Developing an HIV vaccine has been the hope for more than 30 years, when AIDS was first identified—but the task has turned out to be much more complicated than it initially appeared.
Now scientists know more about HIV; they know that making an effective vaccine requires truly historic technology—tools and knowhow to target this and other viruses that are masters at evading the immune system. But with an estimated 33 million infected individuals worldwide at last count, an HIV vaccine is still urgently needed.
Dennis Burton, professor at The Scripps Research Institute (TSRI), is among the select group tasked with creating the next-generation tools to make an AIDS vaccine a reality. Burton directs the International AIDS Vaccine Initiative’s (IAVI) Neutralizing Antibody Consortium on TSRI’s La Jolla, California campus, as well as the National Institutes of Health-sponsored Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). In so doing, he manages some of the most difficult parts of the HIV vaccine enterprise.
Essentially, the goal of next-generation vaccine technology is not simply to provoke antibodies against the virus as the body does naturally—because the immune system normally fails to eliminate HIV from the body. Instead, the goal is to elicit just the right kinds of antibodies—the rare handful that can hit the virus’s well-concealed sites of vulnerability. It was “pie-in-the-sky” stuff decades ago, but Burton’s work has helped make the prospect of such vaccines a question of when rather than if.
“Dennis Burton’s laboratory is at the forefront of global efforts to rationally design new vaccines,” said Wayne C. Koff, chief scientific officer of IAVI. “By understanding the interplay of broadly neutralizing antibodies and virus proteins, [Burton and his team] increase the likelihood for successful future development of vaccines for HIV and other viral diseases.”
A Good Fit
A soft-spoken native of Cumbria in northern England, Burton read chemistry as an undergraduate at Oxford in the early 1970s and worked on nuclear magnetic resonance (NMR) for his PhD work at Lund University in Sweden. Revolutionary techniques in molecular biology were being devised in those days, and Burton found himself moving more and more towards molecular immunology. At Oxford again for his postdoctoral work and at Sheffield University as a junior faculty member, he developed an expertise in the biology of antibodies: the Y-shaped, pathogen-grabbing proteins that serve as the foot soldiers of the adaptive immune response in mammals.
Burton came to TSRI on a sabbatical in 1989 and soon realized the institute was the place to do the kind of research he wanted to do.
It was a good scientific fit. Just months after arriving, Burton and colleagues in Richard Lerner’s laboratory achieved a major advance: the use of new techniques to make mammalian antibodies within easy-to-grow bacterial cells. Employing tiny viruses called phages, they could insert the genes for any antibody into these bacterial cells, make numerous identical copies (“clones”) of the antibody and study it. In principle, they could use these tools to display the entire human antibody repertoire—capable of binding to billions of distinct sites (“epitopes”) on viruses or other targets—in a large cell culture array and screen for those antibodies that had an activity of interest.
That breakthrough led the members of Lerner’s group in many fruitful directions and has already yielded several blockbuster drugs. Burton, who started his own lab at TSRI in 1991, decided to use the new technology to help make better vaccines.
Decoys and Changing Targets
The traditional or “classical” virus vaccine approach has been to mimic large parts of the virus in question, thus displaying to a person’s immune system essentially the same mix of targets it would “see” in a real infection. That approach has been good enough to bring about one of the great revolutions in human health. In places where children are routinely vaccinated, once-common diseases such as smallpox, polio and diphtheria are now virtually unknown.
But some pathogens can’t be beaten this way. HIV, for example, conceals its vulnerable surface protein sites—especially the site where it docks with receptors on human T cells—within deep thickets of sugars, and the parts of the surface protein that are exposed tend to mutate from one viral generation to the next. Most of what the immune system “sees” on HIV are these ever-changing decoy molecules, and so the resulting antibody response is almost always only to single strains of HIV. Inoculating people with traditional-type vaccines doesn’t protect them from the overwhelming majority of the hugely diverse set of HIV strains that circulate globally.
However, using the new technology for growing and studying antibodies, Burton and his colleagues hit upon an alternative vaccine approach. In the early 1990s, they began taking samples from virus-infected individuals, determining what antibodies the individuals were making and studying the same antibodies in the lab dish.
Among other things, they could determine how effective each antibody was at blocking viral infection in the lab dish and in animal models, and how it worked—where it grabbed the virus, in other words.
In 1994, Burton, the late TSRI Professor Carlos Barbas and their colleagues announced that they had found a rare antibody that could block the infectivity of a broad selection of HIV isolates. The antibody, made from B cells harvested from an HIV-positive patient, turned out to work by grabbing a relatively unchanging (“conserved”) structure near a site on the HIV envelope protein that the virus uses to dock with T cells.
The Great Challenge
The discovery of this antibody, b12, suggested that an effective AIDS vaccine was at least possible. But unlike traditional vaccines, this next-gen vaccine would have to provoke the immune system into doing something it never did in a natural HIV infection: produce large numbers of b12 or other such “broadly neutralizing” antibodies.
For Burton and his colleagues, finding a way to generate such a tightly focused immune response has been the great challenge of the past 20 years.
Burton’s lab and others within his consortia have been making notable progress. They have isolated even more broadly and potently neutralizing HIV antibodies than b12. They also have mostly characterized at atomic-scale the viral epitopes where these antibodies bind—itself a hugely difficult task, given the flimsy, tripartite architecture of HIV’s envelope protein.
Taking the structural data on these broadly neutralizing epitopes and using this information to design effective antibody-provoking immunogen proteins—the main ingredients in a vaccine—is still a major unfinished task for HIV vaccinologists. But its achievement could be near at hand. In January 2014, TSRI researchers and their colleagues reported a proof of principle of the next-gen approach in which they designed immunogens that elicit specific neutralizing antibodies against a childhood respiratory virus known as RSV.
That retro-design feat remains to be demonstrated for an HIV vaccine. “But hopefully, there’ll be some indications of success in the next few years that will tell us we’re on the right track,” Burton says. “It will be a major breakthrough when we can design an immunogen that induces significant levels of broadly HIV-neutralizing antibodies.”
Indeed, that feat should pave the way for an effective preventive vaccine. But all this work on neutralizing antibodies could pay off in another way, too. Last year, Burton’s lab, working with Dan Barouch’s lab at Harvard Medical School, reported that infusions of broadly neutralizing anti-HIV antibodies nearly wiped out an HIV-like virus in infected rhesus monkeys. The two labs are now investigating the possibility of using a cocktail of such antibodies, along with anti-HIV drugs and perhaps a strong T-cell-eliciting vaccine, to—as Burton puts it—“clear out the virus from all its reservoirs in the body.” He cautions that it’s unclear so far that they’ll be able to do this, though “it remains an important task.”
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