Seventh International Conference on AIDS: Vaccine Development

Much of the Seventh International Conference on AIDS (June 16-21 in Florence, Italy) was devoted to presentations about vaccine development in laboratory studies, animal models, and human trials. Although vaccines have traditionally been used to prevent uninfected individuals from acquiring a new infection, much of the HIV-related vaccine research is expected to be of use to people who are already HIV-positive. In this article we will provide a brief overview of the status of vaccine trials, in addition to relevant news from the Florence conference. We will focus mainly on the results of studies in HIV-infected individuals.

General Overview

There are currently 13 vaccines in various stages of human testing around the world, including six which are being used in HIV-positive volunteers in an attempt to produce an effective immune response against the virus. Several different approaches are being tried. The overall goal is to use a substance which resembles all or part of HIV and which the human immune system will see as foreign and thus attack. The products generated by this immune response, including antibodies and special types of activated white blood cells, would hopefully also be effective against HIV in the bloodstream, and HIV-infected cells, in people who are already HIV-positive. In order for a vaccine to be useful in this population, the immune response to the vaccine will have to be more effective than that which occurs in the great majority of people after HIV infection.

The substances used in the various vaccines are produced by one of the following methods. The whole virus can be killed or inactivated; the Salk HIV vaccine uses this whole killed virus approach. Alternatively, small portions of the virus, including parts of its outer coat (envelope), or portions of its inner (core) proteins, can be produced by genetic engineering technology. These are called the subunit vaccines. Another approach, using synthetic peptides, is also being tested; these are similar to subunit vaccines, but are smaller and produced using different techniques. (A peptide is simply a small part of a protein.) Finally, some researchers are inserting the gene for one or more of these proteins into different microbes (viruses, yeast, bacteria, etc.) which then produce the protein. When these microbes, known as vectors, are injected into people, they make the HIV proteins which they were genetically engineered to produce. This approach is known as the recombinant vector vaccine. Combinations of these, and other methods of vaccine
production, are currently being tested.

In the United States at least five vaccine candidates are in trials separately or in combination with one another. (1) MicroGeneSys is studying a gp160 subunit vaccine called VaxSyn (gp160 is a protein which is found in the outer envelope of HIV). (2) MicroGeneSys has also produced a p24 subunit vaccine (p24 is one of the inner core proteins of HIV). (3) Bristol-Meyers Squibb has a recombinant gp160 vaccine. By inserting the gene for gp160 into the vaccinia virus, the modified virus makes gp160 in the human body. (The vaccinia virus is the same one used for many years for smallpox vaccines.) (4) Viral Technologies is testing HGP-30, a synthetic peptide fragment of p17, one of the core proteins of HIV. (5) The killed-virus vaccine developed by Jonas Salk, M. D., is also in U. S. human trials; however, no new information about it was presented at the Florence conference.

The AIDS Vaccine Evaluation Units (AVEUs), a group of five universities, are the Federal Government's primary testing sites for vaccines. The AVEUs are located at Johns Hopkins University, St. Louis University, University of Rochester, University of Washington in Seattle, and Vanderbilt University. They have only tested vaccines in HIV-negative volunteers so far, looking for safety data and for the degree of immune response. Two vaccines are also being studied at the National Institutes of Health (NIH) in Bethesda, Maryland; neither of these trials is now recruiting new volunteers. For information on vaccine trials in the U. S., call 800/TRIALS-A.

Outside the U. S., the drug companies Chiron and Ciba-Geigy are jointly developing a gp120 vaccine (gp120 is another envelope protein). A French scientist, Daniel Zagury, M. D., from the University of Paris, is using a novel combination approach which includes some of the products discussed above, in addition to inactivated white blood cells and inactivated products of these cells, in an attempt to restore immune function in people with HIV infection.

Florence Conference News

The overall sentiment of researchers at the Florence conference can be summarized in the following statement by Anthony Fauci, M. D., the U. S. government's highest official AIDS researcher, from the opening session of the conference: "...Vaccine development creates an imposing challenge to the biomedical research community... Hopefully, and I am optimistic in this regard, we will witness the availability of a safe and effective vaccine against HIV in the decade of the 1990s." According to Daniel Bolognesi, M. D., one of the leaders in HIV vaccine research from Duke University, several vaccines should be ready to enter large-scale human trials for testing of effectiveness in the next three years. Currently, several small clinical trials are ongoing. We will describe the preliminary results of most of these studies as they were presented at the conference.

Subunit Vaccine: VaxSyn

The recently published report from the Walter Reed Army Institute of Research, using VaxSyn in thirty HIV-positive volunteers with greater than 400 T-helper cells, received widespread media attention in the United States during the week of the Florence conference (Redfield RR, Birx DL, Ketter N, and others. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. New England Journal of Medicine, June 13, 1991; volume 324, number 24, pages 1677-1684.) This study found that the vaccine was safe and caused an immune response in 19 of the 30 volunteers. Those who were able to mount an immune response tended to have higher T-helper cell counts when they entered the study; they were also more often in the group which received six injections rather than three. T- helper cell counts remained stable in the 19 vaccine responders over a ten-month period, but dropped approximately seven percent in the group which did not respond, suggesting that the immune
response to the vaccine may have had some protective effect.

Another small study of VaxSyn, looking at two doses in 20 patients in Montreal, was presented at the conference (abstract # M. A. 1329). Eight of the nine patients who had been followed for over 180 days were reported to have developed an increased antibody response. In addition, T-helper cell counts stabilized above their baseline values, and HIV could not be cultured from the blood.

VaxSyn is also being studied in HIV-negative volunteers and at several other sites in people with HIV infection. In addition to studies of this compound by itself, it has been combined with several other vaccine approaches.

Combination of Two Subunit Vaccines: VaxSyn Plus p24

Gary Blick, M. D., from Greenwich, Connecticut, reported on the first of two community-based trials of gp160 (the VaxSyn product) in combination with a recombinant p24 vaccine (abstract # M. A. 1343). In the first study, data from 25 patients, including 16 without symptoms and nine with AIDS or symptomatic HIV infection, were presented. The vaccines appeared to be safe and well tolerated. p24 antibodies were increased; analysis of the response to gp160 has not yet been completed. After five months the majority of patients with initial T-helper cell counts above 200 demonstrated small but statistically significant increases in their T-helper cell counts and other T-cell measures. There were no significant increases in the group with T-helper counts less than 200 at study entry. Five of 30 original patients withdrew from the study because of development of new opportunistic infections.

Dr. Blick began a second study in May of this year in which all volunteers receive gp160, but half are randomized to receive the p24 vaccine in addition, with the other half receiving a placebo. This study is designed to learn if adding the p24 increases the effectiveness. In addition, this vaccine will be given by a different route than that used in most other HIV vaccine trials -- by intradermal instead of intramuscular injections. It is possible that the vaccine will produce a greater immune response when deposited directly under the skin, where large numbers of immune cells are located.

All three of the studies using VaxSyn suggest that this vaccine, either alone or in combination with a p24 vaccine, does cause an immune response. There is also preliminary data suggesting that there may be some clinical benefit for individuals with relatively high T-helper counts. None, however, have proven to be effective in helping people with HIV infection stay healthier longer. It is impossible to know whether the immune response elicited by the vaccine will be more helpful than that which the body creates on its own in response to HIV infection. It is clear, however, that the immune response elicited to VaxSyn is different from that elicited by HIV infection (see abstract # M. A. 1344).

Larger, controlled trials will be required to determine if this vaccine will be helpful clinically. It will also be important to learn how to use it in combination with other vaccines, in combination with antiviral and/or immune-enhancing drugs, or when administered by different routes, in different dosages, with different frequencies, etc. None of the studies so far can answer these questions; they do, however, show the importance of further research in this area.

Live Virus Vector Priming Followed by Subunit Boost: HIVAC- 1e, Then VaxSyn

Two studies, one in macaque monkeys and one in HIV-negative people, demonstrated that a technique of using two different types of vaccine elicited a larger, potentially more effective, immune response than did either approach alone. Barney S. Graham, M. D., Ph.D., from Vanderbilt University's AVEU, reported on a small study using Oncogen/Bristol-Myers Squibb's recombinant gp160 vaccinia virus vector (called HIVAC-1e) as a priming immunization, followed several months later by a booster immunization with VaxSyn (oral presentation # F. A. 1). According to the study authors, this combination produced a larger, longer-lasting immune response than either had produced alone. In addition, a greater proportion of those immunized with both vaccines produced so-called neutralizing antibodies, which are expected to be effective against HIV.

Shiu-Lok Hu, M. D., of the University of Washington reported on a study in macaque monkeys using this same approach (abstract Th.A. 12). These monkeys were protected against infection with SIV (simian immunodeficiency virus, which is similar to HIV and infects some kinds of monkeys). Dr. Hu only used one strain of SIV, the same one from which the vaccines were developed; it is not known if this approach would protect the monkeys from infection with another SIV strain.

Dr. Bolognesi noted that the human trials reported by Dr. Graham, and being conducted at the University of Washington in Seattle by Larry Corey, M. D., are showing impressive immune responses in HIV-negative volunteers (keynote speech, June 21 plenary session). However, he warned that the vaccinia virus vector may not be safe for use in HIV-positive individuals. Developing alternative vectors is therefore crucial for the application of this approach to those who are already HIV- infected. He described ongoing research into several alternative vectors, and stated that a combination of vectors and a combination of subunits will probably be even more effective.

Combination Vaccine Approach

from France

A French researcher, Daniel Zagury, M. D., discussed his results from an uncontrolled trial of six individuals with HIV infection (abstract # M. A. 67). Dr. Zagury's strategy combines a number of different elements into what he calls an anti- cytostatic immunization regimen. Although he claims that the patients in his trial have all experienced either stabilization or increases in T-helper cell counts and weight, in addition to other clinical and laboratory signs which suggest improved immune function, criticisms of his program voiced at the conference were significant. Researchers were concerned that Dr. Zagury tested a combination of compounds without testing each one individually, making it impossible to determine which one or ones were effective. In addition, he was criticized for not using a control group to see if there was a difference between those patients treated and those who remained untreated.

Although valid concerns were raised, it was impossible to tell how much of the criticism arose from historical hostility which many of those present at the conference seem to feel towards Dr. Zagury. In any case, Dr. Zagury's combination of HIV peptides, HIV pseudovirions, inactivated alpha-interferon and inactivated suppressor T-cells, a combination which he devised based on a new theory of immune function and dysfunction in HIV infection, is intriguing. The results he claims suggest that this approach deserves serious consideration.

Conclusion

In addition to the human studies discussed above, many reports of progress in the design of new and improved vaccine approaches, and early animal studies in various models of HIV infection, show hopeful signs in the development of safe and effective vaccines. These studies could lead to development of a significant additional tool for the treatment of HIV. For this goal to be achieved, significant funding, along with international scientific and political cooperation, will be crucial.