In South Africa, Thembi Dlamini, 29, is screened at a clinical research site to participate in the trial. (Ryan Lenora Brown/For The Washington Post)

After decades of shadowboxing with the human immunodeficiency virus, researchers were encouraged four years ago when a test of a vaccine on 16,000 people in Thailand turned up a previously unknown vulnerability in the resilient pathogen.

The vaccine was only 31 percent effective and wore off over time, so it could not be approved for use in a general population. But the study’s results allowed scientists to exploit the chink in HIV’s armor, reformulate the drug and bring it back for another clinical trial.

Now all eyes are on South Africa, where researchers will begin inoculating thousands of volunteers Monday in the latest — and, some say, most promising — effort to develop a vaccine that prevents the disease. It is only the seventh full-scale human trial for a virus that infects more than 2 million people and kills more than 1 million every year.

“If this study shows efficacy . . . this would be a tectonic, historic event for HIV,” said Nelson L. Michael, director of the U.S. Military HIV Research Program, which led the Thailand study.

Should the vaccine prove to be 50 percent to 60 percent effective, experts say, that would be sufficient for drugmakers Sanofi Pasteur and GSK to begin licensing negotiations with the South African government. While such a rate is well below the acceptable margin for other vaccines, it would still make this one worth producing here — given that nearly 1 in 5 people are infected.

Aruna Bhoola, a pharmacist at the Medical Research Council in Verulam, South Africa, checks samples of the HIV vaccine. (Ryan Lenora Brown/For The Washington Post)

And an agent that works in South Africa could be adjusted later for use against viral subtypes that circulate elsewhere, including in the United States.

“Given that right now we have nothing, we’d be happy if this vaccine were even 45 or 50 percent effective,” said Gita Ramjee, director of the HIV Prevention Research Unit at the Medical Research Council in Durban, which is running two of the 15 trial sites. “Even a modestly effective vaccine like that would have a huge impact here.”

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About 5,400 people — who must be HIV-negative, sexually active and between the ages of 18 and 35 — are being recruited. Each will receive five injections over the course of the year and then be monitored for two years.

Half the volunteers will receive a placebo so that researchers can measure the vaccine’s efficacy. But that hasn’t deterred South Africans from signing up. Few lives are untouched by the disease.

“I don’t want another generation to go through what I did,” said Thembi Dlamini, 29, who this week was being screened at a clinic for participation in the trial.

Her older sister died of AIDS five years ago in a brutal descent. The only silver lining was its brevity: She was gone in just three months, with a stash of HIV medication in her dresser drawer. Her shame was greater than the fear of wasting away.

At the Medical Research Council in Verulam, South Africa, a poster describes the way HIV drugs work. (Ryan Lenora Brown/For The Washington Post)

Dlamini estimates that half her friends are HIV-positive — hardly an outlandish calculation in a country where about a third of the women in her age group have the virus.

For 18-year-old S’phindile Dlamini, another volunteer who is no relation to Thembi, it was a neighbor whom she remembers dying first. In their community, people normally pitched in when someone fell ill. But the more brittle this woman grew, the farther away people stayed and the louder they whispered.

Between them, Thembi and S’phindile also count a niece, teacher and friends among their losses.

Though HIV has faded from the headlines since the development of antiretroviral drugs made the disease manageable, it is still a pandemic. About 36.7 million people worldwide were living with HIV in 2015, including about 2.1 million who were newly infected, according to the Joint United Nations Program on HIV and AIDS. In the United States, the Centers for Disease Control and Prevention says 1.2 million people are infected.

Globally, 18 million people were able to get the medicines they needed to control the virus last year, according to the U.N. HIV program.

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South Africa has more than 7 million people living with the virus. In some parts of the country, such as the northeastern coastal province of KwaZulu-Natal, where Verulam is located, estimates place the number of HIV-positive people at nearly 30 percent.

There is no preventive drug and no cure. Yet this is the first new human HIV vaccine study in about a decade.

“We need to test more vaccines,” said Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston. “In over 35 years of the epidemic, we’ve only tested four different HIV vaccine concepts. We need more shots on goal.”

But these trials, which have a long history of failure, are difficult to design. They are large, complicated and expensive. And the virus, because of its variability, is an extremely resilient target.

“All of those bugs for which humanity has made vaccines do not insert themselves into the genome of the human they are infecting,” said Barton Haynes, director of the Duke Human Vaccine Institute at Duke University. “HIV inserts its genetic material into the genetic material of the person it infects. That’s why we can’t cure it.”

In 2007, South Africa was one site of a second phase of testing for an HIV vaccine developed by pharmaceutical giant Merck. The study was called off soon after it began, however, when early results from other locations showed that the vaccine seemed to be making people more susceptible to HIV than a placebo.

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Results from the new study are not expected until 2020, though the test could be ended earlier if it shows spectacular results or unexpected problems.

“If we knew we were going to be successful, we wouldn’t have to do the experiment, but we do believe this approach has great promise,” said Glenda Gray, president of the South African Medical Research Council. The longtime HIV researcher is leading the trial. “We’ve grown used to being wrong because of all the failures we’ve had in the HIV field, and I think all of us are quite pragmatic, but we’re still excited.”

Some of that same optimism is shared, albeit cautiously, by others in the international collaboration.

This experiment “is taking the only modestly successful vaccine trial . . . and trying to improve upon it in a higher-risk population,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which is largely funding the $130 million study with help from the Bill & Melinda Gates Foundation.

If Thembi Dlamini and S’phindile Dlamini pass their health screening, they soon will begin receiving the vaccine or the placebo in a brightly lit clinic in a stout brick building behind a funeral parlor on this town’s main strip. All participants will be reminded of the best practices for avoiding the virus, and anyone who becomes infected during the trial will be referred for treatment.

For many, their motivation is the possibility that they could be part of an effort that helps turn the tide.

“I don’t want to lose another member of my family,” Thembi Dlamini said. “I want to be one of the ones who helped prevent this thing for the future.”

Brown reported from South Africa, and Bernstein reported from Washington.