title: A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults.
abstract: Human immunodeficiency virus (HIV)-associated tuberculosis is a major public health threat. We evaluated the safety and immunogenicity of the candidate tuberculosis vaccine M72/AS01 in HIV-positive and HIV-negative Indian adults.Randomized, controlled observer-blind trial (NCT01262976).We assigned 240 adults (1:1:1) to antiretroviral therapy (ART)-stable, ART-naive, or HIV-negative cohorts. Cohorts were randomized 1:1 to receive M72/AS01 or placebo following a 0, 1-month schedule and followed for 12 months (time-point M13). HIV-specific and laboratory safety parameters, adverse events (AEs), and M72-specific T-cell-mediated and humoral responses were evaluated.Subjects were predominantly QuantiFERON-negative (60%) and Bacille Calmette-Guérin-vaccinated (73%). Seventy ART-stable, 73 ART-naive, and 60 HIV-negative subjects completed year 1. No vaccine-related serious AEs or ART-regimen adjustments, or clinically relevant effects on laboratory parameters, HIV-1 viral loads or CD4 counts were recorded. Two ART-naive vaccinees died of vaccine-unrelated diseases. M72/AS01 induced polyfunctional M72-specific CD4 T-cell responses (median [interquartile range] at 7 days postdose 2: ART-stable, 0.9% [0.7-1.5]; ART-naive, 0.5% [0.2-1.0]; and HIV-negative, 0.6% [0.4-1.1]), persisting at M13 (0.4% [0.2-0.5], 0.09% [0.04-0.2], and 0.1% [0.09-0.2], respectively). Median responses were higher in the ART-stable cohort versus ART-naive cohort from day 30 onwards (P ≤ 0.015). Among HIV-positive subjects (irrespective of ART-status), median responses were higher in QuantiFERON-positive versus QuantiFERON-negative subjects up to day 30 (P ≤ 0.040), but comparable thereafter. Cytokine-expression profiles were comparable between cohorts after dose 2. At M13, M72-specific IgG responses were higher in ART-stable and HIV-negative vaccinees versus ART-naive vaccinees (P ≤ 0.001).M72/AS01 was well-tolerated and immunogenic in this population of ART-stable and ART-naive HIV-positive adults and HIV-negative adults, supporting further clinical evaluation.
authors.affiliation: From the YRG CARE Medical Centre, VHS (NK, SP, FEB); and GSK Vaccines, Rixensart/Wavre, Belgium (AB, PM, LNA, M-AD, EJ, OO-A).
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.forename: Selvamuthu
authors.initials: S
authors.lastname: Poongulali
authors.forename: Anne
authors.initials: A
authors.lastname: Bollaerts
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Faith Esther
authors.initials: FE
authors.lastname: Beulah
authors.forename: Leo Njock
authors.initials: LN
authors.lastname: Ayuk
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Demoitié
authors.forename: Erik
authors.initials: E
authors.lastname: Jongert
authors.forename: Opokua
authors.initials: O
authors.lastname: Ofori-Anyinam
mesh_terms: D000293:Adolescent; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D056724:Immunity, Humoral / Q000502:physiology; D007194:India; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000517:prevention & control*; D019562:Viral Load; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D016207:Cytokines; D032581:Tuberculosis Vaccines
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