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

被引:94
作者
Day, Cheryl L. [1 ,2 ,3 ,4 ]
Tameris, Michele [1 ,2 ]
Mansoor, Nazma [1 ,2 ]
van Rooyen, Michele [1 ,2 ]
de Kock, Marwou [1 ,2 ]
Geldenhuys, Hennie [1 ,2 ]
Erasmus, Mzwandile [1 ,2 ]
Makhethe, Lebohang [1 ,2 ]
Hughes, E. Jane [1 ,2 ]
Gelderbloem, Sebastian [1 ,2 ]
Bollaerts, Anne [5 ]
Bourguignon, Patricia [5 ]
Cohen, Joe [5 ]
Demoitie, Marie-Ange [5 ]
Mettens, Pascal [5 ]
Moris, Philippe [5 ]
Sadoff, Jerald C. [6 ]
Hawkridge, Anthony [1 ,2 ]
Hussey, Gregory D. [1 ,2 ]
Mahomed, Hassan [1 ,2 ]
Ofori-Anyinam, Opokua [5 ]
Hanekom, Willem A. [1 ,2 ]
机构
[1] Univ Cape Town, South African TB Vaccine Initiat, ZA-7925 Observatory, South Africa
[2] Univ Cape Town, Inst Infect Dis & Mol Med, Sch Child & Adolescent Hlth, ZA-7925 Observatory, South Africa
[3] Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA
[4] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA
[5] GlaxoSmithKline Vaccines, Rixensart, Belgium
[6] Aeras Global TB Vaccine Fdn, Rockville, MD USA
基金
英国惠康基金;
关键词
tuberculosis; vaccine; T cell; cytokine; proliferation; MYCOBACTERIUM-TUBERCULOSIS; FOXP3; RESPONSES; BCG; IMMUNOGENICITY; EXPRESSION; PROTECTION; EFFECTOR; SAFETY; BLOOD;
D O I
10.1164/rccm.201208-1385OC
中图分类号
R4 [临床医学];
学科分类号
100218 [急诊医学];
摘要
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-Guerin-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).
引用
收藏
页码:492 / 502
页数:11
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