Thirteen years ago, Dr. Julie McElrath came face to face with what it means to lose an entire generation. Driving through the villages around Durban, South Africa, McElrath saw teenagers caring for toddlers and elderly women holding crying babies — and she knew that the kids were probably orphans, their parents killed by AIDS. She also knew that roughly half of the people walking down the dusty roads were infected by the disease, and that there was no way for local doctors to help them.
"I thought I understood how serious AIDS was but seeing it there, in a hard-hit area, was terribly sobering," McElrath said.
Now McElrath and her colleagues in the HIV Vaccine Trials Network, or HVTN, are preparing to launch new clinical trials that could help end HIV. Headquartered on Fred Hutchinson Cancer Research Center's Seattle campus, HVTN is the world's largest network dedicated to testing vaccines designed to prevent HIV. Its latest trials will test the most promising vaccines ever developed and will take place in South Africa.
HVTN staff members have spent the past two years fanning out across the country, scouting sites and laying the foundation for trials that could ultimately involve around 10,000 patients. The HVTN is also finishing a state-of-the-art lab in Cape Town that will analyze the trial's results and help local scientists advance their HIV research.
To McElrath, who heads HVTN's labs program and Fred Hutch's Vaccine and Infectious Disease Division, these latest trials mean another step toward ending the devastation she witnessed on that trip to Durban.
"We wanted to test the vaccines in a place where they could have the biggest benefit," she said, "and because the incidence in South Africa is so high, we can do studies quickly and hopefully make faster progress."
|Dr. Larry Corey|
"Our HIV contributions have been tremendous," said Dr. Larry Corey, Fred Hutch's president and director, "and they're one of the great untold stories at the Hutch."
It might seem strange for an institution with cancer in its name to be integrally involved in HIV research. But HIV leaves patients vulnerable to a variety of cancers, including Kaposi sarcoma and Burkitt lymphoma. And Corey sees HIV research as a natural extension of Fred Hutch's expertise in understanding the immune system and how it can be harnessed to cure disease. The Hutch's researchers pioneered bone marrow transplants and were among the first to develop immunotherapies that use immune cells to destroy cancer.
"That knowledge doesn't always transfer to HIV research, but it creates a solid foundation, and we're seeing more and more synergies," Corey said.
Corey should know – he helped develop some of the first treatments. Working with colleagues at other institutions, including Nobel Prize-winner Dr. Gertrude Elion, Corey proved that antiviral drugs could control human herpes. This provided a roadmap for how the drugs could combat other sexually transmitted viruses, and it ultimately led to antiretroviral drugs that reduce the amount of HIV in the body and slow its progression into AIDS. Thanks in part to Corey's research, there are now dozens of approved drug regimens that can extend an HIV patient's life for decades.
These drugs have been a boon for the HIV patients who have access to them in the U.S. and other developed countries, where in just 30 years HIV has gone from a virtual death sentence into a condition that can be managed long term. However, antiretrovirals are often impractical in developing countries where the vast majority of HIV patients live. The drugs are too expensive for many patients there, they don't work for everyone, and it can be hard for patients who live far from medical care to stay on a consistent drug regimen.
"Antiretrovirals are magnificent, but they're a stopgap – they can't lead us to a world where everyone grows up without fear of AIDS," Corey said. "The only way to accomplish that is with a vaccine."
That's why Corey started the HVTN in 1999 with a grant from the National Institutes of Health. HVTN's goal is to develop vaccines that trigger the immune system to identify and eradicate HIV before it can take hold. Unlike vaccines for other viruses, which inject small doses of a virus into patients, HIV vaccines use vectors and artificial proteins to spur the immune system to create antibodies against the disease.
It's an unprecedented challenge. HIV is fundamentally different from polio and other viruses that have been virtually eradicated by vaccines. It hides inside immune cells, making it hard for the body to detect. It has many different strains and mutates very quickly. And the body can't naturally control even small levels of HIV. That means a successful vaccine must aim for multiple targets and prepare the immune system to quickly produce millions of killer cells.
"HIV is a very, very smart virus," Corey said. "Just when we think we have it pinned down, it slips around our defenses."
While Corey was developing antiviral drugs in the 1980s, Dr. James Kublin was interning at a New York hospital and watching AIDS impact the city's gay population.
"Young men were dying left and right and there wasn't anything we could do — we were essentially delivering hospice care," Kublin said. "It was incredibly tragic."
Dr. Jim Kublin
HVTN scientists also look for HIV's weaknesses and develop strategies to exploit them. Then they take these insights back to drug companies, which redesign and manufacture the
vaccines, and run them through more trials.
HVTN has led more than 50 clinical trials and enrolled more than 13,000 patients. The trials typically focus on people who have an especially high risk of contracting HIV — often young, gay men or people who live in areas with a high HIV prevalence. Some participants get new vaccines, while others get placebos.
To piece together how vaccine candidates interact with the immune system, HVTN relies heavily on the Statistical Center for HIV/AIDS Research & Prevention, which is part of Fred Hutch's Vaccine and Infectious Disease Division. SCHARP biostatisticians, led by Dr. Peter Gilbert, help design HVTN studies. They then analyze the data, looking for patterns or trends that show whether a vaccine protects against infection. The vaccines that show the strongest immune response are advanced through the clinical trials process.
HVTN's biggest breakthrough so far came in 2009, when a trial in Thailand found that a combination of vaccines reduced some patients' risk of contracting HIV by about 30 percent. This kicked off an intense effort to understand exactly how the vaccines suppressed HIV and how they could be improved.
That's where the HVTN's labs program comes in. The network's headquarters contains roughly 9,000 square feet of lab space, where scientists pore over thousands of blood and cell samples from trial participants. Even if a vaccine shows no effect, the samples still yield important clues about how it interacts with the body and the virus.
In the case of the Thai trial, this process led McElrath, Gilbert and their colleagues — including collaborators at Duke University and the Henry M. Jackson Foundation — to a pivotal discovery. For the first time, they pinpointed "immune correlates" that were associated with reduced HIV risk. One of their key findings suggested the vaccines might spur some recipients to make antibodies that prevent HIV infection.
"These correlates are the holy grail of vaccine development," Kublin said. "If we can confirm we found the right ones, it could dramatically accelerate our research."
The South Africa trials will test new, improved versions of the Thai trial vaccines, along with other promising vaccine candidates. Phase 1 studies are already taking place to make sure the vaccines are safe. The goal is to move through phase 2 trials and launch large phase 3 trials — which investigate whether the vaccines are effective — in 2015.
The Bill & Melinda Gates Foundation is providing critical funding to help Fred Hutch finish the South Africa lab and proceed with the trials. If they confirm the Thai trial's results and verify McElrath's correlate discoveries, researchers will know which antibodies future vaccines should aim to produce. That would position HVTN to launch smaller, more targeted trials that try to quickly zero in on a better vaccine.
"If we get the right results, we could potentially make the vaccine far more effective in a relatively short period of time," Corey said.
In South Africa, many children have been orphaned because of the devastating effects of AIDS.
In October, McElrath will return to South Africa for the opening of the new lab in Cape Town. As she thinks ahead to the trip, she's far more hopeful than when she witnessed the virus's grim impact outside Durban.
"I'm 100 percent sold that we'll be able to find a vaccine that works," McElrath said. "It might take a long time, and we're going to need some luck along the way, but we're going to get this done."