When World AIDS Day was first observed 30 years ago, Dr. Larry Corey was already in the thick of it, a scientific leader in the struggle to tame a pandemic that has now taken 35.4 million lives.
Today, the former president and director of Seattle’s Fred Hutchinson Cancer Research Center continues to lead international efforts to stop HIV/AIDS, focused on the search for an effective vaccine. He is a principal investigator of the HIV Vaccine Trials Network, or HVTN, an organization he founded at Fred Hutch in 1998. Today it manages 18 clinical trials at 44 sites worldwide. They include three of the largest and most important trials of HIV vaccines.
In advance of World AIDS Day on Dec. 1, Corey sat down for an interview at his Hutch office about that effort and the goal that has eluded HIV researchers for more than three decades.
“We are cautiously optimistic at this time in HIV vaccine development,” he said. “People look at me and say, ‘Why are you able to be so clear about this strategy?’ And I say, ‘I’ve lived this. This was my life when I was 40 years old.’”
An HIV vaccine, to be clear, is not around the corner. But Corey thinks we are now better equipped to guide the rational development of progressively more-effective vaccine candidates than we were when his HIV-research career began.
From 1987 to 1992, Corey headed the AIDS Clinical Trials Group, a network that shepherded studies of the early AIDS drugs and continues to support HIV research today. Already an acclaimed virologist, he drove the effort to use “viral load,” a measurement of how much HIV is in the bloodstream, to gauge the effectiveness of drug combinations.
It worked. Those trials eventually showed that combinations of antiviral drugs blocked infection and turned HIV into a survivable chronic disease. They now provide a lifeline to nearly 22 million HIV-positive people around the globe.
Corey sees similarities between the development of viral load measurements and the use of molecular cues — called correlates of protection — to tell researchers whether experimental HIV vaccines may be working. Over the past decade, researchers have been identifying and refining their understanding of these cues. One example would be the amount of a certain immune protein called an antibody in the bloodstream that is needed to protect against HIV.
While the development of antiviral drugs to block HIV is one of the most remarkable medical advances of the 20th century, Corey is emphatic that treatment alone will not stop the epidemic.
“In the U.S., for the last decade, we have between 40,000–45,000 new cases each year. Worldwide, there are still 1.8 million new infections per year. That is mind-numbing. That’s a city twice the size of Seattle, every year. That’s why we need an HIV vaccine,” he said.
His cautious optimism is based on three large trials now underway, primarily in Africa and the United States. Each is exploring a different approach. The largest and longest-running is called HVTN 702, which began enrolling 5,400 South African men and women in 2016. Results are not expected until late 2020. This vaccine builds on one tested in Thailand nine years ago that was 31 percent effective in blocking HIV. Not good enough, but it showed for the first time that a vaccine could work. Researchers hope they can improve that performance with a reformulated, improved version now being tested in this trial.
A second trial launched one year ago, HVTN 705, is testing an entirely new approach, using a blend, or mosaic, of genes drawn from many different subtypes of HIV found around the world. The goal is to arouse a such a broad immune response — a flurry of different HIV-targeting antibodies — that the vaccine could protect someone against any HIV variant they might encounter. This trial plans to enlist 2,600 HIV-negative women in South Africa, with results coming in 2021.
The third trial is actually a pair known as the AMP studies, which have been underway since April 2016 in southern Africa, Brazil, Peru, Switzerland and the U.S. They are now fully enrolled with more than 4,600 participants. When antibodies lock on to the surface of a virus, they block its ability to infect healthy cells. But HIV is notorious for its ability to evade antibodies through mutations of those surface sites. The AMP studies were designed to find out whether rare proteins called broadly neutralizing antibodies — which bind to molecules on the HIV surface that are less likely to mutate — can provide protection against the virus.
“To have enrolled this many people to receive intravenous infusions every two months is one of the great tour de forces in investigative medicine,” Corey said. “To date, more than 30,000 infusions have been given, without a single infusion-related infection.”
Results are expected in 2020. If they show a protective effect, efforts will be made to blend in additional broadly neutralizing antibodies, with modifications so they can be given more conveniently, by injection, and less frequently, every four to six months. Prototypes are already in clinical trials.
“Broadly neutralizing antibodies and vaccines are now sort of where we were with AZT in those early trials,” Corey said, referring to the first AIDS drug ever approved. “We hope AMP sets a target as to what level of neutralization of HIV is associated with protection. If we can do that, we know we can improve upon AMP.”
As the due dates for these studies show, 2019 is planned to be a quiet year for HVTN’s most important trials. Every six months, independent monitors will get a peek at the results to assure that the trials are running properly and are not harming any volunteers.
“We want these vaccines to work, but more than anything we want to understand the correlates of protection,” Corey said. “So, if we get 60 percent efficacy, we can move that up to 90 percent, or even 95 percent.”
The HIV vaccine work at Fred Hutch draws on the expertise of cancer immunologists at the research center, and in turn it informs their efforts to coax the immune system into fighting cancer. “There is always cross-fertilization,” Corey said.
He noted that research suggests some vaccines may have failed because a person’s own immune system may react against and eliminate the HIV-blocking antibodies the vaccines were designed to produce. Such an autoimmune reaction is of interest to cancer researchers and infectious disease researchers alike.
“You look at some of the mechanisms by which cancer escapes the immune response, and those mechanisms help to understand how this happens,” Corey said. “Cross-fertilization in science often leads to the unexpected. That’s the beauty of being in an institution with first-rate people.”
Corey hangs on to the hope that the steady progress in understanding the immune response to HIV and candidate vaccines will bear fruit, but he acknowledges that this effort has been “a bigger slog” than the earlier work that led to effective HIV medications.
“I need to temper my enthusiasm,” he said. “I’ve been disappointed by vaccine development in the past. You don’t go into this business of tackling the world’s largest problems by thinking this is easy. But to do this you have to have passion and, some would say, a tolerance for failure. But I’ve learned in the process of science that if an immunogen does not work, it’s not a failure. We have to understand why it didn’t work or, especially, if it partially works, and then build on that.”
Dec. 1 is the 30th annual World AIDS Day. It will be marked by many events in the Puget Sound region. A selection:
Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at firstname.lastname@example.org.