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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

CONSORT diagram of study flow. CW = consent withdrawal, not due to an adverse event, LTF = subject lost to follow-up and/or migrated from the study area, N or n = number of subjects who received the vaccine, Other = other reasons, SAE [death] = serious adverse event; subject died of a cause not related to vaccination, UC = subject unable to come to the site for the visit at the time-point given.
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Figure 1: CONSORT diagram of study flow. CW = consent withdrawal, not due to an adverse event, LTF = subject lost to follow-up and/or migrated from the study area, N or n = number of subjects who received the vaccine, Other = other reasons, SAE [death] = serious adverse event; subject died of a cause not related to vaccination, UC = subject unable to come to the site for the visit at the time-point given.

Mentions: Of the 240 subjects enrolled, 203 (97 M72/AS01 and 106 placebo recipients) completed year 1 (Figure 1). In the ART-stable, ART-naive and HIV-negative cohorts, 9, 3, and 11 M72/AS01 recipients, and 1, 4, and 9 placebo recipients, respectively, withdrew, predominantly because these subjects had migrated and/or were unavailable for follow-up at month 13. Two ART-naive recipients died of vaccine-unrelated diseases (described below). The majority of the study population were BCG-vaccinated, and the majority of the HIV-positive subjects were QFT-negative (Table 1). Expectedly, nadir CD4 counts were higher in the ART-naive subjects than in ART-stable subjects. CD4 nadirs and counts at screening were comparable between the vaccine and placebo groups in both HIV-positive cohorts.


A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults
CONSORT diagram of study flow. CW = consent withdrawal, not due to an adverse event, LTF = subject lost to follow-up and/or migrated from the study area, N or n = number of subjects who received the vaccine, Other = other reasons, SAE [death] = serious adverse event; subject died of a cause not related to vaccination, UC = subject unable to come to the site for the visit at the time-point given.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: CONSORT diagram of study flow. CW = consent withdrawal, not due to an adverse event, LTF = subject lost to follow-up and/or migrated from the study area, N or n = number of subjects who received the vaccine, Other = other reasons, SAE [death] = serious adverse event; subject died of a cause not related to vaccination, UC = subject unable to come to the site for the visit at the time-point given.
Mentions: Of the 240 subjects enrolled, 203 (97 M72/AS01 and 106 placebo recipients) completed year 1 (Figure 1). In the ART-stable, ART-naive and HIV-negative cohorts, 9, 3, and 11 M72/AS01 recipients, and 1, 4, and 9 placebo recipients, respectively, withdrew, predominantly because these subjects had migrated and/or were unavailable for follow-up at month 13. Two ART-naive recipients died of vaccine-unrelated diseases (described below). The majority of the study population were BCG-vaccinated, and the majority of the HIV-positive subjects were QFT-negative (Table 1). Expectedly, nadir CD4 counts were higher in the ART-naive subjects than in ART-stable subjects. CD4 nadirs and counts at screening were comparable between the vaccine and placebo groups in both HIV-positive 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