Preclinical study and phase I clinical safety evaluation of recombinant
Mycobacterium tuberculosis ESAT6 protein.
Author(s): Du WX(1), Chen BW, Lu JB, Gao MQ, Shen XB, Yang L, Su C, Wang GZ, Sun QF, Xu M.
Affiliation(s): Author information:
(1)National Institutes for Food and Drug Control, Beijing, PR China.
Publication date & source: 2013, Med Sci Monit Basic Res. , 19:146-52
BACKGROUND: To investigate the ability of rESAT6 to identify different
mycobacteria-sensitized guinea pigs and its safety in preclinical and phase I
clinical study.
MATERIAL AND METHODS: Guinea pigs were sensitized with different Mycobacteria.
After sensitization, all animals were intradermally injected with rESAT6 and
either PPD or PPD-B. At 24 h after the injection, the erythema of the injection
sites were measured using a double-blind method. For the preclinical safety
study, different doses of rESAT6 and BSA were given 3 times intramuscularly to
guinea pigs. On day 14 after the final immunization, the guinea pigs were
intravenously injected with the same reagents in the hind legs and the allergic
reactions were observed. A single-center, randomized, open phase I clinical trial
was employed. The skin test was conducted in 32 healthy volunteers aged 19-65
years with 0.1 µg, 0.5 µg, and 1 µg rESAT6. Physical examination and laboratory
tests were performed before and after the skin test and adverse reactions were
monitored. The volunteers' local and systemic adverse reactions and adverse
events were recorded for 7 days.
RESULTS: Positive PPD or PPD-B skin tests were observed in all
Mycobacteria-sensitized guinea pigs; the diameters of erythema were all >10 mm.
The rESAT6 protein induced a positive skin test result in the guinea pigs
sensitized with MTB, M. bovis, M. africanum and M. kansasii; the diameters of
erythema were 14.7±2.0, 9.3±3.8, 18.7±2.4, and 14.8±4.2 mm, respectively. A
negative skin test result was detected in BCG-vaccinated and other NTM-sensitized
guinea pigs. The rESAT6 caused no allergic symptoms, but many allergic reactions,
such as cough, dyspnea, and even death, were observed in the guinea pigs who were
administered BSA. During the phase I clinical trial, no adverse reactions were
found in the 0.1 µg rESAT6 group, but in the 0.5 µg rESAT6 group 2 volunteers
reported pain and 1 reported itching, and in the 1 µg rESAT6 group there was 1
case of pain, 1 case of itching, and 1 case of blister. No other local or
systemic adverse reactions or events were reported.
CONCLUSIONS: The rESAT6 can differentiate effectively among MTB infection, BCG
vaccination, and NTM infection and is safe in healthy volunteers.
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