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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

Safety and reactogenicity including HIV-specific parameters. Percentage of doses with 95% CI followed by solicited local (A) and general (B) AEs reported within 7 days postvaccination are shown for all subjects for whom at least 1 administration of vaccine or control was documented (the Total Vaccinated Cohort). GI sympt.: gastro-intestinal symptoms. CD4+ T-cell counts (C) and HIV-1 viral loads (D) obtained from the Total Vaccinated Cohort were measured at screening (SCR), prior to each vaccination (D0 and D30), and 1, 6, or 12 months after the 2nd dose (D60, M7, M13). In addition, HIV viral loads were measured at 7 days post each dose (D7 and D37). The detection limit of the HIV-1 viral load assay was 40 copies/mL. AE = adverse event, CI = confidence interval, HIV = human immunodeficiency virus.
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Figure 2: Safety and reactogenicity including HIV-specific parameters. Percentage of doses with 95% CI followed by solicited local (A) and general (B) AEs reported within 7 days postvaccination are shown for all subjects for whom at least 1 administration of vaccine or control was documented (the Total Vaccinated Cohort). GI sympt.: gastro-intestinal symptoms. CD4+ T-cell counts (C) and HIV-1 viral loads (D) obtained from the Total Vaccinated Cohort were measured at screening (SCR), prior to each vaccination (D0 and D30), and 1, 6, or 12 months after the 2nd dose (D60, M7, M13). In addition, HIV viral loads were measured at 7 days post each dose (D7 and D37). The detection limit of the HIV-1 viral load assay was 40 copies/mL. AE = adverse event, CI = confidence interval, HIV = human immunodeficiency virus.

Mentions: Injection-site pain was the most commonly reported solicited local AE in both the HIV-infected and the HIV-uninfected comparative cohorts (Figure 2A). Irrespective of cohorts, after all doses, grade 3 pain was reported infrequently and only in the M72/AS01 groups (≤7.6%). Across groups and cohorts, the frequency of swelling (any intensity) after all doses was low (≤8.9%) and no grade 3 swelling was reported.


A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults
Safety and reactogenicity including HIV-specific parameters. Percentage of doses with 95% CI followed by solicited local (A) and general (B) AEs reported within 7 days postvaccination are shown for all subjects for whom at least 1 administration of vaccine or control was documented (the Total Vaccinated Cohort). GI sympt.: gastro-intestinal symptoms. CD4+ T-cell counts (C) and HIV-1 viral loads (D) obtained from the Total Vaccinated Cohort were measured at screening (SCR), prior to each vaccination (D0 and D30), and 1, 6, or 12 months after the 2nd dose (D60, M7, M13). In addition, HIV viral loads were measured at 7 days post each dose (D7 and D37). The detection limit of the HIV-1 viral load assay was 40 copies/mL. AE = adverse event, CI = confidence interval, HIV = human immunodeficiency virus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Safety and reactogenicity including HIV-specific parameters. Percentage of doses with 95% CI followed by solicited local (A) and general (B) AEs reported within 7 days postvaccination are shown for all subjects for whom at least 1 administration of vaccine or control was documented (the Total Vaccinated Cohort). GI sympt.: gastro-intestinal symptoms. CD4+ T-cell counts (C) and HIV-1 viral loads (D) obtained from the Total Vaccinated Cohort were measured at screening (SCR), prior to each vaccination (D0 and D30), and 1, 6, or 12 months after the 2nd dose (D60, M7, M13). In addition, HIV viral loads were measured at 7 days post each dose (D7 and D37). The detection limit of the HIV-1 viral load assay was 40 copies/mL. AE = adverse event, CI = confidence interval, HIV = human immunodeficiency virus.
Mentions: Injection-site pain was the most commonly reported solicited local AE in both the HIV-infected and the HIV-uninfected comparative cohorts (Figure 2A). Irrespective of cohorts, after all doses, grade 3 pain was reported infrequently and only in the M72/AS01 groups (≤7.6%). Across groups and cohorts, the frequency of swelling (any intensity) after all doses was low (≤8.9%) and no grade 3 swelling was reported.

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