Long-term safety and immunogenicity of the M72/AS01(E) candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial

OBJECTIVES: To assess the long-term safety and immunogenicity of the M72/ Adjuvant System (AS01(E)) 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/AS01(E) (M72/AS01(E) 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-γ) 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/AS01(E) 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/AS01(E) recipients, no notable decrease in the frequency of M72-specific CD4(+) T-cells expressing ≥2 immune markers among interleukin-2 (IL-2), IFN-γ, tumour necrosis factor alpha (TNF-α) 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/AS01(E) 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).