Traditionally, most vaccines for diseases other than HIV/AIDS have used weakened versions of the pathogens (viruses and bacteria) that would normally cause the disease. Over 200 years ago, the first vaccine ever discovered was to protect against smallpox. A virus that causes a skin disease in cows was given to people to protect them from the related human virus that causes smallpox. The success of this vaccine led people, about 100 years later, to find ways to weaken the disease-causing pathogens. Often this is done by growing the virus for a long time in artificial conditions in tissue culture until the virus mutates—its genetic material changes—so that this “live–attenuated” (weakened) virus is safe and it protects against disease. The Sabin oral polio vaccine and vaccines against measles, mumps, rubella (German measles), chickenpox, and yellow fever, among others, are made in this way. Because they are still quite similar to the disease-causing (pathogenic) virus these vaccines cause a very strong immune response and often give lifelong protection against the disease. Other viruses, such as hepatitis A virus, are simply killed and used as vaccines.
New approaches needed for HIV
HIV mutates very rapidly, changing its genetic structure even within one infected individual. So it is not practical to make a live, attenuated AIDS vaccine that could grow since it might mutate to become pathogenic and then cause disease in the vaccinated person. A killed AIDS vaccine has been considered, but the practical problem of proving that the HIV is completely inactivated (dead) and the failure of killed vaccines to protect monkeys against simian immunodeficiency virus (SIV, the monkey equivalent of HIV) have led scientists to look for better and safer ways of making an AIDS vaccine.
Viral vectors as delivery systems
Most of the more promising AIDS vaccine candidates currently being developed and tested use viral vectors. A vector is another virus that is not harmful and acts as the delivery system to carry HIV antigens to the immune system. Scientists design a vector to carry only a small part of the HIV genetic material so that there is no way it can cause HIV infection. Once inside the body’s cells, this genetic material is converted to protein. The small piece of HIV protein is called an “immunogen” because it causes an immune response.
Researchers are trying to develop a vaccine so that when the immune system sees the HIV immunogen it responds just as it does to any foreign substance. It is hoped that T and B cells, which are part of the immune system, will respond strongly to the immunogen and some of these cells will then survive for many years (see February and March 2004 Primers on Understanding the Immune System, Part I and II). The aim is to get the immune system to recognize the HIV proteins and prepare long-lived memory cells that will “remember” the HIV proteins and act against the whole virus if a person later becomes exposed naturally through high-risk behavior.
Different viral vectors
Scientists have been developing a number of different viruses as vectors for vaccines. The different vectors all have their own advantages and disadvantages.
Several viral vectors belong to the poxvirus family, relatives of vaccinia (the smallpox vaccine). Some members of this family are safe because they cannot replicate (grow) in humans. Among the poxviruses are modified vaccinia Ankara (MVA), which is weakened vaccinia virus. Scientists have studied MVA as a vector for many years and candidate MVA vector vaccines are in clinical trials. These trials are still ongoing but unfortunately the MVA vaccines have not produced very strong immune responses so far. Other poxvirus vectors in testing include canarypox (made from a vaccine for birds) and fowlpox.
Another viral vector that is being tested in human clinical trials is adenovirus type 5 (Ad5), which is related to the virus that causes some forms of the common cold. The Ad5 vector is modified so that it cannot grow. The current Ad5 vaccine candidate induces strong cell-mediated immunity (see March 2004 Primer on Understanding the Immune System, Part II). A “proof of concept” Phase II trial is about to begin that will test whether cell-mediated immunity can either prevent infection or lessen disease if vaccinated people are later exposed to HIV through high-risk behavior.
Other viral vector AIDS vaccines in clinical trials include adeno-associated viruses and alphaviruses. Adeno-associated virus is not an adenovirus but is often found in adenovirus infections. The alphaviruses being developed as vaccine vectors include weakened forms of three viruses named VEE, Sindbis and SFV. The VEE vector is currently being tested in clinical trials.
Sometimes a viral vector vaccine may be used in a two-step “prime boost” strategy. Usually a small portion of HIV genetic material (in the form of a DNA vaccine) is given first to “prime” the immune system, followed by a viral vector vaccine “boost.” The hope is that the “prime” inoculation will focus the immune response better against the HIV immunogen rather than the proteins that make up the viral vector. Some scientists have used the same immunogen carried by two different viral vectors, one to prime and the other to boost at a later time.
The use of viral vectors is a promising method for developing an effective AIDS vaccine that is safe and effective, but more clinical trials will be needed before the ideal vector or combination is identified and the full potential of this approach is shown.