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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

M72-specific CD4+ T-cell responses following vaccination with M72/AS01. Blood samples were obtained prior to each vaccination (D0 and D30), at 7 days post each dose (D7 and D37), and at 1, 6, or 12 months after the 2nd dose (D60, M7 and M13). Data from all subjects (A) and from all M72/AS01 vaccinees presented according to their QFT status (B) are reported as the percentages of M72-specific CD4+ T cells expressing (after in vitro stimulation) at least 2 immune markers among IFN-γ, IL-2, TNF-α, and CD40L of all CD4+ T cells, with 1st and 3rd quartiles, and the minimum/maximum values measured. Statistical analyses were performed by the Wilcoxon rank-sum test (level of significance P < 0.05). IFN-γ = interferon gamma, IL-2 = interleukin 2, QFT = QuantiFERON-TB, TNF-α = tumor necrosis factor alpha.
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Figure 3: M72-specific CD4+ T-cell responses following vaccination with M72/AS01. Blood samples were obtained prior to each vaccination (D0 and D30), at 7 days post each dose (D7 and D37), and at 1, 6, or 12 months after the 2nd dose (D60, M7 and M13). Data from all subjects (A) and from all M72/AS01 vaccinees presented according to their QFT status (B) are reported as the percentages of M72-specific CD4+ T cells expressing (after in vitro stimulation) at least 2 immune markers among IFN-γ, IL-2, TNF-α, and CD40L of all CD4+ T cells, with 1st and 3rd quartiles, and the minimum/maximum values measured. Statistical analyses were performed by the Wilcoxon rank-sum test (level of significance P < 0.05). IFN-γ = interferon gamma, IL-2 = interleukin 2, QFT = QuantiFERON-TB, TNF-α = tumor necrosis factor alpha.

Mentions: Several subjects in both groups exhibited preexisting M72-specific CD4+ T cells expressing at least 2 markers (Figure 3A). After administration of placebo, no increase in the median responses was observed until 1 year postvaccination. In contrast, 1 dose of M72/AS01 induced already at day 7 a modest increase in the median response in each cohort. After the 2nd dose, at day 37, these responses had increased further to levels exceeding those at day 7, and persisted in each cohort at month 13, albeit at lower levels (P < 0.001 vs prevaccination). Vaccine-induced responses in the ART-stable cohort were significantly higher compared with those in the ART-naive cohort from day 30 onwards, and compared with those in the HIV-negative cohort from day 60 onwards. Median responses were significantly higher in the HIV-negative cohort than in the ART-naive cohort at all postvaccination time-points except days 37 and 60.


A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults
M72-specific CD4+ T-cell responses following vaccination with M72/AS01. Blood samples were obtained prior to each vaccination (D0 and D30), at 7 days post each dose (D7 and D37), and at 1, 6, or 12 months after the 2nd dose (D60, M7 and M13). Data from all subjects (A) and from all M72/AS01 vaccinees presented according to their QFT status (B) are reported as the percentages of M72-specific CD4+ T cells expressing (after in vitro stimulation) at least 2 immune markers among IFN-γ, IL-2, TNF-α, and CD40L of all CD4+ T cells, with 1st and 3rd quartiles, and the minimum/maximum values measured. Statistical analyses were performed by the Wilcoxon rank-sum test (level of significance P < 0.05). IFN-γ = interferon gamma, IL-2 = interleukin 2, QFT = QuantiFERON-TB, 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 3: M72-specific CD4+ T-cell responses following vaccination with M72/AS01. Blood samples were obtained prior to each vaccination (D0 and D30), at 7 days post each dose (D7 and D37), and at 1, 6, or 12 months after the 2nd dose (D60, M7 and M13). Data from all subjects (A) and from all M72/AS01 vaccinees presented according to their QFT status (B) are reported as the percentages of M72-specific CD4+ T cells expressing (after in vitro stimulation) at least 2 immune markers among IFN-γ, IL-2, TNF-α, and CD40L of all CD4+ T cells, with 1st and 3rd quartiles, and the minimum/maximum values measured. Statistical analyses were performed by the Wilcoxon rank-sum test (level of significance P < 0.05). IFN-γ = interferon gamma, IL-2 = interleukin 2, QFT = QuantiFERON-TB, TNF-α = tumor necrosis factor alpha.
Mentions: Several subjects in both groups exhibited preexisting M72-specific CD4+ T cells expressing at least 2 markers (Figure 3A). After administration of placebo, no increase in the median responses was observed until 1 year postvaccination. In contrast, 1 dose of M72/AS01 induced already at day 7 a modest increase in the median response in each cohort. After the 2nd dose, at day 37, these responses had increased further to levels exceeding those at day 7, and persisted in each cohort at month 13, albeit at lower levels (P < 0.001 vs prevaccination). Vaccine-induced responses in the ART-stable cohort were significantly higher compared with those in the ART-naive cohort from day 30 onwards, and compared with those in the HIV-negative cohort from day 60 onwards. Median responses were significantly higher in the HIV-negative cohort than in the ART-naive cohort at all postvaccination time-points except days 37 and 60.

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&ndash;Gu&eacute;rin-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&ndash;1.5]; ART-naive, 0.5% [0.2&ndash;1.0]; and HIV-negative, 0.6% [0.4&ndash;1.1]), persisting at M13 (0.4% [0.2&ndash;0.5], 0.09% [0.04&ndash;0.2], and 0.1% [0.09&ndash;0.2], respectively). Median responses were higher in the ART-stable cohort versus ART-naive cohort from day 30 onwards (P&#8202;&le;&#8202;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&#8202;&le;&#8202;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&#8202;&le;&#8202;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