ORIGINAL RESEARCH A Randomized, Controlled Dose-Finding Phase II Study of the M72/AS01 Candidate Tuberculosis Vaccine in Healthy PPD-Positive Adults

Purpose In this dose-finding Phase II study (NCT00621322), we evaluated the safety and immunogenicity of different formulations of the candidate tuberculosis vaccine containing the M72 antigen (10/20/40 μg doses) and the liposome-based AS01 Adjuvant System. We aimed to select the lowest-dose combination of M72 and AS01 that was clinically well tolerated with immunogenicity comparable to that of the pre-viously tested M72/AS01B (40 μg) candidate vaccine. Methods Healthy PPD-positive (induration 3–10 mm) adults (18–45 years) in The Philippines were randomized (4:4:4:4:1:1) to receive 2 injections, 1 month apart, of M72/AS01B (40 μg), M72/AS01E (10 μg), M72/AS01E (20 μg), M72/AS02D (10 μg), M72/Saline (40 μg) or AS01B alone, and were follow-ed up for 6 months. AS01E and AS02D contain half the quan-tities of the immunostimulants present in AS01B. AS02D is an oil-in-water emulsion. Vaccine selection was based on the CD4+ T-cell responses at 1 month post vaccination. Results All formulations had a clinically acceptable safety profile with no vaccine-related serious adverse events report-ed. Two vaccinations of each adjuvanted M72 vaccine in-duced M72-specific CD4+ T-cell and humoral responses persisting at 6 months post vaccination. No responses were observed with AS01B alone. One month post second vaccina-tion, CD4+ T-cell responses induced by each of the threeM72/ AS01 vaccine formulations were of comparable magnitudes, and all were significantly higher than those induced by M72/ AS02D (10 μg) and M72/Saline. Conclusions The formulation with the lowest antigen and adjuvant dose, M72/AS01E (10 μg), fulfilled our pre-defined selection criteria and has been selected for further clinical development