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Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial.

ABSTRACT: OBJECTIVES:To assess the long-term safety and immunogenicity of the M72/ Adjuvant System (AS01E) candidate tuberculosis (TB) vaccine up to 3 years post-dose 2 (Y3) in human immunodeficiency virus (HIV)-positive (HIV+) and HIV-negative (HIV-) Indian adults. METHODS:This phase II, double-blind, randomised, controlled clinical trial (NCT01262976) was conducted at YRG CARE Medical Centre, in Chennai, India, between January 2011 and June 2015.Three cohorts (HIV+ participants stable on antiretroviral therapy [ART; HIV+ART+], HIV+ ART-naïve [HIV+ART-], and HIV- participants) were randomised (1:1) to receive 2 doses of M72/AS01E (M72/AS01E groups) or saline (control groups) 1 month apart and were followed up toY3. Latent TB infection was assessed at screening using an interferon-gamma (IFN-?) release assay (IGRA). Safety and immunogenicity results up to Y1 post-vaccination were reported elsewhere. Here, we report serious adverse events (SAEs), humoral and cell-mediated immune (CMI) responses to M72 recorded at Y2 and Y3. RESULTS:Of 240 enrolled and vaccinated participants, 214 completed the long-term follow-up part of the study.In addition to SAEs previously described, between Y1 and Y2 1 M72/AS01E recipient in the HIV+ART+ cohort reported 2 SAEs (sinus cavernous thrombosis and gastroenteritis) that were not considered as causally related to the study vaccine.Vaccination elicited persistent humoral immune responses against M72. At Y3, seropositivity rates were 97.1%, 66.7%, and 97.3% and geometric mean concentrations (GMCs) were 22.0? ELISA units (EU)/mL, 4.9?EU/mL, and 24.3?EU/mL in the HIV+ART+, HIV+ART-, and HIV- cohorts, respectively. Humoral immune response was lowest in the HIV+ART- cohort.In M72/AS01E recipients, no notable decrease in the frequency of M72-specific CD4 T-cells expressing ?2 immune markers among interleukin-2 (IL-2), IFN-?, tumour necrosis factor alpha (TNF-?) and CD40 ligand (CD40L) was observed at Y3 post-vaccination. Median values (interquartile range) of 0.35% (0.13-0.49), 0.05% (0.01-0.10), and 0.15% (0.09-0.22) were recorded in the HIV+ART+, HIV+ART- and HIV- cohorts, respectively. CD4 T-cell response was lowest in the HIV+ART- cohort.No CD8 T-cell response was observed. CONCLUSION:The cellular and humoral immune responses induced by M72/AS01E in HIV+ and HIV- adults persisted up to Y3 post-vaccination. No safety concerns were raised regarding administration of M72/AS01E to HIV+ adults. CLINICAL TRIAL REGISTRATION:NCT01262976 (www.clinicaltrials.gov).

SUBMITTER: Kumarasamy N

PROVIDER: S-EPMC6250513 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial.

Kumarasamy Nagalingeswaran N Poongulali Selvamuthu S Beulah Faith Esther FE Akite Elaine Jacqueline EJ Ayuk Leo Njock LN Bollaerts Anne A Demoitié Marie-Ange MA Jongert Erik E Ofori-Anyinam Opokua O Van Der Meeren Olivier O

Medicine 20181101 45

<h4>Objectives</h4>To assess the long-term safety and immunogenicity of the M72/ Adjuvant System (AS01E) candidate tuberculosis (TB) vaccine up to 3 years post-dose 2 (Y3) in human immunodeficiency virus (HIV)-positive (HIV+) and HIV-negative (HIV-) Indian adults.<h4>Methods</h4>This phase II, double-blind, randomised, controlled clinical trial (NCT01262976) was conducted at YRG CARE Medical Centre, in Chennai, India, between January 2011 and June 2015.Three cohorts (HIV+ participants stable on ...[more]

PMID: 30407329

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Project description: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.

Project description:Abstract Background An effective tuberculosis (TB) vaccine is urgently needed to support the End TB Strategy to reduce the number of new TB cases by 80% by 2030. M72/AS01E candidate vaccine is an adjuvanted recombinant fusion protein derived from Mycobacterium tuberculosis Mtb32A and Mtb39A proteins. Methods We conducted a randomized, double-blind, placebo-controlled phase 2b trial (NCT01755598) in Southern and Eastern Africa to assess M72/AS01E’s efficacy against bacteriologically confirmed pulmonary TB disease in HIV-seronegative (HIV–) adults aged 18–50 years infected with Mtb (defined by a positive IFN-? release assay). Participants were randomized 1:1 to receive M72/AS01E or placebo at day D0 and D30. Reactogenicity, safety, immunogenicity were assessed, and incident TB disease measured from D30 postdose 2 up to ?24 months for this analysis (follow-up ongoing up to 37 months). Efficacy against various TB disease case definitions (Figure 1) was estimated. Primary objective: efficacy against culture- or PCR-confirmed pulmonary TB disease in HIV– adults (case definition 1; success criterion: lower limit of 90% 2-sided CI >0%, power: 80%). Results Demographic characteristics were similar between M72/AS01E (1786) and placebo (1787) recipients. Efficacy against pulmonary TB disease case definition 1 was 54.0% (90% CI: 13.9, 75.4; P = 0.042); efficacy against other case definitions and a sensitivity analysis are shown in Figure 1. Leading solicited symptoms were pain, fatigue, and headache (Figure 2). In all recipients, unsolicited symptoms (D0–29) were more frequent after M72/AS01E (67.4%) than placebo (45.4%), mainly attributable to increased injection site reactions and flu-like symptoms. Serious adverse events (D0–month 7) incidences were similar between groups (M72/AS01E: 1.6%; placebo: 1.8%). During the study, 24 adults died (14 due to traumatic events); all deaths were unrelated to the trial. Conclusion M72/AS01E presents a clinically acceptable safety profile and significantly reduces bacteriologically confirmed pulmonary TB disease incidence in HIV– adults with latent Mtb infection. Funding. BMGF; Aeras; DFID UK; DGIS; AusAID; GlaxoSmithKline Biologicals SA. Disclosures O. Van Der Meeren, GSK: Employee and Shareholder, Salary. M. Hatherill, Aeras: Investigator, Research grant. R. J. Wilkinson, GSK: Grant Investigator, indirect funding. H. M. Ayles, GSK: Grant Investigator, Research grant. G. Henostroza, Aeras: Investigator, Grant recipient. M. A. Demoitié, GSK: owns stocks and is named inventor on patent applications relating to certain uses of M72/AS01E, Salary. T. Singh, GSK: Employee and Shareholder, Salary. E. J. Akite, GSK: Employee, Salary. A. K. Azam, GSK: Employee, Salary. A. Bollaerts, GSK: Employee, Salary. A. M. Ginsberg, GSK: Collaborator, Research support. BMGF: Grant Investigator, Grant recipient. UK DFID: Grant Investigator, Grant recipient. P. Gillard, GSK: Employee and Shareholder, Salary and stock. D. R. Tait, Aeras: Employee, Salary. GSK: Shareholder, Salary.

Dataset Information

Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial.

Publications

Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial.

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