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Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

2013; American Thoracic Society; Volume: 188; Issue: 4 Linguagem: Inglês

10.1164/rccm.201208-1385oc

1535-4970

Cheryl L. Day, Michèle Tameris, Nazma Mansoor, Michele van Rooyen, Marwou de Kock, Hennie Geldenhuys, Mzwandile Erasmus, Lebohang Makhethe, E. Jane Hughes, Sebastian Gelderbloem, Anne Bollaerts, Patricia Bourguignon, Joe Cohen, Marie‐Ange Demoitié, Pascal Mettens, Philippe Moris, Jerald Sadoff, Anthony Hawkridge, Gregory Hussey, Hassan Mahomed, Opokua Ofori‐Anyinam, Willem A. Hanekom,

Immunotherapy and Immune Responses

Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines.Objectives: 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.Methods: 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.Measurements and Main Results: 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.Conclusions: 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).