authors.initials: JC
authors.lastname: Sadoff
authors.forename: Anthony
authors.initials: A
authors.lastname: Hawkridge
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Hussey
authors.forename: Hassan
authors.initials: H
authors.lastname: Mahomed
authors.forename: Opokua
authors.initials: O
authors.lastname: Ofori-Anyinam
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
mesh_terms: D000328:Adult; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D013019:South Africa; D013601:T-Lymphocytes / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology*; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D020381:Interleukin-17; D032581:Tuberculosis Vaccines