The study aims to enrol 5,400 sexually active young men and women.
About seven million people in South Africa are living with the virus, which is one reason why the trial is taking place there.
Experts hope the vaccine will be "the final nail in the coffin" for HIV.
The vaccine regime being tested is based on one used in a trial in Thailand in 2009, which had a protection rate of about 30%. Results from South Africa are expected in four years.
Since the HIV virus was identified in 1983, efforts to develop an effective vaccine have proved unsuccessful.