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A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Immune-marker expression profiles following vaccination with M72/AS01. Phenotypes of M72-specific CD4+ T cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L are shown. Box-and-whiskers plots represent the percentages of CD4+ T cells with 1st and 3rd quartiles, and the minimum/maximum values measured. Pie charts represent the mean proportions of cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L marker-positive CD4+ T cells out of the total immune marker-expressing CD4+ T-cell response, at days 0, 7, 30, 37, 60 and months 7 and 13. Pie sizes reflect the mean frequencies (%) of total CD4+ T cells producing at least one marker, relative to the other time-points in the same cohort. IFN-γ = interferon gamma, IL-2 = interleukin 2, TNF-α = tumor necrosis factor alpha.
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Figure 4: Immune-marker expression profiles following vaccination with M72/AS01. Phenotypes of M72-specific CD4+ T cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L are shown. Box-and-whiskers plots represent the percentages of CD4+ T cells with 1st and 3rd quartiles, and the minimum/maximum values measured. Pie charts represent the mean proportions of cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L marker-positive CD4+ T cells out of the total immune marker-expressing CD4+ T-cell response, at days 0, 7, 30, 37, 60 and months 7 and 13. Pie sizes reflect the mean frequencies (%) of total CD4+ T cells producing at least one marker, relative to the other time-points in the same cohort. IFN-γ = interferon gamma, IL-2 = interleukin 2, TNF-α = tumor necrosis factor alpha.

Mentions: Characterization of immune-marker expression showed that in each cohort, the vast majority of vaccine-induced CD4+ T cells were polyfunctional (coexpressing at least 2 immune markers) up to at least 1 year postvaccination (Figure 4). Mainly CD40L+ IL-2+, single-positive CD40L+, CD40L+ IL-2+ TNF-α+, and quadruple-positive T-cell subsets were induced. At prevaccination, the degree of CD4+ T-cell polyfunctionality was higher in HIV-negative versus HIV-positive subjects, however from day 7 onwards the polyfunctional profiles were comparable between cohorts.


A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults
Immune-marker expression profiles following vaccination with M72/AS01. Phenotypes of M72-specific CD4+ T cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L are shown. Box-and-whiskers plots represent the percentages of CD4+ T cells with 1st and 3rd quartiles, and the minimum/maximum values measured. Pie charts represent the mean proportions of cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L marker-positive CD4+ T cells out of the total immune marker-expressing CD4+ T-cell response, at days 0, 7, 30, 37, 60 and months 7 and 13. Pie sizes reflect the mean frequencies (%) of total CD4+ T cells producing at least one marker, relative to the other time-points in the same cohort. IFN-γ = interferon gamma, IL-2 = interleukin 2, TNF-α = tumor necrosis factor alpha.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998253&req=5

Figure 4: Immune-marker expression profiles following vaccination with M72/AS01. Phenotypes of M72-specific CD4+ T cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L are shown. Box-and-whiskers plots represent the percentages of CD4+ T cells with 1st and 3rd quartiles, and the minimum/maximum values measured. Pie charts represent the mean proportions of cells expressing (after in-vitro stimulation) single markers and any combination of TNF-α, IFN-γ, IL-2, and CD40L marker-positive CD4+ T cells out of the total immune marker-expressing CD4+ T-cell response, at days 0, 7, 30, 37, 60 and months 7 and 13. Pie sizes reflect the mean frequencies (%) of total CD4+ T cells producing at least one marker, relative to the other time-points in the same cohort. IFN-γ = interferon gamma, IL-2 = interleukin 2, TNF-α = tumor necrosis factor alpha.
Mentions: Characterization of immune-marker expression showed that in each cohort, the vast majority of vaccine-induced CD4+ T cells were polyfunctional (coexpressing at least 2 immune markers) up to at least 1 year postvaccination (Figure 4). Mainly CD40L+ IL-2+, single-positive CD40L+, CD40L+ IL-2+ TNF-α+, and quadruple-positive T-cell subsets were induced. At prevaccination, the degree of CD4+ T-cell polyfunctionality was higher in HIV-negative versus HIV-positive subjects, however from day 7 onwards the polyfunctional profiles were comparable between cohorts.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus