Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial

Objective: Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART. Design: A randomized, observer-blind, controlled trial (NCT00707967). Methods: HIV-infected adults on cART in Switzerland were randomized 3 :1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N=22, N=8 and N=7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4(+) cell counts below 200 cells/mu l were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210. Results: Thirty-seven individuals [interquartile range (IQR) CD4(+) cell counts at screening: 438-872 cells/mu l; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4(+) cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4+ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L(+)IL-2(+)TNF-alpha(+) CD40L(+)IL-2(+) and CD40L(+)IL-2(+)TNF-alpha+IFN-gamma(+)]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end. Conclusion: M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.