After twenty-three years of intense research into the human immunodeficiency virus (HIV), together with the accumulated experience of more than twenty million deaths from the in-fection worldwide, there is still no prospect of a vaccine to prevent AIDS. Is the discovery of a vaccine simply a matter of time? Or has this virus presented scientists with a hitherto underestimated, perhaps even impossible, challenge?
The International AIDS Vaccine Initiative (IAVI), the world’s largest single organization devoted to finding an AIDS vac-cine, has argued that the obsta-cles to progress are clear and resolvable—lack of political commitment and inadequate scientific resources. With offices in New York, Amsterdam, Nairobi, and New Delhi, it has invested $100 million in the search for a vaccine. At the Bangkok AIDS conference held in July of this year, Seth Berkley, IAVI’s president, argued that “only a vaccine can end the epidemic,” that “a vaccine is achievable,” and that spending on vaccine research must double to $1.3 billion annually in order to find it. “The world is inching toward a vaccine, when we should be making strides,” he said. The present situation was little short of “a global disgrace.”
But contrary to the predictions and promises of most AIDS experts, the signs are that a vaccine to prevent HIV infection will not be found for, at the very least, several decades to come—if at all. Those responsible for carrying on the global fight against AIDS do not accept this grim outlook, at least publicly. Yet it is a conclusion, based on all the evidence gathered so far, which increasingly defies rebuttal. Until the gravity of this scientific failure is openly acknowledged, a serious debate about how to end HIV’s lethal grip on some of the poorest and most vulnerable human populations in the world cannot take place.
The holy grail of AIDS prevention is a single-dose, safe, affordable, oral vaccine that gives lifelong protection against all subtypes of HIV. The first hurdle facing vaccine designers, therefore, is dealing with the extraordinary genetic complexity of the HIV epidemic.
HIV exists as two strains—HIV-1, which dominates the epidemic, and HIV-2, which is largely confined to West Africa. So far, at least ten different patterns of HIV-1 infection have been identified. These patterns reflect particular geographic and genetic profiles of viral spread. For example, HIV-1 subtype B (there are nine genetic subtypes) is the common form of the virus in North America and Western Europe. India, by contrast, is under threat from HIV-1 subtype C. In Africa, where some two thirds of those with HIV now live (about 25 million people) and where there were three million new infections in 2003 alone, the situation is more diverse. Southern and eastern regions of the continent face a predominantly HIV-1 subtype C epidemic. Central Africa sees a highly mixed picture—HIV-1 subtypes A, D, F, G, H, J, and K. The implications of these differences for vaccine development remain uncertain. The best guess is that the genetic complexity of HIV will influence the effectiveness of any tested vaccine.
There are also over a dozen virus variants, called circulating recombinant forms, whose genomes have a structure that lies in between those of known subtypes. They also contribute to the difficulty of creating a one-size-fits-all vaccine. At present, scientists do not know if each subtype and every variant will need its own specific vaccine. It may well be that they will.
Worse still, a given subtype of the virus does not stay the same. HIV is continually evolving. The ingenuity of the virus in adapting to prevailing pressures in its environment—such as the existence of a vaccine that triggers an attempt by the human body to eradicate it—is owing to an enzyme called reverse transcriptase. This enzyme is essential for viral replication but it makes mistakes as it goes about its work. These mistakes, together with an extremely high rate of virus production, help HIV to produce an enormous family of genetically varied offspring.
Even if a vaccine were available, these different forms of HIV would almost certainly allow some of the virus to “escape” from any protective immune response that the human body mounted against it after vaccination. Some of these randomly generated “escape mutants,” as they are called, would then be selected for survival in succeeding generations of the virus, since they would possess the advantage of being “fitter”—avoiding the body’s immune response—than their nonmutated counterparts.
These problems become easier to understand when one considers how a vaccine to prevent HIV infection would have to work if it was to produce what experts call sterilizing immunity—that is, complete protection from infection. The normal immune system has two ways of responding to infection. The first depends on the antibodies we all produce in our bodies. These large molecules bind to the virus particle and neutralize it, preventing HIV from going on to infect human cells. There are two critically important proteins on the surface of HIV-1, which are called gp120 and gp41. They are the means by which the virus enters human cells and they are the main targets of the neutralizing antibodies. The difficulty is that crucial parts of these surface molecules are hidden from the attacking antibodies. Such resilient viral topography, together with several molecular tricks that enable HIV to evade human defenses, severely weakens the body’s immune response. Antibodies alone are therefore very unlikely to protect us from HIV.
The second response of the immune system involves not the production of antibodies but the rallying of cells to combat infection. There are two types of blood cell that are involved in an effective immune response to HIV—CD4+ and CD8+ T-lymphocytes, cells that develop within the thymus gland. The CD4+ cell is HIV’s primary target. It is this cell type that is hit hardest by the virus, causing the typical immunodeficiency that characterizes AIDS. CD8+ cells—also called cytotoxic T-lymphocytes (CTLs)—matter because, among other actions, they kill cells that become infected with HIV. They are usually assisted in their task by CD4+ lymphocytes, which are, appropriately, also known as T-helper cells. This mopping-up operation has the potential to damp down the damage that HIV can do to the body.
Once a person is infected, a contest begins between the virus, which is trying to establish a foothold in the body, and the cellular immune response, which is trying to stop the virus from doing so. A vaccine should tip the balance of this contest in favor of the immune system by increasing the numbers of CD4+ and CD8+ cells that are poised to swing into action if HIV gains entry to the body at some point in the future.
In truth, a vaccine that strengthens this kind of cell-mediated immunity would probably not prevent infection. It would likely slow the rate at which the virus took over and destroyed the body’s immune system; and such control of viral replication would be immensely helpful if it could be achieved. Indeed, the notion of a CTL-based HIV vaccine is surprisingly popular in view of the technical difficulties of producing it. David Garber and Mark Feinberg, respected HIV investigators at the Emory Vaccine Research Center in Atlanta, write:
If widely implemented, such vaccines may have a significant impact on improving the quality and length of life for HIV-infected individuals, while at the same time reducing the rate at which HIV continues to spread throughout the human population.1
But despite the importance of these T-cell responses against HIV, especially in the acute phase of infection, they ultimately fail to control HIV’s effects. Nobody knows exactly why. It is clear that a CTL-based HIV vaccine would have to improve upon the immune response that is induced by natural infection. This is a huge demand to put on a vaccine and it is far from clear that it could be achieved. Vaccines of this kind would face the additional problem of overcoming HIV’s remarkable genetic diversity.
The sum total of our knowledge about the genetics, biology, and geographical distribution of HIV indicates that vaccine scientists may have met their match in this adaptable foe. The reality seems to be that a vaccine against AIDS is becoming little more than a pipe dream.
Despite these sobering concerns, the rhetoric surrounding AIDS vaccines continues unabated. At the Bangkok AIDS conference this July, for example, IAVI’s publication Scientific Blueprint 2004 strongly advocated the acceleration of global efforts to discover an AIDS vaccine. It deplored the fact that less than one percent of all health product research and development spending is currently allocated to finding a vaccine to prevent HIV infection. But IAVI is less clear about how the new money it is demanding—$650 million—should be spent.
The IAVI’s position is troubling. It raises the expectation that if only enough money were thrown into AIDS vaccine research, then a solution would appear in the not too distant future. But the implication that money is by itself the answer is wrong. The difficulties facing vaccine researchers are far more complex.
Meanwhile, in June of this year, at its Sea Island Summit, the G8 nations endorsed the creation of a new consortium—the Global HIV Vaccine Enterprise. It remains unclear exactly what this new organization will do.2 Such lack of clarity did not stop Lee Jong-wook, the World Health Organization’s director-general, from calling it “a new political and financial dimension” to HIV vaccine development. It is neither political nor financial.
There is talk of greater scientific collaboration, along the lines of the Human Genome Project. The words “strategy” and “synergy” are often mentioned in documents discussing the enterprise, words that certainly indicate good intent. For example, the UK government’s program for tackling HIV and AIDS in the developing world, which was published shortly after the Bangkok meeting, makes the unqualified comment that the enterprise “will accelerate research and development of an effective vaccine.” But so far the enterprise has no formal organization, no overall leadership, and no new money for research—just a $15 million start-up grant to create a “virtual center,” which will likely be located in an already existing American institution.
One reason why scientists created IAVI in 1996 and lobbied for the Global HIV Vaccine Enterprise in 2004 was a sense of collective failure to deliver on earlier commitments to develop a vaccine. Since 1987, there have been over eighty trials of thirty different candidate AIDS vaccines. All have proven to be disappointing. The results of the world’s first two large-scale vaccine studies were reported in 2003. Again, both failed to show any benefit. Given these early disappointments, what can we expect from HIV vaccine research in the future?
The perfect vaccine would be a live but inactive or attenuated version of HIV—that is, a virus which has been disabled and cannot cause disease. This type of vaccine would resemble those already used to prevent polio, measles, and yellow fever. Indeed, the vaccine that eradicated smallpox was a live but attenuated form of the smallpox virus. But the great anxiety about a live attenuated HIV vaccine is that it would be unsafe. Since there is a small possibility that the vaccine could cause the infection it was trying to prevent, the risk, as of now, is simply too great to take.
See David A. Garber and Mark B. Feinberg, "AIDS Vaccine Development: The Long and Winding Road," AIDS Reviews, Vol. 5, No. 3 (2003), pp. 131–139.↩
The idea for a Global HIV Vaccine Enterprise was first raised in 2003 by leading representatives of the Bill and Melinda Gates Foundation, the National Institutes of Health, the Centers for Disease Control and Prevention, UNAIDS, and IAVI. The proposal gave details about structures and standardizations for laboratories, clinical trials, and manufacturing. There was an implicit assumption, nowhere argued cogently, that the science will one day deliver a vaccine. See Richard D. Klausner and colleagues, "The Need for a Global HIV Vaccine Enterprise," Science, Vol. 300 (2003), pp. 2036–2039.↩
See David A. Garber and Mark B. Feinberg, “AIDS Vaccine Development: The Long and Winding Road,” AIDS Reviews, Vol. 5, No. 3 (2003), pp. 131–139.↩
The idea for a Global HIV Vaccine Enterprise was first raised in 2003 by leading representatives of the Bill and Melinda Gates Foundation, the National Institutes of Health, the Centers for Disease Control and Prevention, UNAIDS, and IAVI. The proposal gave details about structures and standardizations for laboratories, clinical trials, and manufacturing. There was an implicit assumption, nowhere argued cogently, that the science will one day deliver a vaccine. See Richard D. Klausner and colleagues, “The Need for a Global HIV Vaccine Enterprise,” Science, Vol. 300 (2003), pp. 2036–2039.↩