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 previously tested M72/AS01(B) (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/AS01(B) (40 μg), M72/AS01(E) (10 μg), M72/AS01(E) (20 μg), M72/AS02(D) (10 μg), M72/Saline (40 μg) or AS01(B) alone, and were followed up for 6 months. AS01(E) and AS02(D) contain half the quantities of the immunostimulants present in AS01(B). AS02(D) 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 reported. Two vaccinations of each adjuvanted M72 vaccine induced M72-specific CD4(+) T-cell and humoral responses persisting at 6 months post vaccination. No responses were observed with AS01(B) alone. One month post second vaccination, CD4(+) T-cell responses induced by each of the three M72/AS01 vaccine formulations were of comparable magnitudes, and all were significantly higher than those induced by M72/AS02(D) (10 μg) and M72/Saline. CONCLUSIONS: The formulation with the lowest antigen and adjuvant dose, M72/AS01(E) (10 μg), fulfilled our pre-defined selection criteria and has been selected for further clinical development.