Induction and Regulation of T Cell Immunity by the Novel TB Vaccine M72/AS01 in South African Adults
Abstract
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 BCG-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 following 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 the majority of 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, following vaccination. Specific T cell subsets were present at significantly higher frequencies following 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, following novel TB vaccination of Mtb-infected and uninfected individuals.
Citation
Day, C.L.; Tameris, M.; Mansoor, N.; van Rooyen, M.; de Kock, M.; Geldenhuys, H.; Erasmus, M.; Makhethe, L.; Hughes, E.J.; Gelderbloem, S.; Bollaerts, A.; Bourguignon, P.; Cohen, J.; Demoitié, M.A.; Mettens, P.; Moris, P.; Sadoff, J.C.; Hawkridge, A.; Hussey, G.D.; Mahomed, H.; Ofor-Anyinam, O.; Hanekom, W.A.i. Induction and Regulation of T Cell Immunity by the Novel TB Vaccine M72/AS01 in South African Adults. American Journal of Respiratory and Critical Care Medicine (2013) : [DOI: 10.1164/rccm.201208-1385OC]