The study, called HVTN 702, involves a new version of the only HIV vaccine candidate ever shown to provide some protection against the virus.
It aims to enrol 5,400 men and women, making it the where more than 1,000 people become infected with HIV every day.
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"Even a moderately effective vaccine would significantly decrease the burden of HIV disease over time in countries and populations with high rates of HIV infection, such as South Africa," said Fauci.
The HIV Vaccine Trials Network (HVTN) is conducting the trial at 15 sites across South Africa. Results are expected in late 2020.
The experimental vaccine regimen being tested in the trial is based on the one investigated in the earlier RV144 clinical trial in Thailand led by the US Military HIV Research Programme and the Thai Ministry of Health.
The Thai trial delivered landmark results in 2009 when it found for the first time that a vaccine could prevent HIV infection, albeit modestly.
The new regimen aims to provide greater and more sustained protection than the RV144 regimen and has been adapted to the HIV subtype that predominates in southern Africa, a region that includes the country of South Africa.
"The people of South Africa are making history by conducting and participating in the first HIV vaccine efficacy study to build on the results of the Thai trial," said Glenda Gray, CEO of the South African Medical Research Council.
"HIV has taken a devastating toll in South Africa, but now we begin a scientific exploration that could hold great promise for our country," Gray said, who is also a professor at the University of the Witwatersrand.
"If an HIV vaccine were found to work in South Africa, it may dramatically alter the course of the pandemic," she said.
The experimental vaccine regimen tested in the Thai trial was found to be 31.2 per cent effective at preventing HIV infection over the 3.5-year follow-up after vaccination.
In the HVTN 702 study, the design, schedule and components of the RV144 vaccine regimen have been modified in an attempt to increase the magnitude and duration of vaccine-elicited protective immune responses.
HVTN 702 begins just months after interim results were reported for HVTN 100, its predecessor clinical trial, which found that the new vaccine regimen was safe for the 252 study participants and induced comparable immune responses to those reported in RV144.
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