It was a bold promise made on an April day in 1984. Secretary of Health and Human Services Margaret Heckler proclaimed that a preventive vaccine for a newly identified virus named human T-lymphotrophic virus type III, or HTLV-III, would be available within two years. Many scientists who heard her claim shuddered.
More than 27 years later, the chill those researchers felt is understandable. For while the promise and confidence of Heckler's statement have dulled, the virus, now known as human immunodeficiency virus, or HIV, has carved a deep niche, becoming a global threat that, according to UNAIDS, infected nearly 2.7 million people throughout the world in 2010. In addition, that same year saw an estimated 34 million people worldwide, more than 1 million in the United States alone, living with HIV or AIDS, the syndrome of illnesses the virus can spawn. And in 2010, 1.8 million people died of AIDS.
In the shadow of these numbing statistics, researchers worldwide toil to develop a vaccine to stymie the virus. This global network of investigators includes many at Harvard Medical School. The perseverance of these scientists is fierce, as is their conviction that a vaccine will be found.
"Finding a successful vaccine is challenging," says Ruth Ruprecht, an HMS professor of medicine, cancer immunology, and AIDS at Dana–Farber Cancer Institute, "because we're shooting at a moving target."
The virus has an uncanny ability to mutate as it replicates, producing different strains, each with its own molecular idiosyncrasies and clinical manifestations. Further, HIV has distinct subtypes, or clades, each of which is associated with a specific geographic region. Another difficulty for researchers, then, lies in developing a vaccine that will offer protection against all HIV clades.
The virus' ability to mutate also makes the use of traditional vaccine strategies—a killed form of the virus or an attenuated form, which is live but weakened—risky and impractical. In general, vaccines try to mimic the body's response to an infection, but the traditional paradigms of vaccine development don't hold with HIV. Although in many cases the body eventually develops antibodies against HIV, these antibodies develop too late in most people infected with the virus, giving it too many chances to mutate and thus escape the actions of neutralizing antibodies.
"Historically, vaccines have quite clearly been our most potent weapon against viral diseases of medical importance," says Ronald Desrosiers, an HMS professor of microbiology and immunology. "The list of diseases controlled or eliminated from the face of the Earth by vaccines is impressive."
HMS scientists have spent the past two decades searching for the right combination to unlock the HIV vaccine mystery. Although none of their attempts has resulted in the perfect vaccine, their investigations have provided key information on the biology of AIDS and have laid the foundation for future efforts.
Bruce Walker, an HMS professor of medicine and the director of the Ragon Institute at Massachusetts General Hospital, MIT, and Harvard, is one of the researchers who has dedicated much of his career to the study of HIV. He leads an international research effort to understand how HIV infection in some people is controlled spontaneously, without medications.
More than five years ago, Walker and his colleagues began studying the genetic characteristics of nearly 1,000 people around the world who are so-called HIV controllers. Though infected with HIV, these people keep their viral load, a measure of the severity of an infection, below 2,000 virus particles per milliliter of blood; a subset called elite controllers keep it below 50. The average untreated HIV patient has, by comparison, a peak viral load of more than 5 million particles per milliliter at the time of acute infection.
"HIV is all about viral load," Walker says. "If a vaccine could keep the viral load below 2,000 particles, we might be able to stop the progression of the disease and transmission might be contained. If you could then replicate this in everybody, the disease would go away."
Other HMS researchers have looked at the effectiveness of vaccine types. The safety of a live, attenuated HIV vaccine, for example, has been debated by researchers for years. In 1992, as other HIV vaccines were failing, a research team led by Desrosiers re-evaluated the risks of a live vaccine by inoculating an animal model with a genetically altered live version of SIV, the simian form of HIV. Three years after vaccination, the animals' immune systems had mounted a successful defense against SIV: They were protected against the disease. At the time, Desrosiers' work was a defining moment for live vaccines; however, subsequent trials of this type of vaccine failed.
In an animal-model study published in Nature in January 2012, Dan H. Barouch, an HMS professor of medicine, and a team of scientists at Beth Israel Deaconess Medical Center showed that an experimental HIV vaccine could partially protect animals against an aggressive, virulent form of SIV. Two different vaccine approaches reduced the chances of infection per virus exposure by 80 to 83 percent. In addition, viral loads were significantly reduced. Although the protection was only partial, the study could become a tipping point for HIV vaccine development for humans: It is among the first to show infection prevention against a difficult-to-block, HIV-like virus.
In 2008, Barouch, together with Lindsey Baden, an HMS assistant professor of medicine and an infectious disease specialist at Brigham and Women's Hospital, spearheaded one of the School's first human tests of an HIV vaccine. Vaccines use a vector, or chemically weakened virus, to stimulate an immune response. Many HIV vaccine candidates have used an adenovirus serotype known as Ad5, which commonly causes respiratory infections such as the common cold, as a vector. Ad5, however, is so common in the environment that many people harbor a pre-existing immunity to it, making it ineffective at inducing an immune response to HIV. For this ongoing trial, Baden and Barouch gave 60 healthy volunteers two or three immunizations using another vector, Ad26, or adenovirus serotype 26. This adenovirus is less commonly encountered in the general population, but it has the ability to induce a potent immune response. Testing of this vaccine candidate is currently underway in sub-Saharan Africa.
The HIV vaccine field reached a turning point in 2009 when researchers reported that a prime-boost approach, one designed to kill cells infected with HIV and to prevent HIV from gaining a foothold in an uninfected person, had cut the HIV infection rates among participants in a large clinical study conducted in Thailand. The prime-boost approach combined two vaccines, which had separately failed to be effective. When mixed together, however, the duo cut the infection rate by 31 percent—not enough of a decrease to make the vaccine combination feasible for widespread human use, but certainly enough to suggest that the development of an HIV vaccine may indeed be possible. Interestingly, Barouch's recent study sheds light on this result, indicating that antibody responses to the envelope protein on the surface of the virus may have contributed to the effectiveness of the vaccine.
Pushing the Envelope
A study by Ruprecht recently identified a portion of HIV's envelope protein as a promising vaccine target. A contorted strand of the protein, known as the V3 loop, was originally thought to be an unlikely target because it is highly changeable. However, a portion of the V3 loop known as the crown is conserved and, thus, provides an attractive bull's eye; antibodies aimed at it may protect against multiple strains of HIV.
Ruprecht introduced a monoclonal antibody, a laboratory-produced substance that binds to specific molecules, into an animal model. The monoclonal antibody was isolated from a person infected with a specific HIV clade. The researchers then tested a hybrid virus made from SIV and the envelope from a different HIV clade in the animals. While the researchers knew the monoclonal antibody would attach itself to a portion of the V3 loop and stop the virus from infecting nearby cells, they weren't sure if the antibody would prevent infection by another virus subtype.
The investigators found that the monoclonal antibody was protective and kept those animals receiving it virus-free; however, the researchers detected high viral counts in serum from animals that had not received the virus. Ruprecht says her findings, the first evidence of its kind, won't necessarily result in an HIV vaccine, but they do demonstrate that complete cross-clade protection is possible. Because more than 90 percent of all HIV infections in the world are caused by four clades, such protection would make developing a "universal" vaccine more manageable.
HMS researchers say we are closer to an HIV vaccine than ever before, but caution that we are still years away from an effective vaccine being tested in humans, let alone being on the market. One of the biggest hurdles to vaccine research today is not researchers' understanding of the science of HIV and AIDS, it's dwindling government support for fundamental HIV vaccine research. Desrosiers and others say many good vaccine concepts are going unfunded while many established projects are languishing.
But this hurdle is not deterring scientists, especially those at HMS, who have made such great strides in a relatively short amount of time. Some of their hope comes from history—it took 92 years to develop an effective flu vaccine. "We're climbing a steep hill," says Walker, "but we are making progress."
Scott P. Edwards is a Massachusetts-based science writer.