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| The Challenges of Vaccine Development |
Scientists have taken a number of approaches to the development of a vaccine for HIV, but the nature of the virus presents significant challenges. HIV infects only humans and chimpanzees. Evaluating vaccine effectiveness in the chimpanzee model is problematic for several reasons. Chimpanzees are scarce, expensive, and do not show signs of disease when infected. There are also ethical concerns raised because chimpanzees are our closest evolutionary relatives. An alternative is the development of a monkey model using simian immunodeficiency virus (SIV) that has been genetically engineered to express HIV components. The downside to this approach is the difficulty of predicting what will happen when a vaccine that was developed using monkey models is administered to humans.
The route of transmission of HIV also presents a challenge for vaccine producers. Typically, an individual is exposed to the virus at a mucosal surface where a particular type of antibody molecule, IgA, mediates immunity. The ideal vaccine should stimulate production of this type of antibody, not just the type found in the circulation (IgG). But even if a vaccine stimulates the production of the appropriate type of antibody, an increasing number of investigators are convinced that it may not be enough. Circulating antibodies cannot clear a latent virus, and infected cells seem to persist in the body for long periods. So it may be necessary to stimulate cellular as well as humoral immunity. Another challenge to vaccine production is the variety of viral subtypes. Because distinct HIV subtypes are more prevalent in certain locations, some scientists have asked whether HIV vaccines need to be developed specifically for certain geographical regions. Alternately, immune stimulation must be accomplished using an antigen, or antigens, common to all subtypes.
Another major impediment to vaccine development is HIV's rapid mutation rate and the presence of multiple viral variants within a given individual. Traditional vaccines, such as those for childhood illnesses, consist of live attenuated (weakened) pathogens, dead pathogens, or parts of organisms. Attenuated HIV vaccines are not likely to be pursued because of the risk of infection - whole, killed HIV is a safer alternative. But, given the rapid mutation rate of the virus, many believe that a variant of the virus unaffected by the immune response would evolve quickly.
Vaccines based on pieces of HIV are safer and easier to prepare. Many efforts have been directed to the production of recombinant HIV proteins that can serve as vaccines. For example, vaccines consisting of the gp120 surface protein, which is needed for virus to adhere to cells, could elicit an immune response, inhibiting viral adherence. Unfortunately, gp120 vaccines may not be successful: the site on gp120 that binds CD4 and CCR5 is apparently buried in a molecular pocket, which is not blocked by antibody.
The AIDS epidemic has spurred additional vaccine production strategies that use genetic engineering techniques. Many scientists are examining strategies for generating cellular and humoral immunity; for example, live non-pathogenic bacteria or viruses can be engineered to express HIV antigens. Researchers at Merck Corporation have inserted the gag gene, which encodes a viral core protein, into modified adenovirus. They hope that as cell-mediated immunity is mounted against adenovirus, the response will also target HIV-infected cells. The protein encoded by gag is among those found unchanged in most HIV variants; therefore, researchers hope that the vaccine could circumvent the genetic variability problem.
The gag gene is also the basis of one of several DNA-based vaccines under investigation. Such vaccines contain "naked" DNA (not associated with chromosomes or other structures), which is injected directly into muscle tissue. The expectation is that some of the DNA will be taken up and expressed by human cells. The immune response directed against these cells is hoped to carry over to HIV-infected cells. Some investigators are combining strategies; for example, Harriet Robinson and her colleagues at Emory University are trying DNA priming, followed by a booster of recombinant pox virus.
More than two dozen experimental HIV vaccines are being studied worldwide. For a given vaccine to be proven safe and effective it must pass through three stages of human testing. Phase I addresses safety and dosage, and involved the administration of the vaccine to dozens of people. Phase II examines efficacy, the ability of the vaccine to elicit an immune response, and involves hundreds of people. Phase III involved thousands of people who are followed for a long periods to establish that the vaccine is indeed protective.
At the outset of the AIDS epidemic some scientists anticipated the availability of a vaccine in two or three years. More than twenty years into the epidemic, a vaccine is still down the road and few believe it will be available soon. The idea of distributing a less-than-perfect vaccine is controversial. Some believe protecting only a certain percentage of the population could limit the spread of the disease. Others believe an imperfect vaccine could provide a false sense of security such that individuals might increase risky behaviors.