The development of a safe, effective HIV vaccine has remained an elusive goal throughout the HIV epidemic. Various approaches to vaccine development have been tried without success. Today, however, there are new innovations in vaccine research that have led members of the HIV community to be optimistic about the possibility of a viable vaccine. The Community Forum on May 2 introduced audience members to immune system function and to the rationale behind vaccine candidates currently in clinical trials. The focus in vaccine research today is not to prevent HIV infection altogether but to train the immune system to wage a response against HIV when it is exposed to the virus. This mechanism is similar to the immune system response to the chicken pox virus -- once you have had chicken pox, you can resist a breakout from future exposures.
Mr. Jefferys first discussed the T-cells, which are immune system cells that protect humans against disease. These specialized white blood cells are produced in the bone marrow, acquire a special marker (CD4 or CD8) in the thymus, and develop a receptor that is specific to a particular foreign matter (also known as an antigen). This receptor is one of a possible 250 million specialized receptors. The T-cell leaves the thymus to circulate through the blood and the lymph nodes. At this stage, the T-cell is "naive" -- that is, it has not been exposed to any foreign matter.
If foreign matter enters the body, it is processed by another type of cell called a dendritic cell. The dendritic cell "presents" the antigen on its surface for identification by a T-cell. The dendritic cells migrate to the lymph nodes (found in the neck, the groin, and the armpits, among other places), where naive T-cells pass. When a naive T-cell encounters an antigen that it recognizes, it becomes activated and proliferates (copies itself) at a rapid rate. This results in a large number of identical T-cells, all of which recognize the foreign matter. The CD4 T-cells (helper T-cells) direct the action of CD8 T-cells (killer T-cells) to destroy the invader. Once the T-cells have done their work, most die off, but some are preserved as "memory" cells -- they remember the antigen and can be activated quickly if the antigen strikes again, allowing the body to be more efficient in its immune response the next time around. The genes in memory cells are permanently changed after their attack on the antigen. As a result, they can recognize the antigen faster than naive cells, release chemical messengers called chemokines and cytokines to help coordinate the immune response faster, and have a longer lifespan than naive cells.
(For a further discussion of the role of T-cells, see Mr. Jefferys' article, "Second Time Around: T-cell Memory and HIV," in CRIA Update, Fall 2000.)
So how does this immune system information apply to HIV, and to an HIV vaccine? As Mr. Jefferys explained it, it has been observed that long-term non-progressors (people who have been infected with HIV for a long time but who maintain stable immune function) have vigorous memory cell responses when exposed to HIV. People who are not long-term non-progressors, however, do not have a vigorous memory cell response and have a harder time fighting back against HIV. Long-term non-progressors have a more vigorous CD8 T-cell response than progressors. This means that their immune systems attack HIV-infected cells more rapidly and are better at "shutting down" HIV before it has a chance to make even more copies.
The ideal for a vaccine is "sterilizing immunity" -- that is, even if you are exposed to a virus, you will not become infected. The virus is stopped dead in its tracks. Because HIV is not readily recognized by the immune system and can infect cells rapidly, sterilizing immunity may not currently be a realistic goal for an effective HIV vaccine. Instead, researchers are focusing on finding a vaccine that confers "controlling immunity," which Mr. Jefferys described as immunity that enables the body to keep infection under control when it occurs and to prevent re-infection by future exposures. This is a memory T-cell based vaccine, and it mimics the immune function of a long-term non-progressor. One benefit to this approach is that it may be beneficial in both HIV-infected and HIV-uninfected individuals.
To develop this type of vaccine, researchers have determined that they must expose individuals to components of HIV so that the immune can be "trained" to recognize HIV and generate an immune response. One major challenge has been deciding which part of HIV to use to generate an immune response without risking HIV infection in HIV-uninfected individuals. One possibility is a "whole killed" vaccine, like Remune, which has all of the components of the virus. Studies so far suggest that Remune does not spark a strong enough response to confer controlling immunity, however. Another approach is to use a vector, that is, a substance that gets HIV proteins into the body so that a response can be generated. It is possible to use vectors such as harmless bacteria or viruses (like weakened adenoviruses, which in their natural form cause colds) to get HIV's genetic material into host cells to produce HIV proteins so that an immune response occurs. Mr. Jefferys explained that this process could occur without actually infecting an individual with HIV.
In the second presentation of the evening, Michael Robertson spoke further about immune system function and the vaccine development program at Merck Pharmaceuticals. Mr. Robertson described three types of immunity: innate immunity, acquired immunity, and cellular immunity.
Innate immunity is an immunity with which we are born. We have immune system cells such as natural killer cells and macrophages that attack any foreign matter without specificity. Acquired immunity is specific; it occurs after exposure to a certain antigen. Acquired immunity involves substances such as antibodies that are produced in response to an antigen. Antibodies assist in immune response by tagging foreign matter for destruction. The third type of immunity, cellular immunity, is the immunity described previously by Mr. Jefferys. Cellular immunity is the most powerful because it produces memory cells for use in future exposure.
So why focus on cellular immune response in HIV vaccine development? According to Mr. Robertson, there are several reasons. For some diseases, a virus-neutralizing antibody vaccine may be used -- the antibody attaches to the antigen and renders it unable to infect other cells. This is not effective in HIV infection, however, because the response is too weak and may be type-specific (the antibody neutralizes one type of HIV, for example, the strain found in North America, but not the strains found in Africa). A cellular immune response model for HIV vaccines has shown promise in the test tube and in animals. In immunized monkeys, boosted CD8 T-cell responses to HIV have resulted in substantially lower viral loads and slower disease progression.
Mr. Robertson described some of the goals of Merck's vaccine research program. The researchers are attempting to develop a compound that will bring about a potent and broad cellular immune response against HIV that will lessen the likelihood of persistent viral infection and/or lead to the establishment of a lower viral load after infection. For people who are already infected, a goal of the vaccine is to use it in combination with HAART therapy to boost the immune system and lessen the effects of established infection.
There are two major candidates for the vaccine. One candidate contains the gene (a strand of DNA) for the HIV gag protein (Merck plans to also add genes for nef and pol). Another candidate is a defective adenovirus that has parts of HIV's genetic material incorporated into its genetic material. Merck plans to study these products both as therapeutic (in the hope of inducing immune system control after stopping HAART drugs) and preventive vaccines. It is undecided whether these candidates will be used alone or in a combination approach, but preliminary studies will be getting underway in the New York area (Cornell and Mount Sinai) in the coming months to start looking for some answers.
HIV vaccine development is our greatest challenge and our best hope for curbing the HIV epidemic. Newly identified candidates will be tested in clinical trials, and, hopefully, a safe, effective vaccine will soon be a reality.