Our learned or acquired immune system is slower to respond at first, but it is highly specific in its activity and can respond fiercely and briskly once it has learned a task. It includes specialized CD4+ T cells, CD8+ T cells and B cells. Unlike the innate immune response, these specialized cells will walk right past a group of neighborhood thugs (e.g., the flu virus, the fungal infection, etc.) to find a specific wrong-doer (e.g., HIV). If they're HIV-specific cells, they will seek out and destroy HIV-infected cells or if they are HIV-specific antibodies, they will seek out HIV floating in the blood.
HIV-specific cells learn by seeing. Other immune cells show CD4+ cells bits and particles of HIV that they have found while surveying the immune system for trouble. Once these other cells find a CD4+ cell that can learn about HIV (a naive cell), the CD4+ cell communicates with other cells and provides instructions on how to respond. Depending on how HIV is shown or presented to the CD4+ cell, the cell will send out different chemical messages to activate a response.
One type of response is antibody (also called humoral) responses, which are generated by B cells. Generally these battle virus that is free floating in the blood (outside of cells). Another type of response is cellular responses, which are largely carried out by CD8+ cells. These destroy HIV-infected cells (eliminates virus that is inside of cells). Both humoral and cellular responses are believed to be important in controlling HIV replication, though some scientific debate remains about which, if either, is more important.
In the early 1990s, Genentech proceeded with a large study of its therapeutic HIV vaccine, rgp160. Results suggested that the vaccine made no impact on HIV disease progression and there was some indication that people who received the vaccine did slightly worse than those on the placebo. Genentech stopped the study and abandoned efforts in this arena. (Note: This vaccine was later sold to VaxGen, who modified it and is researching it as a preventive vaccine called AIDSVax.)
Results of a large study of Immune Response Corp.'s (IRC) vaccine, the HIV-1 Immunogen (also known as Remune) suggested that the product had little to no impact on CD4+ cell counts or viral load. Unfortunately the study was not large enough to detect differences in the rate of HIV disease progression among those receiving the vaccine compared to the placebo. Pfizer Corporation, which was the principal investor in IRC, abandoned further development efforts of this product.
Many therapeutic vaccine products have been shown to elicit HIV antibody responses and some induce HIV-specific cellular responses in animal, test tube and human studies. Reports from complete and ongoing research will often highlight results from previous studies highlighting a product's immunogenicity. Immunogenicity is the degree to which the vaccine induces immune responses. Whether or not these responses will have any impact on HIV disease is unknown. Both the Genentech and the IRC vaccines were shown to induce at least transient and modest levels of HIV-specific immune responses but neither showed measurable benefits in people living with HIV. Whether larger and more lasting responses will make a difference remains to be seen. Ongoing studies should soon begin to provide answers to this question as some new vaccines, such as that from Merck, produce dramatically higher and longer lasting levels of these responses than any previous vaccine.
Some HIV vaccines have been shown to prevent infection in animal studies, including the Genentech vaccine referred to above. The new Merck DNA vaccine did not prevent infection, but it did appear to alter the course of the disease in animals that were later infected with an aggressive animal virus. Prior vaccination did not prevent the animals from developing disease, but it appeared to significantly slow disease progression. A few other vaccine products have shown similar results in animal studies. Humans do not react the same way to vaccines as animals. While results from animal studies may provide encouragement to vaccine developers to move forward into human studies, they may tell us very little about how the product will (or won't) work in humans. Also, not all animal models are the same -- the types of animals used in a study are presumed to give better or worse information about what the human experience might be like. The kind of virus used to infect the animals in the studies might also make a difference in terms of how the information applies to the human setting.
One aspect of the excitement over animal study results of the Merck DNA vaccine may have to do with the kind of animal used in the studies. The animals used are known to develop a very aggressive form of AIDS following infection. That the product slowed disease in the animals was encouraging. Animals used in other studies do not develop disease following infection with HIV, so some researchers have been less enthused about results of studies where infection was blocked in those models. Of greater interest in the Merck studies is a compilation of new data showing that when the vaccine is used with the right adjuvant (a booster), it produces the strongest cellular immune responses yet seen from a vaccine. Still, researchers are not willing to predict whether it will work well enough to prevent infection altogether or provide therapeutic benefit to those infected already.
The way researchers report therapeutic vaccine study results can be a little misleading and generally this is not intentional or deliberate. The only way, truly, to report on initial findings of small studies of candidate vaccines is to discuss the immunogenicity of the product and any safety concerns. Generally speaking, when you hear or read that a vaccine product or a treatment strategy enhances HIV-specific immunity (either cellular or antibody) it's wise to remember that we have no idea if that is functional immunity or what level of this type of immunity is needed to make a clinical difference.
When considering therapeutic HIV vaccine human study results, look for:
Generally speaking, HIV vaccines are believed to be relatively safe. Likely, vaccines will be given periodically, such as monthly, and side effects might predictably primarily be pain, redness and/or swelling at the site of injection and perhaps fever, fatigue and/or joint pain and stiffness -- as one might expect with any vaccine. In some HIV vaccine studies, more serious reactions have been observed (in a few rare cases there have been ulcerations at the injection site). It's quite possible that people with autoimmune diseases (e.g., lupus, arthritis, etc.) will be excluded from initial studies -- as stimulating the immune system with vaccination has shown to worsen some of these conditions. It's even possible that stimulating the immune system with an HIV vaccine could worsen HIV disease progression. Results of previous studies don't suggest this is a major concern, but it is possible.
Initially, new therapeutic HIV vaccines will be researched in conjunction with anti-HIV therapy. Some proposed study designs include the use of therapeutic vaccine or placebo in a structured anti-HIV therapy interruption model. The hope is that the HIV-specific immune responses induced by the vaccine will suppress HIV rebound following therapy discontinuation longer than what might be observed among people not receiving the vaccine. If you're considering participating in such a study it's important to understand the potential risks of structured treatment interruption.
When HIV mutates and becomes resistant to the effects of drugs, this is called HIV drug resistance. When HIV mutates and becomes resistant to the effects of the immune system this is called immune escape. At least one previous study suggests that the virus can mutate around the immune response. Theoretically, it's possible that HIV can become resistant to new, functional and potent HIV-specific immune responses. How much this will present a problem for therapeutic or preventive vaccines remains to be seen.
Finally, the potential of HIV vaccines is great. Despite years of research, however, this remains a field of study in its infancy. Many small studies have built the foundation for recent advances and researchers, activists and people living with HIV alike await the results of studies of new vaccine approaches to see where the next steps in this important area might lead.
Back to the Project Inform Perspective March 2002 contents page.