HIV vaccine clinical trial launches in South Africa

A much-anticipated clinical trial has begun in South Africa to test a modified version of the so-called Thai vaccine, the only experimental vaccine regimen so far to show modest protection against HIV/AIDS.

In the Thai study, published in 2009, vaccine recipients had a 31 percent lower risk of becoming infected with HIV, the virus that causes AIDS, compared to placebo recipients. That was not enough protection to warrant licensing, but it was the first evidence that a vaccine could protect people from HIV and was widely hailed as a breakthrough in the decades-long struggle to develop one.

For the South Africa study, the Thai vaccine regimen has been altered with the aim of making it more protective as well as longer-lasting. The trial, called HVTN 100, will start out small, with 252 volunteers, to test for safety and to see if the regimen induces the predicted immune system response.

If all goes as hoped, the next phase will be a larger trial beginning in late 2016 or early 2017 to test for efficacy, or whether the vaccine actually protects those who receive it from being infected with HIV. That trial could lead to the first licensed HIV vaccine.

“This is what the next few years are all about. Can we build on [the Thai vaccine] and get as good results or better and make it more durable?” said Dr. Linda-Gail Bekker, who is leading the trial. She is deputy director of the Desmond Tutu HIV Centre at the University of Cape Town and chief operating officer of the Desmond Tutu HIV Foundation in South Africa.

Bekker spoke in Seattle at the fall meeting of the HIV Vaccine Trials Network (HVTN), which is conducting the South Africa trials. Headquartered at Fred Hutchinson Cancer Research Center and supported by a cooperative agreement with the U.S. National Institute of Allergy and Infectious Diseases (NIAID), the HVTN is the largest publicly funded global network striving to develop vaccines to prevent HIV/AIDS. Its vaccine trial units are located at leading research institutions in more than 30 cities on five continents.

A core partner in the vaccine effort is what is generally called “the community” — the thousands of volunteers who will take part in the trials and those who serve on volunteer community advisory boards, or CABs.

“It has been a long road to reach this point,” said Dr. Fatima Laher, director of the Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital in Soweto, South Africa, and a co-leader of the new trial, in a statement released by NIAD. “People in the South African communities where HVTN 100 will take place are excited that this is a critical trial on the path toward finding a safe and effective HIV vaccine.”

South Africa has the largest HIV epidemic in the world, with an estimated 6.3 million people infected with the virus, or about 19 percent of the adult population. This means that not only is the need for a vaccine great, but that clinical trials there can be both smaller and done more quickly precisely because the population being tested is at higher risk and more likely to encounter HIV.

‘I was chosen for having the will to learn’

Mmapule Raborife learned firsthand how significant a role she plays in the vaccine endeavor when she came to Seattle last fall from her home in Soshanguve, South Africa, for an HVTN meeting. She could not get over the fact that she was given her own room at the downtown Grand Hyatt Seattle hotel.

Raborife, 52, joined a CAB in Soshanguve in August, and the Seattle conference was both her first meeting of the full HVTN and first trip overseas. She’d expected to share a room with three other community volunteers from South Africa.

“Just being here says it all,” she said. “The HVTN does not treat us differently. We are important too.”

The mission of the community advisory boards, said HVTN community engagement officer Gail Broder, is “to keep the research grounded in the lives of the community. The whole principle around community engagement is to build relationships where there is trust.”

The HVTN, formed in 1999, is known for incorporating community members at every level, including scientific committees and operational committees. To attend one of the network’s twice-a-year full-group meetings is to grasp not just the immensity of the task of developing an HIV vaccine but the small army determined to achieve it, from the scientists who do the research and oversee the trials to the HVTN staffers who identify and organize trial sites to community outreach specialists to the community members themselves.

Before joining an HIV community group, Raborife knew little about the science of HIV but far too much about its ravages. The mother of three nearly grown children, she adopted a young niece and nephew after a beloved aunt and another niece died of AIDS. She also lost friends to the disease.

At first, she felt she would never grasp the unfamiliar terms or understand the research. She thought to herself, “I don’t belong here. Maybe they made a mistake.”

But she persevered, took notes, asked questions.

“The HVTN doesn’t discriminate, respective of your background and education,” she said. “I was chosen for having the will to learn.”

At the HVTN conference in Seattle, Raborife and other community members met among themselves to exchange tips, attended science sessions and hosted scientists for several “layperson’s lunches,” during which researchers like Bekker explained their work in ways that non-scientists can understand.

The importance of good communication was underscored by a study published in the New England Journal of Medicine earlier this month examining why a clinical trial of anti-HIV microbicide gels and pills conducted in South Africa, Zimbabwe and Uganda by another network showed no protection. It turned out that participants rarely took the antiviral medications, which were supposed to be taken daily.

Researchers were surprised by the disparity between what the women reported to investigators about taking the pills or gels and what drug-level blood measurements showed. The women’s social context apparently influenced their drug usage. Some feared the medication would be unsafe. Many did not want to be stigmatized as having HIV. And some just found it hard to take medication because of their economic and social relationships with partners and families. This experience illustrates the importance of understanding community and participant concerns.

CAB members are a bridge between researchers and the community. Although they don’t recruit volunteers — that is the responsibility of HVTN staff — they serve as the eyes and ears of the communities they represent, bringing those concerns to researchers and explaining in turn how clinical trials work to community members.

The turning point

Understanding HIV can be challenging, starting with why it’s been so hard to develop a protective vaccine. The virus kills the very immune cells used in defending the body against it. It mutates rapidly within individuals and across geographical locations, making it a moving target for vaccines. And until the 2009 Thai trial results, no vaccine candidate had shown any protection, so there were no known “correlates of protection” that scientists could search for as an early sign of whether a vaccine might be effective or use as a target for improving vaccines.

“This was the turning point, the milestone,” said Bekker, a star of the layperson’s lunch who typically abandons her podium to bound around the room like a talk-show host.

In the years since the Thai trial ended, scientists have been working to analyze the data, gain insight into the types of antibodies and cellular immune responses induced, and come up with modifications that would make the vaccine regimen more potent and durable. Among other changes, they have added an additional booster shot, developed a new adjuvant to enhance the body’s immune response, and developed an insert to make the regimen more responsive to the subtype of HIV that is found in South Africa, which is called clade C. As with the original Thai vaccine, the clade C insert uses HIV pieces that are made in a laboratory and cannot cause HIV infection.

In the HVTN 100 study, 210 volunteers will receive the vaccine regimen and 42 will receive a placebo. Participants will be carefully monitored for any negative reactions, intolerance or side effects and also for immune response. The timeline calls for making a go/no-go decision on expanding to a larger efficacy trial in 2016.

Because it is unethical to deliberately expose people to HIV, testing to see whether a vaccine provides protection involves waiting several years and seeing how many people become infected naturally. (Again for ethical reasons, all participants are counseled on HIV prevention and offered options such as condoms and male circumcision to reduce the risks of contracting the virus.)

Scientists and volunteers alike are “blinded,” or kept ignorant, of whether the injection each trial participant receives is the experimental vaccine or a placebo; the two groups are compared and statisticians tally which had more infections. If all goes according to plan, results of the larger trial could be seen by 2019.

Public health experts generally want a vaccine to protect at least 70 to 80 percent of people vaccinated, but scientists and government regulators have said they would consider licensing an HIV vaccine if it protects at least 50 percent of those who receive it.

The HVTN is conducting the new HVTN 100 trial and related research studies with funding from NIAID, the Bill & Melinda Gates Foundation and the South African Medical Research Council. Novartis Vaccines and Sanofi Pasteur manufactured the two experimental vaccines being used in the regimen, a series of eight inoculations given over a year, including boosters.

All of these groups, along with the U.S. Military Research Program, are part of the Pox-Protein Public-Private Partnership, or P5, which was formed in 2010 specifically to follow up on the results of RV144, as the Thai trial was named.

‘You are the most important link’

As the last community session was wrapping up at the fall HVTN conference, in strolled Dr. Larry Corey, HVTN founder and principal investigator, Fred Hutch president and director emeritus, and an internationally recognized expert in virology, immunology, and vaccine development.

“I’ve come to see the important people,” he said.

Corey is the force behind the HVTN’s reputation for working with communities; the third person he hired for the network was Steve Wakefield, a community engagement specialist and today HVTN director of external relations. Corey’s presence at the closing community session underscored a commitment born out of his decades of work on the AIDS epidemic and his encounters with early advocates.

What is the norm today was radical in 1989 when activists stormed the fifth International AIDS Conference in Montreal demanding a voice. People with AIDS urged scientists to allow those most affected by the epidemic to help determine acceptable risks in clinical trials. Corey was one of those scientists. He got the message.

After thanking the volunteers and taking questions on what the HVTN leadership could do better, the scientist trained to be skeptical and tempered by years of vaccine disappointments rallied the troops.

“Developing an HIV vaccine seems really possible,” Corey told the volunteers as they prepared to head home. “The science has moved to a point where we have — I guess the scientific term is guarded optimism. We have the momentum. The march may take five or six or seven years as we go through these trials. But I hope people walk away with a sense of energy, of the importance of the work and of the collaboration and cooperation with communities to help us get where we’re going. You are the most important link in the whole organization.”