The Hunt for the 'Most Satisfying Solution': Fauci, Researchers Discuss Search For AIDS Vaccine
Published Online: April 21, 2014
Tracey L. Regan
The search for a vaccine to combat the human immunodeficiency virus (HIV), a pathogen “notorious for its rate of mutation and variability,” in the words of Larry Corey, MD, principal investigator for the HIV Vaccine Trials Network (HVTN), was never going to be simple or straightforward.
In a recent confirmation of this challenge, the HVTN, an international collaboration of scientists and educators that conducts clinical trials around the world, ran squarely into failure last year when its multisite, US-based study, HVTN 505, was forced to stop after data showed that the vaccine neither prevented infection nor reduced viral load in those infected with HIV.
“The vaccine failures we’ve experienced have given us humility and served as a reality test,” observes Anthony Fauci, MD, the longtime director of the National Institute of Allergy and Infectious Diseases (NIAID), which sponsors the HVTN. “The development of the vaccine does not follow the usual paradigm, in which we’re taught to look at infection and response and then mimic what has been induced by natural infection. Not only does the body not produce an adequate response to HIV, there are documented cases of superinfection. This means that someone who is already infected gets infected with HIV again, indicating that the original infection clearly did not induce an immune response that could protect the person from getting a repeat infection.”And yet acquired immunodeficiency syndrome (AIDS) researchers and policy experts are far from disheartened.
Fauci says the disappointments represented by trial failures such as HVTN 505 coincide with important scientific and technical breakthroughs on several fronts that are now leading research in promising directions. He describes a 3-pronged approach to vaccine development that includes an all-out research effort into what he calls “the most satisfying solution,” a vaccine based on broadly neutralizing antibodies with potency against the widest possible array of HIV-1 strains; further research into a nonneutralizing antibody that prevented infection in about a third of enrollees in a recent clinical trial; and a “third path” that induces powerful CD8-positive T-cells that can destroy infected cells and clear the virus.
The most effective HIV vaccine could potentially include a combination of these approaches, he and other researchers say. Over the past 3 years, newly gleaned insights into broadly neutralizing antibodies, including breakthrough discoveries enabling researchers to identify, isolate, and characterize the evolutionand behavior of both the antibodies and their antigens, has changed the landscape of HIV research. “A B-cell-lineage design approach that selects out B cells that can recognize epitopes or antigens on the HIV envelope and stimulate the B cells to make broadly neutralizing antibodies (bNAbs) would be the most widely effective tool,” Fauci says. “This is difficult, but we’re working on a good, solid scientific basis.”
One of the principal challenges is that while some people infected with HIV produce these antibodies naturally, they have proved largely ineffective in fighting the virus. “Twenty percent of people infected with HIV can make bNAbs, but only after at least 2 years of stimulation by the virus. At this point, the cells are very mutated. They have developed affinity maturation, and although they are broadly neutralizing, they often don’t help much, as the person has lived through at least 2 years of infection and the virus is firmly established in the body,” Fauci notes. Another long-standing frustration of B-cell research has been the difficulty in reaching the regions on the viral envelope that would be susceptible to an orchestrated attack.
“There are only a few vulnerable areas on the HIV envelope protein–these are conserved regions where antibodies can bind and inactivate the virus. Current HIV vaccines are unable to induce antibodies to these vulnerable regions of the viral envelope,” says John Mascola, MD, director of the Dale and Betty Bumpers Vaccine Research Center (VRC) at NIAID, adding that the epitopes “are particularly difficult to reach because the viral envelope is covered by glycans (sugar molecules).”
Indeed, proving bNAbs existed at all was a critical first step. “We started by studying the serum taken from a large group of people in the early stages of HIV infection. This allowed us to identify donors with potent serum-neutralizing antibody titers against most strains of HIV,” he recounts. “We screened the sera against a large panel of viruses and found that about 20% of people make broadly neutralizingantibodies and we focused on the best of these donors. By sorting HIV-specific single B cells, we were able to isolate HIV monoclonal antibodies with broad and potent neutralizing activity.”
Since then, research by Barton Haynes, MD, director of the Duke Human Vaccine Institute at Duke University School of Medicine, Mascola, and others has mapped the evolutionary paths of both antibodies and different virus strains.1 “We performed B-cell genetic analyses early after an infection and then tracked how antibodies evolve over the course of 2 years. It takes months for the immune system to generate broadly active antibodies against the virus, because it takes that amount of time for antibodies to hone in on a conserved area of the virus,” Mascola explains.
In a May 2013 paper published in Science, Mascola, working with Peter Kwong and NIH colleagues, detailed an important advance in identifying serum-neutralizing antibodies’ responses that could potentially guide future vaccine development.2 The tool they developed, known as “neutralization fingerprinting,” allows researchers to identify which types of bNAbs exist in an individual blood sample and to measure which virus strains these particular antibodies block and with what intensity.
“The next step in developing a vaccine is designing an immunogen that mimics the right viral structure. From everything we know about vaccinations and viruses, if we are able to effectively stimulate the right type of antibody, it is likely that the vaccine could work to block HIV infection,” Mascola notes. Technical advances are playing a key role in what is increasingly interdisciplinary vaccine research. Working together, a group of biochemists, immunologists, and computer scientists at Duke University, for example, were able to determine the structure of a part of the HIV envelope protein, the gp41 membrane proximal external region (MPER), which may prove to be an important target for a broadly neutralizing antibody. Further, they were able to capture the conformational changes in the viral protein as it prepares to insert its genetic material into the host cell, and pinpoint what they believe is an optimal point in that process for a vaccine to bind.
“There has been an evolution in thinking about how gp41 operates, making it important to identify the key intermediate steps in the path gp41 takes when the virus merges with the cell’s membrane in order to develop an effective antibody,” notes Leonard Spicer, PhD, a professor of biochemistry and radiology at Duke and senior author of a study the group published in the Proceedings of the National Academy of Sciences. “As it turns out, 2 of the neutralizing MPER antibodies do not bind well with the resting phase of the virus, but rather at a site where the activity is, and so the intermediate we constructed had to be a dynamic one. The proteins that act on the virus must have a dynamic nature and make conformational changes. The idea is to catch them in the process and to bind at a point in the virus’s action.”3
In order to better observe the virus’s structural changes and its interaction with the antibody, Patrick Reardon, PhD, until recently a student in Spicer’s lab and the first author of the study, engineered a protein that incorporated the HIV MPER and associated directly with the membrane surface. “The MPER is an important target for vaccine development because it is a conserved region that binds several broadly neutralizing antibodies,” says Reardon, now a Wiley postdoctoral fellow at the Environmental Molecular Sciences Laboratory at the Department of Energy’s Pacific Northwest National Laboratory. “The question was whether the neutralizing antibodies would recognize our construct, which was designed to mimic the dynamic intermediate stage that we thought was occurring during viral fusion.” To their satisfaction it did, the study’s authors reported.
“A vaccine must mimic the virus in several ways. It must be a structure recognized by B cells and have properties that induce antibody development customized to the native behavior of the virus,” Spicer said. “In the case of the gp41 envelope protein, we know dynamics are involved—that’s the nature of the viral fusion machine.”
Spicer, a physical biochemist, previously worked with Haynes to develop another domain of the envelope protein, the V3 loop in gp120, with structural and dynamic characteristics that look like those on the viral protein. While bNAbs research is generating excitement in the scientific community, HIV policy experts say it is also important to conduct follow-up studies on the DNA prime/protein boost vaccine model tested in a study known as RV144 study, a collaboration between the Thai Ministry of Health and the US Military HIV Research Program. The vaccine used in that study produced some degree of protection—an overall efficacy rate of 31.2%—without eliciting broadly neutralizing antibodies, although its mechanisms are still unclear, researchers say.
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