Friday, January 20, 2006

Where's The Vaccine 40 Million People Are Dying For?

In 1997, President Clinton challenged the scientific community with a lofty goal: to develop an AIDS vaccine by 2007. With just two years left, experts agree that there is no chance a vaccine will be available by then – highly unfortunate, since by current estimates, 40 million people worldwide suffer from HIV / AIDS, including one out of every three people in regions of sub-Saharan Africa. What, exactly, has made AIDS vaccine development so difficult, and how far away is it?

First, it helps to understand how immune responses and vaccines work. If I sneeze and a friend of mine breathes in the virus, her immune system recognizes that the virus is not something normally found in her body. It then reacts by making many copies of specific proteins called antibodies that bind to and neutralize the virus in what is called an antibody-mediated immune response.

Unfortunately, despite the vitamin C she takes every morning, my friend’s body requires time to make these antibodies at first, and by the time there are enough, the virus may already have found its way into her cells and begun replicating. Her body then initiates a different immune response, called a cell-mediated response, in which other immune cells attack and kill her virus-infected cells.

Often, the combination of these two types of immune responses is enough to clear an infection, as in the case of a cold. (A cold is not very fun, but it only lasts a few days.) Unfortunately, HIV has a number of built-in defenses, and the body cannot kill it off on its own.

In order to be effective, an HIV vaccine would have to boost immune responses sufficiently to prevent, or at least significantly limit, HIV infection. But researchers are currently debating one fundamental question about HIV vaccine design: what kind of immune response would it need to spark?

Most vaccines work by initiating an antibody-mediated response, one that attacks viruses (or other pathogens) before they have the chance to enter cells and replicate. This type of vaccine presents the body with innocuous particles having a structure similar to the virus or to a protein produced by it. The body then creates antibodies against the particles – the same antibodies that would attack the real virus. These vaccine-induced antibodies remain in the system, primed for attack, so that when the body encounters the “real thing” in the future, it effectively eliminates the virus before it can establish an infection.

Such a vaccine is particularly difficult to design for HIV because the virus has a highly complex structure, exists in different forms called clades and has the ability to modify its genetic information within the body. A vaccine that induces the production of antibodies against one form of HIV, for instance, does not prepare the body to fight against another. The 2005 AIDS Vaccine Advocacy Coalition Report states, “Anyone who has been tenacious enough to follow AIDS vaccine research over the past two decades knows that the ability to make a vaccine that could induce effective antibodies against circulating strains of HIV remains one of the great unsolved mysteries.”

Because eliminating the virus before it enters cells is so difficult, most researchers have instead focused on developing a vaccine that induces a cell-mediated response, killing already infected cells. This can be done by injecting particles called vectors that have been engineered to carry various viral components inside them. These viral components lead to the activation of particular immune cells which become primed to attack body cells if they ever become infected with HIV. This approach can slow the development of infection and potentially eliminate HIV from the body altogether.

Currently, most of the HIV vaccines being clinically tested – there are over 30 – elicit only this cell-mediated immune response. Some scientists fear that ignoring the antibody-based approach is a bad move. “To have a highly effective vaccine, the broadly neutralizing antibody remains the Holy Grail,” explains Gary Nabel, Director of the Vaccine Research Center at the National Institutes of Health in Bethesda, Maryland, in an interview published in the International Aids Vaccine Initiate Report. If he’s right, then it will be back to square one: researchers will have to find antibodies capable of attacking multiple forms of HIV and will have to incorporate these into a new vaccine.

So, how and when will the scientific community know if, indeed, the cell-mediated response is enough? Scientists are hoping that one recently designed vaccine will answer that question. The New Jersey-based pharmaceutical company Merck has recently begun large-scale efficacy trials in the US, Australia, Caribbean and Latin America for its new HIV vaccine, which uses a cold virus as a vector containing three HIV proteins from one particular clade. Results from this trial are expected in 2008, and they will indicate whether research has been moving in the right direction. “The next three years will bring important decisions for the AIDS vaccine pipeline,” states the 2005 AIDS Vaccine Advocacy Coalition Report.

This is not to say that a vaccine is potentially three years away – to the contrary, the AVAC report admits, “We know that an AIDS vaccine is not around the corner and that making time-bound predictions only serves to raise unrealistic expectations.” Even if the Merck trial is successful, the vaccine will have to enter full scale clinical trials, which will take years even if all goes well. And if the Merck vaccine is not effective, then the scientific community has a lot of work to do. But Nabel is optimistic nonetheless: “We are in the midst of an incredible renaissance in the field of HIV vaccines,” he says in the International Aids Vaccine Initiate Report interview. “The science and technology that we can now apply to advance the field is unprecedented.”


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