Scientists compare the hunt for an AIDS vaccine to the search for the Holy Grail. And for three decades, it has proved to be about as difficult to find.
Since Robert Gallo and Luc Montagnier identified HIV — the virus that causes AIDS — in 1983, only three vaccine trials have been completed. The first failed to prevent or control infection. The second also failed, mysteriously increasing infection. The third, completed in 2009, provided protection to only about a third of the people receiving it — but how it did that is still unknown.
Yet, leaders in AIDS vaccine research say they may finally be on the cusp of a period of major discovery leading to a vaccine.
“The past few years have been a turning point,” said Gary Nabel, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. “I’m more optimistic than I’ve probably ever been in my career.”
The optimism stems from recent strides in understanding antibodies — the first weapons the human immune system deploys to fight an infection.
When a person is exposed to the AIDS virus, the immune system churns out millions of antibodies to fight it. HIV shakes off the vast majority of them, so researchers are focused on the remaining minority. These “broadly neutralizing” antibodies bind powerfully to HIV’s outer shell and prevent the virus from invading cells.
Until recently, scientists had been able to identify only four such antibodies. But in the past three years, they have worked out the structures of nearly two dozen, and they have developed the technology to find more.
If they can trigger these antibodies in healthy people, researchers suspect, they can create an effective AIDS vaccine.
HIV is a master at replicating quickly — and during that process, it acquires many small mutations that create subtle changes to the contour of its shell. As a result, the immune system must play a constant game of cat-and-mouse: As soon as the body makes a new antibody to attack HIV’s outer coat, the virus has crafted a new one.
“When you’re fighting a war like this, especially with a very clever virus, it’s not going to just roll over and die when the first responder comes in. It will just put on a new mask and go on,” Nabel said.
Because the virus can mutate so easily, people with AIDS have millions of slightly different copies of HIV in their bloodstreams. With 35 million people currently infected with HIV globally, this amounts to a staggering number of viral disguises — and a successful AIDS vaccine would have to train the immune system to recognize all of them.
Nonetheless, there are vulnerable regions in HIV’s shape-shifting armor that persist across all strains, scientists say. The one garnering most interest is called “Env,” short for “envelope glycoprotein.” Resembling spikes on the virus’s surface, each Env can bind to a white blood cell called the CD4 T cell and then pull the whole virus inside. There, HIV begins its cycle of invasion, replication and escape to other white blood cells, which ravages the immune system and leads to AIDS.
Broadly neutralizing antibodies give researchers hope because they bind to these Env spikes and surround them, blocking their ability to invade the white blood cells. All of these antibodies are good at recognizing the many strains of HIV, but different ones bind to different parts of the spike.
Unfortunately, these antibodies are rare: Only 10 to 30 percent of people infected with HIV make them. And they only appear in a person’s blood three or more years after infection — by which time millions of white blood cells have been breached and the virus is beyond the reach of antibody counterattack.
But studies have shown that injecting these antibodies into monkeys protects them temporarily against infection by HIV, and scientists suspect the same might happen in humans. A vaccine that introduced replicas of parts of Env into the blood might provide a healthy person with a dress rehearsal — a chance for the person’s body to make these antibodies and, hopefully, remember how to do it again quickly if faced with the real virus.
“The existence of broadly neutralizing antibodies proves that an AIDS vaccine is possible,” said Dennis Burton, a professor at the Scripps Research Institute in California and a member of the International AIDS Vaccine Initiative. The problem in the past was that the four known antibodies, though potent, were not ideal for a vaccine — and for nearly two decades, from 1992 to 2009, scientists couldn’t find any more.
Then, through a combined effort of researchers at Burton’s program and Nabel’s center, that began to change. Burton’s team led the way, discovering two new antibodies, dubbed PG9 and PG16 that are at least 10 times more effective at latching on to HIV and disabling it than any of the previous four antibodies.
Last year, 17 more were found. Called the PGT family, these antibodies are 100 times more potent than the pre-2009 antibodies.
“The fact that a single antibody can neutralize over 90 percent of circulating HIV-1 isolates is unreal,” said Peter Kwong, a scientist on Nabel’s team involved in the vaccine initiative. “This is a global pandemic affecting over 30 million people. With all of that global diversity, the fact that even one of these antibodies exists is extraordinary.”
The next step, Burton said, is to figure out which combinations of broadly neutralizing antibodies can best work together against the greatest number of HIV strains. Then, scientists can begin to design a vaccine that would trigger the immune system to produce this combination on its own. (Another approach to reduce the risk of infection by HIV, a drug called Truvada, was approved by the FDA last week. The pill, which must be taken daily and has strong side effects, reduced infection by 75 percent in one large study.)
Researchers attribute the explosive rate of discovery in the last three years to advances in technologies used to look at B cells, which make antibodies.
Momentum grew in 2009 when the Burton team used a tool called the single-cell microneutralization assay. It allowed them to collect millions of B cells from HIV-infected blood and check each cell for its ability to make antibodies that attack HIV.
A second technology of promise is called deep sequencing. John Mascola of Nabel’s team and Kwong have adapted the technology — once used in the Human Genome Project — to collect complete sets of antibody-coding genes from the B cells of people infected with HIV. Kwong described the process as creating a “B cell Library of Congress.”
Deep sequencing’s potential lies in tracing how some B cells in infected people have evolved over years of fighting HIV to create broadly neutralizing antibodies. Kwong said he hopes this knowledge will help create a vaccine that provokes B cells in a healthy person to develop these rare antibodies in the same way.
“If you need to get an antibody from Washington to L.A., you could send it on a random walk and hope it makes it — or you could provide a path that mimics the naturally successful one by planting big road signs that help the antibody get to its final destination,” he said. Large-scale studies are now being conducted around the world to study how B cells evolve in people from the first months of HIV infection.
While antibodies are the first line of defense against HIV, researchers say they are only part of a fight that involves many kinds of immune cells. Understanding that broader response will be key to coming up with a vaccine.
Evidence from the 2009 “RV 144” human vaccine trial, which was conducted in Thailand, suggests that the antibodies produced by the 31.2 percent of those who were protected were not the broadly neutralizing type. Instead, these antibodies may have worked as messengers, calling up other immune cells to kill white blood cells already invaded by HIV.
The Thailand study suggests, Kwong said, that all immune cells must be considered in vaccine design and that more human trials are badly needed.
Scientists working in all facets of AIDS vaccine research share his sentiment.
“Every time we do a human trial, it’s told us something we haven’t anticipated,” said Bruce Walker, a collaborator of Burton’s who leads the Ragon Institute in Boston. “I just don’t think we’re smart enough to be ruling out any concepts just yet.”
For vaccine researchers, the long game is often the only game. After all, smallpox scourged humanity from as early as 10,000 B.C., but it wasn’t until 1796 that Edward Jenner pioneered a vaccine against it and not until 1980 that the World Health Organization declared smallpox eradicated.
From this perspective, Burton — who has been in the AIDS vaccine field for decades — believes optimism is justified. “It’s an exciting time all around. . . . We just have so much more to work with.” Which means the Holy Grail may be within reach.