About three years ago, Dr. Leo Stamatatos, an internationally known immunologist then at Seattle BioMed, was ready to abandon his efforts to develop the “holy grail” of HIV vaccine research – a vaccine that would stimulate the production of so-called broadly neutralizing antibodies that defend against infection by a wide spectrum of HIV strains.
“Everything had been tried, everything had failed, and I said, ‘Come on, that’s it,’” he said. “There was no reason I was going to keep doing the same thing over and over.”
But a presentation by a visiting researcher gave him a new way of looking at the problem – and sent him and his lab team back to the drawing board to continue their quest.
The results, published today in the journal Science, suggest why previous vaccine formulations haven’t been able to elicit broadly neutralizing antibodies and describe a potential way forward to hit exactly the right B cells, which are a type of immune cell.
“This is the next wave,” said Dr. Julie McElrath, senior vice president and director of the Vaccine and Infectious Disease Division at Fred Hutchinson Cancer Research Center, where Stamatatos and his team moved in October. “Their findings give us new clues to improve our chances of inducing broadly neutralizing antibodies, which is the holy grail of an HIV vaccine.”
Most vaccines work by inducing B cells to produce antibodies so that down the road if a person is exposed to the pathogen, they will be equipped to fight it. One way that antibodies block infection is by binding to and inhibiting, or neutralizing, a pathogen. Typically, neutralizing antibodies narrowly focus on a specific pathogen; most HIV antibodies are specific for a single strain of HIV.
But scientists discovered that after several years of being infected with HIV, about 20 percent of people naturally produce rarer broadly neutralizing antibodies that work against many different strains, although by the time they develop them it is too late to block the virus. Researchers have long believed that to be effective, an HIV vaccine would have to elicit these kinds of broadly neutralizing antibodies, among other types of responses, because the global HIV pandemic mutates so prolifically. So far, there’s been no evidence that any of the candidate vaccines have been able to do so.
In fact, in the 30 years since the AIDS virus was identified, only one vaccine candidate has shown any protection at all against infection. The so-called Thai vaccine, named for the study concluded in that country in 2009, elicited a type of antibody that works by a different mechanism: Rather than neutralizing a pathogen on its own, it binds to and recruits other parts of the immune system to help kill the virus. The Thai vaccine reduced the risk of contracting HIV by 31 percent, not enough to warrant licensing but nonetheless hailed as a breakthrough because it provided the first evidence that developing a protective vaccine was even possible. (In January in South Africa, the Fred Hutch-based HIV Vaccine Trials Network will begin testing a new version of the Thai vaccine that has been modified to boost its potency and durability.)
The idea that convinced Stamatatos to not give up on the quest for a vaccine to induce broadly neutralizing antibodies came from a paper delivered by Dr. Dimiter Dimitrov, a researcher from the National Cancer Institute.
“He said the precursor of one particular broadly neutralizing antibody was not binding HIV,” Stamatatos said. “He had a very narrow sample, but basically, that’s the moment I said, ‘Well, maybe that’s the reason – things just don’t start. For me, it was a light bulb.”
To elicit the type of broadly neutralizing antibody that Stamatatos is after, a vaccine has to stimulate B cells with antibodies that hit a target on the HIV envelope that has a consistent structure across strains. The vaccine candidates that have been tried in the past were effective at stimulating the production of antibodies that targeted parts of the HIV envelope that vary widely between strains, thus blocking only one or a few strains.
Antibodies evolve to bind viruses better as the immune response progresses. So working backwards from broadly neutralizing antibodies that had evolved in patients, the researchers were able to recreate the initial antibodies that first encountered the virus – the ones expressed on the B-cell surface that the virus initially bound to and stimulated. They then tested how well both the mature and precursor antibodies responded to previous vaccine candidates. In a paper published in 2013 in the Journal of Experimental Medicine, they reported that B cells with the mature antibodies on their surface – the ones that had evolved some 10 years after infection – responded well, but the precursors did not respond at all. That’s because the vaccines were made from engineered HIV proteins, and HIV has evolved specifically to avoid detection by those B cells.
“The key thing is that there are the precursors that give rise to those antibodies,” said Dr. Andy McGuire, a postdoc in Stamatatos’ lab who, as a self-described “yeast guy who works in immunology,” brought new thinking to HIV research. “You have to start the process in a naïve B cell. It’s not just broadly neutralizing antibodies per se but the B cells and precursors that give rise to them that we’re studying.”
The new paper, by McGuire, Stamatatos and collaborators at The Rockefeller University and Institut Pasteur, describes a way to modify the vaccine candidate so that neutralizing antibody precursors can target it while it slips away from the other B cells.
“The key was when Andy found out the modification that’s required to start the process,” said Stamatatos.
The work that Stamatatos and his team are doing to stimulate broadly neutralizing antibodies so far has only been done in the lab. But if all goes according to plan, it could be in human trials in about two years.
The trials would be for proof of concept, to show whether researchers can, for the first time in humans, stimulate the right B cells and start the process of making broadly neutralizing antibodies.
“It’s something completely different – the hypothesis and the approach – from what’s been done before,” said Stamatatos. “Just for that, I feel optimistic that we’re going to be one step ahead of where we were. But it’s a long way still. It’s not going to happen overnight.”
Even if human trials show that a vaccine can elicit broadly neutralizing antibodies, researchers would need to find ways to maintain those antibodies for a long period of time. A vaccine would also probably need to elicit other immune responses as well.
“We think now that broadly neutralizing antibodies will be a critical component of an effective vaccine, but I don’t think personally it will be the only one,” Stamatatos said.
One possibility – if trials are successful – would be to combine a vaccine candidate that elicits broadly neutralizing antibodies with, for example, the Thai vaccine, adding to the effect already seen there.
Those are the kinds of challenges that keep Stamatatos and other researchers going through the long years of trying to develop a successful vaccine against HIV.
“You’re not thinking, ‘It’s a failure,’” he said. “We approach it as a problem: Why can’t we make broadly neutralizing antibodies? The daily thoughts center around solving experimental problems.”
Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.
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