skip navigation

Skip Nav

HIV/AIDS News

Testing AIDS Vaccines: What Do All Those Terms Mean?

Date: July 1, 1992
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)

In a person infected with HIV, the immune system gradually develops a Jekyll-and-Hyde-like quality. HIV infiltrates the immune system's intricate network though its chief cell, then multiplies and spreads throughout the body. Such a clever strategy poses an extraordinarily difficult challenge to scientists who design AIDS vaccines.
To develop an effective AIDS vaccine, researchers need to know which immune responses might protect against HIV infection. Clues about these so-called correlates of immunity have been uncovered, but their precise identity is so far unknown.
The several candidate AIDS vaccines now in human trials were made using the most up-to-date information available about HIV and modeled after successful vaccines for other diseases. In analyzing the data from these trials, researchers first look for any adverse side effects caused by the vaccine as well as evidence of a vaccine's immunogenicity, the ability to stimulate an immune response.
Immune Responses
There are two main types of immunity: humoral immunity and cellular immunity. Humoral immunity refers to protection provided by factors that circulate in body fluids, primarily blood and lymph. The key components of humoral immunity are antibodies, custom-made proteins produced by B cells, a type of immune cell, in response to a foreign invader like HIV.
Several different kinds of antibodies exist. Binding antibodies are made in response to parts of the vaccine itself. These antibodies can attach to HIV and prevent the virus from infecting other cells.
More important, neutralizing antibodies destroy HIV directly. The V3 loop on HIV's gp120 envelope protein has been identified as the primary region that stimulates these antibodies. For this reason, gp120 and its precursor protein, gp160, often form the basis of recombinant AIDS vaccines. Neutralizing antibodies also are called functional antibodies because of their ability to kill HIV directly.
The second type of immunity, cellular immunity or cell-mediated immunity, refers to two specific immune responses: those of the cytotoxic T cell or lymphocyte (white blood cell) and those of the regulatory T cell. Cytotoxic T cells (abbreviated CTL) have been nicknamed "T killer cells" because they also destroy HIV directly. (Cytotoxic T cells carry CD8 receptors on their surfaces and also are referred to as CD8+ T cells.)
Regulatory T cells are lymphocytes or white blood cells that direct the immune response much like a conductor leading a symphony orchestra.
One important kind of regulatory T cell is the T helper cell, which is the main target of HIV. The virus latches on to the cell through a receptor, called CD4, carried on its surface. Hence the other name for T helper, CD4+ T cells.
In contrast to CTLs, a subset of T helper cells called T memory cells, which are evoked upon first exposure to an invading organism, kill HIV indirectly. The name "memory" reflects their specialized function, which is to create a "criminal record file" on the organism. If it enters the body again, T memory cells will recognize it immediately and quickly stir the immune system into action.
The most common way to measure T memory cells is by a test called the T lymphocyte proliferation assay, which detects any cells circulating in the blood that have CD4 receptors. The vast majority of these will be T helper cells.
To be effective, a vaccine may have to stimulate mucosal immunity, a response of cells of the immune system located in the mucous membranes where HIV is likely to enter the body.
Strain Variation
One element critical to consider in designing vaccines against HIV is strain variation. Strain variation is a comparative measure of genetic relatedness among the various strains of HIV found to infect people.
Based on genetic relatedness, scientists have ordered the know HIV strains into five groups. The envelope region of HIV in each group differs from that of all others by an average of 32 percent.
HIV undergoes a continuing evolution within one person and within populations. Strain variation can result from many factors: random mutations, migration and differences arising from the development of drug resistance. The typical mutation rate is about one percent per year. Scientists still do not know how much HIV strain variation bears on the success or failure of a vaccine, although to date, most neutralizing antibodies produced to one HIV strain have not successfully neutralized another HIV strain.
The first AIDS vaccines constructed used a strain of HIV called LAI. Since then, this laboratory-propagated virus has been found in very few people. Newer vaccines have been based on SF-2 or more recently MN, the most common strain found in Europe and North America. Strains found in Africa and other parts of the world also are being incorporated into vaccines.
Potency Boosters
Because the HIV proteins used to make vaccines so far stimulate a weaker immune response than desirable, some scientists have focused their efforts on making new vaccine adjuvants, substances that enhance the potency of a vaccine. Currently only one adjuvant-alums-is approved for use in humans. New adjuvants and novel uses of them may revolutionize the design of all vaccines.
A different way to boost immune responses is the prime-boost vaccine strategy. In two ongoing trials, researchers first primed volunteers with a deactivated vaccinia virus (the virus used vaccinate against smallpox), containing HIV genetic material. The vaccinia virus, therefore, becomes a carrier (or vector) for the gp160 HIV gene. This vaccine stimulated T memory cells but few antibodies. Next, the researchers boosted the same volunteers with a recombinant form of the same HIV protein, gp160. This approach generated higher levels of neutralizing antibodies than any vaccine thus far used alone.
One concern of this approach is that an improperly deactivated vaccinia virus could be produced by accident. If used as a vaccine, vaccinia virus could potentially harm HIV-infected people with damaged immune systems who have never been exposed to either the smallpox virus or to the vaccine. Thus, other carriers of HIV genes also are being developed or evaluated. One new carrier, a canary poxvirus that closely resembles vaccinia, is in clinical trials already. Another carrier being considered and known to be safe is BCG, the tuberculosis vaccine, the most widely used vaccine in the world today.
Stages of Testing
Once preclinical work has demonstrated the apparent safety of any vaccine for humans, it next must show safety and effectiveness in three stages of human clinical testing before it can be made widely available.
A Phase I trial is the first setting in which such an experimental vaccine is given to humans. Phase I HIV vaccine trials enroll a small number of non-HIV-infected volunteers, usually fewer than 20. The purpose of a Phase I trial is to assess any side effects of the vaccine and gather initial data on the vaccine's immunogenicity. Researchers also try to determine how large a dose of vaccine can be tolerated without compromising safety. A Phase I trial usually lasts one to two years. All of the dozen or so AIDS vaccines currently being tested in uninfected people are in Phase I trials.
If Phase I testing shows that a vaccine is safe, it can proceed into Phase II trials. These trials enroll much larger numbers of patients, as many as a few hundred. Here researchers gather more information about safety and immune responses and begin to ask questions about whether a vaccine is effective against HIV infection. Phase II trials can take from one to two years to complete.
In Phase III trials, also known as efficacy trials, the vaccine is tested in an uninfected population at high risk for acquiring HIV. HIV vaccine's safety and effectiveness will be compared with those of a control vaccine or an unrelated vaccine known to be safe, such as the hepatitis B vaccine. An efficacy trial can involve thousands of volunteers and thus takes much longer, at least four years, to complete.
National Institute of Allergy and Infectious Diseases, National Institutes of Health
Monday, July 20, 1992
AIDS Vaccine Stimulates Antibodies; Immune Stimulant Produces Some Side Effects
An experimental AIDS vaccine coupled with a novel immune stimulant (MTP-PE) in an oily emulsion (MF59) has elicited high levels of anti-HIV proteins. These proteins, called antibodies, can neutralize HIV-1 or prevent it from spreading between cells, according to Raphael Dolin, M.D., of the Rochester Medical Center in New York, who will present these findings in Amsterdam.
One-third of the volunteers who received the vaccine with the immune stimulant, MTP-PE/MF59, had significant systemic side effects, such as fever, muscle aches or headaches. When the vaccine was given with MF59 alone, however, patients still developed antibodies and few side effects occurred.
The vaccine used is a recombinant form of HIV's envelope protein gp120 (env 2-3 made by Biocine-Chiron/CIBA-GEIGY). It was given along with MTP-PE combined with MF59, which is an experimental formulation used to boost the potency of the vaccine, and is referred to as an adjuvant. Currently, only one adjuvant, alum, is approved for use in humans.
Thirty-six volunteers received 30 micrograms of vaccine plus one of six doses (0 to 100 micrograms) of MTP-PE with MF59. The vaccinations took place at zero, 30, and 180 days. A fourth dose is planned to be administered at one year.
Reactions were mild if no MTP-PE was given; however, the severity of the side effects did not increase directly with increasing dosages of MTP-PE. Significantly, 18 volunteers who received only MF59 and vaccine appear to have similar antibody responses but only mild side effects compared with those who received the complete adjuvant plus vaccine.
The researchers say that, although some side effects occurred, the results are encouraging in that they show good antibody production, as well as some evidence of neutralizing antibodies, those that kill the virus directly.
Results are still being analyzed to determine which dose of MTP-PE, if any, is required for the most effective production of neutralizing antibodies.
National Institute of Allergy and infectious Diseases, National Institutes of Health
Monday, July 20, 1992
Vaccine Protective in Chimpanzees Shows Early Promise in Humans
A candidate AIDS vaccine made from a bioengineered form of the HIV envelope protein gp120 was well tolerated by volunteers at two different doses and evoked a variety of immune responses, Mary Lou Clements, M.D., M.P.H., of the Johns Hopkins Center for Immunization Research is expected to report at the Conference.
The vaccine, IIIb gp120 given in alum, is made by Genentech, Inc., South San Francisco, Calif. Prior studies showed that this vaccine protected chimpanzees against an intravenous challenge with the same strain of the virus as used in the vaccine.
In the human trial, 28 uninfected adult volunteers were chosen at random to receive either 100 mcg of the vaccine (10 volunteers), 300 mcg of the vaccine (10 volunteers) or alum alone (eight volunteers). The investigators followed the same immunization schedule as in the chimpanzee trial, injecting three doses of vaccine at zero, four and 32 weeks.
The most promising news, says Dr. Clements, is that after the third vaccination, nine out of 10 volunteers in the high-dose group produced neutralizing antibodies. The vaccine also stimulated T memory cells.
Dr. Clements and her colleagues will give this same group of volunteers a booster dose of the identical vaccine or a similar one made by Genentech with gp120 prepared from the MN strain, the most prevalent strain in the United States and Europe.
Dr. Clements, principal investigator, is carrying out this trial in collaboration with the St. Louis University School of Medicine AVEU led by Robert Belshe, M.D., and with Thomas J. Matthews, Ph.D., of the network's Central Immunology Laboratory at Duke University.
National Institute of Allergy and Infectious Diseases, National Institutes of Health
Monday, July 20, 1992
Novel HIV Vaccine Passes Safety Test
The first recombinant gp160 vaccine (Immuno AG) designed to match the shape of the naturally occurring gp160 HIV protein stimulates antibodies against HIV and is well-tolerated in adult volunteers, according to Robert Belshe, M.D., of St. Louis University School of Medicine.
"The results of this multicenter trial are encouraging because the vaccine is safe and the antibody responses are larger than those observed with similarly low doses of other HIV vaccines," says Dr. Belshe, who plans to present the results in a poster session at the Conference.
For the study, 60 HIV-negative volunteers, 27 women and 33 men, at the five AIDS Vaccine Evaluation Units (AVEUs) were chosen to receive four injections of either 12.5 or 50 micrograms of the vaccine or alum in a novel carrier, deoxycholate, an adjuvant that served as a comparison control. They received a primary shot and, later, three boosters at one, six, and 12 months.
Multiple doses of the vaccine evoked binding antibodies to HIV's envelope proteins. After just two doses of vaccine, all of the eight volunteers tested showed T-memory cell responses. Geoffrey Gorse, M.D., also of the St. Louis AVEU, plans to present data about the stimulation of these memory cells by the vaccine.
As is common practice, this first study of the vaccine started at a low dose, and the antibody responses elicited, according to Dr. Belshe, was not strong enough to neutralize HIV. "At a higher dose (200 micrograms)." Dr. Belshe says, "we hope to see functional antibody that will attack and kill HIV." This trial extension, scheduled to begin soon, will involve 25 volunteers.
The Immuno AG vaccine was developed under a research agreement between NIAID, the National Cancer Institute and Immuno AG of Vienna, Austria. It was the first candidate AIDS vaccine made from a recombinant HIV protein produced in mammalian cells. This unique process produces a vaccine that more closely mimes
the gp160 protein of HIV. The investigators hope this strategy stimulates a better antibody response.
Dr. Belshe served as principal investigator of this study, which was conducted at all five AVEUs.
National Institutes of Allergy and Infectious Diseases, National Institutes of Health
Monday, July 20, 1992
"Prime-Boost" Vaccine Strategy Analyzed and Improved
At last year's international AIDS conference, Barney S. Graham, M.D.,Ph.D., reported on a combination of two vaccines that produced better immune responses than any single vaccine tested thus far. After analyzing data from their ongoing study in more detail, the Vanderbilt University School of Medicine researcher plans to report at this year's Conference on how to enhance the "prime-boost" strategy:
0 a longer interval between vaccine primer and booster increases the antibody responses;
0 two inoculations of the live vector vaccine used for priming improves response to the booster; and
0 individuals who have the best gp160 antibody response to the primary vaccination also will have the best antibody response to the booster.
Based on this new information, two new trials have begun in the NIAID-sponsored network. Both will employ two doses of the same primer vaccine: inactivated vaccinia virus that acts as a shuttle for the HIV gp160 gene. The original booster was recombinant purified gp160 made in insect cells (MicroGeneSys); newer recombinant booster vaccines will to be used in the new trails. These are made in mammalian cells to preserve the structural integrity of the gp160, a strategy that is expected to induce better immune responses. Four-to eight-month intervals will be required between primer and booster vaccinations.
Dr. Graham serves a principal investigator of this study, which is being carried out at all five AIDS Vaccine Evaluation Units (AVEUs).
National Institute of Allergy and Infectious Diseases, National Institutes of Health
Monday, July 20, 1992
Third Booster Shot Enhances Antibody Responses
Results from the longest-running prime-boost trial show that a third booster dose significantly increases antibody responses overall but does not improve levels of neutralizing antibody. Julie McElrath, M.D.,Ph.D., of the University of Washington School of Medicine in Seattle plans to discuss these findings at the Conference.
In the trial, twelve healthy uninfected volunteers (10 immune to vaccinia, 2 not) had previously received two doses of the vaccinia-recombinant gp160 primer vaccine (HIVAC-le, Bristol-Myers-Squibb). One year later, the researchers gave the volunteers two booster doses,8 week apart, with the MicroGeneSys recombinant gp160 vaccine.
The third booster vaccination, administered 12 to 20 months after the second, increased overall antibody levels two to five times more than the second shot. Levels of neutralizing antibodies levels, however, remained unchanged.
The vaccine also stimulated strong T-memory cell responses four to eight weeks after the third booster shot; these responses were equal to those seen after the second booster.
According to Dr. McElrath, it appears to be the primer-booster combination, not repeated boost with the recombinant protein alone, that stimulates higher levels of neutralizing antibody. She and her colleagues currently are revaccinating the study population with HIVAC-le.
This study differs from the one directed by Barney Graham, M.D., of the Vanderbilt University School of Medicine AVEU in variations in the immunization schedule and its inclusion of people already have immunity to vaccinia.
The University of Washington School of Medicine AVEU, the site of this trial, is headed by principal investigator, Larry Corey, M.D.