Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults

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-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/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-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/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).

The Systematic Review and Meta-Analysis on the Immunogenicity and Safety of the Tuberculosis Subunit Vaccines M72/AS01E and MVA85A

“…Several types of preclinical studies have verified that humoral immunity may give protection against M. tuberculosis ( 53 – 55 ). M72/AS01 E vaccination-induced M72-specific antibodies persisted for a maximum of 3 years ( 56 ). In particular, two-doses of the vaccination seem to have strong long-term protection.…”

Immunogenicity and Safety of the M72/AS01E Candidate Vaccine Against Tuberculosis: A Meta-Analysis

“…Meanwhile, there was a sharp increase in the seroconversion rates after the second vaccine dose compared with the first. Kumarasamy et al reported that M72-specific antibodies induced through vaccination with M72/AS01 E persisted for a maximum of 3 years (27). Notably, two-dose vaccination offered more durable long-term protection.…”

Clinical Development of New TB Vaccines: Recent Advances and Next Steps

“…M72/AS01 E showed an acceptable safety profile and did not affect HIV viral load or CD4 cell counts in HIV-infected Swiss adults, most of whom were receiving ART (Thacher et al, 2014). In a second trial in India, M72/AS01 E vaccination was well tolerated and induced a polyfunctional M72-specific CD4 T-cell response that persisted through 1 year, and which was higher in patients receiving ART compared to those who were ART-naïve (Kumarasamy et al, 2016(Kumarasamy et al, , 2018. However, the crux of the problem is that the period of maximal risk for HIV-associated TB is the period prior to immune reconstitution, before starting ART (Lawn et al, 2009).…”

“…Live mycobacterial vaccines like BCG, VPM1002, and MTBVAC have an unfavorable risk profile for persons with HIV infection (Hesseling et al, 2008); and therefore inactivated mycobacterial, viral-vectored and proteinsubunit candidate vaccines, including M72/AS01 E , might be more appropriate for vaccination of individuals with HIV and other immune-suppressive conditions (Thacher et al, 2014;Kumarasamy et al, 2016Kumarasamy et al, , 2018. Studies of vaccination of HIV-infected individuals have reported lower induced immune responses, compared to HIV-uninfected individuals, which were partly restored by antiretroviral therapy (ART) (Thacher et al, 2014;Kumarasamy et al, 2016Kumarasamy et al, , 2018. M72/AS01 E showed an acceptable safety profile and did not affect HIV viral load or CD4 cell counts in HIV-infected Swiss adults, most of whom were receiving ART (Thacher et al, 2014).…”