The Dream of a Vaccine
The Dream of a Vaccine
Despite all the research that has gone into developing treatments for HIV and AIDS, many experts believe that prevention of HIV infection in the first place remains the best hope for halting the epidemic. To that end, experts believe that an HIV vaccine is required since, historically, only vaccines have been able to eradicate a given disease. As Sam Avrett, the associate scientific director of the International AIDS Vaccine Initiative (IAVI), explained:
Vaccine research is critical because a vaccine is one of the best foreseeable ways to control the AIDS epidemic, both in the U.S. and around the world. Anyone who has worked in HIV prevention knows that, while behavioral change and condoms and clean needles go a long way toward preventing HIV, staying uninfected is hard.… Although behavior change can do a lot, it is just not realistic to expect individual behavior change, by itself, to control this epidemic.39
Some experts hope that not only might HIV vaccines prevent infection, but that because they boost the immune system, many of the vaccines in development might also be therapeutic. In other words, even in HIV-positive individuals, vaccination could have a positive effect by keeping an HIV infection from developing into AIDS.
The financial commitment of governments and private foundations is one measure of the importance policy makers place on vaccine research. In the United States alone, some $456.3 million is earmarked for HIV vaccine research in 2004. Experts believe that the amount of money spent will continue to increase disproportionately to other components of HIV research because of the great value of effective HIV vaccines. Vaccine development, however, has not been a straightforward endeavor; after decades of research, although a number of different approaches have been identified, there has been no definitive success.
In the 1980s, when scientists first began to search for a vaccine to prevent HIV infection, they approached the problem as they had for other diseases such as polio: first cripple the virus, and then use the crippled virus to train the body's immune system to deal with the real infection. With polio, the crippled virus was inactive, and the vaccination was safe—that is, there was no chance that the vaccination would cause the disease it was supposed to prevent. For the most part, scientists felt that it would be fairly easy to develop an HIV vaccine. As Gallo recalled in 2001, "I thought it would be exceedingly difficult to get new therapy against HIV; [I] thought [it would be easier] to get a vaccine."40 Gallo now admits that he and many others were wrong. In the case of HIV, the virus has proven far too complicated for the traditional approach to work; it mutates so rapidly and produces so many viral variants that vaccinating a patient against one strain will not necessarily confer immunity against all forms of HIV. It requires a deeper understanding of HIV at a molecular level for a successful vaccine to be developed.
With further research, many molecular details of HIV have been revealed and understood. Scientists have discovered the structure of the virus and the way that HIV latches on to helper T cells. The virus's ability to mutate and the extent of the mutations are better understood. With the new information, slow progress has been made toward vaccine development.
By the early 1990s, scientists had begun to see initial successes in animal subjects. For example, in 1990, three groups of scientists at Immuno AG in Vienna, Genentech in south San Francisco, and the Pasteur Institute in Paris were able to use HIV vaccines to protect chimpanzees from infection. Building on these initial triumphs, vaccines for humans were soon ready to be tested.
In 1992, human clinical trials of AIDSVAX, a vaccine developed by a California company called VaxGen, began. Specific for strains of HIV common in North America, AIDSVAX was made of synthetic proteins that are copies of a protein found on the surface of HIV. This surface protein, called gp120, facilitates the binding of HIV to helper T cells. AIDSVAX essentially tricked the immune system into mounting an immune response against the synthetic gp120 proteins, even though there was no accompanying HIV infection. Since only gp120 viral proteins are introduced, patients could not get AIDS from the vaccine. Rather, the hope was that the vaccine recipient would get a head start in developing HIV-specific antibodies, and presumably, real HIV particles would be destroyed in the bloodstream before infection could occur.
After it was proven safe in the first two phases of clinical trials, AIDSVAX became the first AIDS vaccine to enter the final phase of testing. Two large-scale trials were put into place to test the vaccine's ability to prevent HIV infection. The first involved fifty-four hundred volunteers from the United States, Canada, Puerto Rico, and the Netherlands, and the second involved twenty-five hundred intravenous drug users in Thailand. At regular intervals, the participants were screened for HIV to test whether the vaccine conferred any protection.
Both trials proved disappointing to the vaccine's creators. In February 2003, initial results from the first trial were released, followed in November 2003 by the initial results from the Thai trial. It was clear from the data that the HIV-infection rate for the volunteers who received AIDSVAX was not significantly different from the HIV-infection rate of those people who only received a placebo. Furthermore, the secondary goal of the vaccine—to slow the progression of AIDS in already infected individuals—also was not achieved. Both trials were halted.
Scientists now know why AIDSVAX failed. The vaccine was designed around gp120 because it was thought that this protein was essential to HIV and would stay fairly constant. As it turns out, the gp120 that is part of HIV can mutate into a number of forms, and the virus's ability to destroy the immune system is not impaired.
Exploiting a Natural Immunity
While AIDSVAX was being tested, another very different vaccine was being developed. Doctors in Nairobi, Kenya, had noticed that about 5 percent of the two thousand prostitutes studied at an HIV clinic seemed to have developed a natural immunity against the virus. Though these women were repeatedly exposed to HIV, they remained uninfected. As the director of the clinic, Dr. Omu Anzale, explained, "The very first exposure wasn't able to cause infection, but was able to prime their immune system."41 In fact, T cell production in these women actually increased significantly. Somehow, these women's bodies were able to mount effective defenses against the initial onslaught of HIV. Furthermore, instead of being left with weakened immune systems that succumbed more readily to HIV upon the next exposure, these women seemed to be prepared for the virus and continued to win the battle against HIV.
Researchers at the United Kingdom's Oxford University and at the University of Nairobi, in partnership with the IAVI, developed a vaccine meant to mimic the resistance seen in the Nairobi women. The researchers designed the vaccine, named DNA-MVA, based on the A strain of HIV, the dominant strain found in Kenya and much of eastern Africa. DNA-MVA would introduce portions of HIV viral DNA into the recipient. Rather than using viral proteins directly as happened with AIDSVAX, with DNA-MVA, viral proteins are produced when the viral DNA enters the recipient's cells. The presence of these foreign proteins tricks the immune system into producing antibodies. This bit of trickery gives the immune system an advantage that might prevent real HIV from overpowering the immune system as efficiently.
To get around the problems caused by HIV's rapid mutation rate, the researchers picked twenty short DNA sequences that correspond to fragments of HIV proteins, rather than whole proteins. Smaller targets for the antibodies would presumably mutate to a lesser degree; furthermore, the variety of antibodies produced in response to the vaccine would ensure greater effectiveness in the long run.
Researchers noticed that some of the initially HIV-resistant prostitutes—if they stopped unsafe sexual practices for a time and then returned to work later—did develop HIV infection. From this, researchers concluded that constant exposure is key to HIV resistance. An effective vaccine, then, would probably include periodic booster treatment. All these observations were factored into the vaccine design.
Clinical trials using this vaccine began in 2000 in the United Kingdom and Kenya. In the first phase, the vaccine proved safe in a small group of volunteers. By 2002, the second phase began, and the clinical trials had expanded to larger groups of volunteers. Preliminary results indicated that between 60 and 70 percent of the people injected with the vaccine show early signs that their immune systems might fend off HIV. If results continue to look promising, the final phase of clinical trials is slated to begin in Uganda, Kenya, and a third country not yet determined. If the final phase begins as planned, definitive results on whether the vaccine works or not would be expected at approximately the end of 2006.
A Single Solution
Even if DNA-MVA does prove effective, however, it will not have any effect on the spread of HIV in most of Europe and North America. This is because the DNA-MVA vaccine is specific for the A strain of HIV, whereas in Europe and North America, what is called the B strain of the virus is most common. In fact, there are five different strains of HIV altogether, and many of the vaccines in development are strain specific. Many of the vaccines currently in development are based on the B strain of HIV, but, as in the case of DNA-MVA, scientists around the globe have pushed ahead on vaccines for other HIV strains. For example, in India, where HIV research has yielded some positive results, officials announced in October 2003 that a vaccine specific for the form of HIV predominant in India, the C strain, had been developed and that human trials would follow.
Scientists think that either completely different vaccines would be needed to combat each of the other strains of HIV, or that the vaccine design would have to incorporate aspects of HIV that are not strain specific. To that end, some scientists, including Dr. Anne De Groot, chief executive officer of EpiVax, a vaccine development company in Providence, Rhode Island, are attempting to develop a vaccine that would train the immune system to target elements shared by all strains of HIV.
De Groot's plan takes the idea behind DNA-MVA—to use a large number of small protein fragments as templates for antibody production by the immune system—one step further: instead of limiting the protein fragments to one strain of HIV, De Groot plans to use those sequences that are common to all five HIV strains. According to De Groot, "There is something about these peptides [short protein fragments] the virus needs, something that really can't change very much, so they are conserved in all strains."42
De Groot's plan depends on a long-known fact about proteins. Proteins are long chains of amino acids that bend and curl to form three-dimensional structures. On the surface, the shape, or topography, of these three-dimensional structures is distinctive—though topography can be similar in related proteins, most of the time, different proteins take on different shapes. Antibodies are designed to recognize specific topographies, so De Groot is attempting to design protein sequences that will fold to look like the topography of HIV. In this way, antibodies to HIV can be produced before actual infection takes place.
The process to find these sequences is long and tedious, mainly because it is not enough to identify short, shared protein fragments—the fragments must also assemble into a shape that can be recognized by the immune system. De Groot and her collaborators must find a handful of protein fragments that share structural similarities for the vaccine, but in the process, they must sort through more than sixty-five thousand potential fragments.
The fragments for De Groot's vaccine will be taken from an HIV protein called env, which is necessary for the virus to form the correct structure. When the prospective protein fragments are identified, DNA that codes for those fragments would be synthesized for the vaccine. In each molecule of vaccine, De Groot plans to put in at least one hundred fragments to enable an extensive immune response. Says De Groot, "There is a lot of evidence in HIV research that the broader the immune response you create, the better you will be able to contain the virus."43
In addition to a preventive application, De Groot envisions that this multistrain HIV vaccine could have a lot of benefit for people already infected with HIV. In research in animals, vaccination after antiretroviral drug therapy boosts the immune system. De Groot feels that this vaccine could help HIV-positive individuals build up their immune systems back to a level where therapy with antiretroviral drugs will no longer be necessary.
De Groot's efforts are being matched in other laboratories around the world. As of 2003, there were dozens of different HIV vaccines at different stages of clinical trials, with dozens more still in development, which altogether represented at least seven completely different scientific approaches to vaccine development. Scientists have found advantages and disadvantages to each approach, and no vaccine has yet been proven effective enough to proceed beyond clinical trials into actual usage. Said Dr. Wayne Koff, IAVI's senior vice president for research and development, "No one knows the magic recipe for an AIDS vaccine. The surest path is to try multiple approaches at once, comparing them against each other to see which are best."44
Indeed, scientists are hopeful that an HIV vaccine may finally be within reach. Even Gallo, whose earlier comments about an HIV vaccine were proven incorrect, is willing to voice his optimism. In 2002, he commented, "We'll solve this problem. I will never again make specific predictions, but I believe that despite what some scientists think, we will find a vaccine. And I'll take on anyone with that bet."45
Still, the optimism is tempered with caution: Experts believe that, as of 2004, a usable HIV vaccine is still a decade away, and it is highly likely that the first vaccines will not be 100 percent effective. Additionally, as research into HIV and AIDS continues, scientists gain new understanding of the virus and its action mechanism. Through this greater knowledge, new and better solutions to the vaccine problem will be designed.
While the world waits for an HIV vaccine, scientists remain open to other alternatives. In fact, a great deal of research is aimed at other forms of prevention and treatment, as well as at clarifying the molecular characteristics of HIV. For example, when scientists finally understood the genetic diversity of HIV and its strains, a new focus was placed on the study of genetics—both of the virus and of the human victims—to find future treatments. Continued research designed to understand HIV more thoroughly is essential for improved treatment of HIV-positive individuals.