Vaccine Approaches Currently In Development
The need for an effective HIV vaccine has never been greater. Worldwide, more than 30 million people have been infected with HIV, and each day nearly 9,000 new infections occur, more than 90 percent of these in developing countries. In the United States, an estimated 40,000-80,000 new infections occur each year.
For most of the world's HIV-infected individuals, recent advances in the treatment of HIV/AIDS will have little impact. The high cost of developing and producing new drugs and the lack of available funds for health care in many countries make it unlikely that the new therapies will ever be widely available in the developing world.
Significant obstacles remain in the effort to develop an effective HIV vaccine. Primary among these are: 1) a lack of understanding by researchers of what constitutes the so-called "correlates of immunity" that protect against HIV infection or disease; 2) the highly variable nature of HIV; and 3) the lack of an ideal animal model to test HIV vaccines.
Discussed below are some of the more promising vaccine approaches that are currently in development.
Subunit vaccines (gp120 vaccines), which are produced by genetic engineering, include a portion of HIV located on the outer surface of the virus (also known as the envelope or glycoprotein). Two types of HIV subunit vaccines, gp160 and gp120, have been tested in a wide range of clinical studies. Both Chiron Corp. and Genentech, Inc. (Genentech's HIV vaccine program has been spun off to a newly created company, VaxGen) are developing gp120 vaccines that have been widely tested in Phase I and II studies.
In June, 1994, the NIH decided not to proceed with a large scale Phase III study of the gp120 vaccines in the United States. Supporters of the decision noted that the vaccines did not generate antibodies capable of neutralizing primary isolates, that is, samples of virus obtained from HIV-infected people, as opposed to laboratory-grown virus. The vaccines also failed to generate a type of cellular immune response that researchers have reason to believe important in preventing HIV infection. Those opposed to the decision noted that the gp120 vaccines had protected a number of chimpanzees from HIV infection and that efficacy studies were the only definitive way to determine whether the vaccines were effective. Despite the NIH decision, Chiron's gp120 vaccines continue to be studied in Thailand and as part of a prime boost (see below) combination in the United States. VaxGen is planning a Phase III efficacy study of its gp120 vaccine in Thailand. The company also hopes to initiate a Phase III study in the U.S. as well.
For the subunit vaccines to be tested in Thailand, both VaxGen and Chiron have incorporated new gp120 components derived from freshly isolated HIV. VaxGen has also done so for the candidate vaccine that it plans to test in the U.S.
Recombinant vector vaccines utilize live virus or bacteria (known as a vector) to transport an HIV gene into the body to create an immune response to the product of that gene. The most promising live vector vaccine currently in clinical trials is the "ALVAC" class of vaccines. These vaccines, which consist of HIV genes inserted into a live canarypox virus, are produced by the French pharmaceutical company Pasteur-Merieux-Connaught (PMC). The ALVAC products are being studied in combination with a booster shot of a gp120 vaccine. Another recombinant vector that is being studied in human HIV vaccine trials is vaccinia (used in the smallpox vaccine). Other vectors which are in the pre-clinical development stage include: polio virus, BCG (bacillus Calmette-Guerin, a strain of mycobacterium used as a tuberculosis vaccine), Salmonella, Venezuelan equine encephalitis virus, and adenovirus.
Prime boost regimens utilize a combination of vaccines to induce both cellular and antibody responses. Generally, the prime will include a recombinant vector vaccine which will, it is hoped, induce cellular immune responses. The boost usually consists of multiple injections of a candidate vaccine (such as a subunit vaccine) that stimulates antibody production and T-helper cells. Researchers hope that the combination of the ALVAC prime plus Chiron's gp120 boost will generate strong cellular and antibody responses that can protect against HIV infection.
Preliminary data suggests that the combination of the ALVAC vaccine and a gp120 boost is safe and can induce new cellular responses to HIV in 25 to 50 percent of participants. A Phase II study of this prime boost combination recently began in the United States, and the NIH and PMC are currently discussing plans for a Phase III efficacy study.
DNA vaccines are being studied for a wide variety of diseases, including HIV, influenza, tuberculosis and malaria. Also known as naked DNA vaccines or nucleic acid vaccines, these vaccines utilize the direct injection of selected genes of the pathogen directly into the body. These genes, when taken up by the cells, enable the individual's own cells, in effect, to make selected HIV proteins. By doing so, these vaccines attempt to induce an immune reaction akin to that induced by a live vaccine without using a live virus.
In animal studies, DNA vaccines have demonstrated the ability to generate significant cellular immune responses. Another advantage of DNA vaccines is that they can be produced relatively inexpensively. Companies with HIV DNA vaccine development programs include Merck, PMC, and Chiron, and smaller biotechnology companies such as Apollon and Auragen. Of these companies, only Apollon has initiated human studies. One of these studies examined the use of an HIV DNA vaccine as an immune therapy in HIV-positive patients. According to the company, the vaccine appears to be safe and immunogenic in these individuals. Apollon has also initiated Phase I studies of two different HIV DNA candidate vaccines in HIV-negative volunteers, in conjunction with NIAID. Recently, Merck announced that it was expanding its HIV DNA vaccine program.
Whole-killed vaccines (also known as whole-inactivated vaccines) are used to prevent a broad range of diseases, including polio, influenza, and a number of bacterial infections. Whole-killed vaccines are produced by inactivating a virus or bacteria. A number of different methods of inactivation can be used, including inactivation by chemicals or irradiation.
To date, only one whole-inactivated HIV vaccine has reached human trials. The vaccine, known as Immunogen (the anti-HIV "Salk vaccine") is produced by the Immune Response Corp. and has been studied as an immunotherapy in HIV-infected individuals.
In early studies, whole-killed vaccines (using inactivated simian immunodeficiency virus) demonstrated promising results in macaque monkeys. However, later studies indicated that the protection was based on both the vaccine and on the challenge virus having been grown in human rather than monkey cell lines. In studies in which both the vaccine and challenge virus were grown in monkey cells, whole-inactivated SIV vaccines failed to provide consistent protection. Nevertheless, many researchers believe that whole-killed vaccines are still a potentially viable HIV vaccine approach.
Companies that are currently conducting pre-clinical studies of whole-killed HIV and SIV vaccines include the Immune Response Corp., the Austrian pharmaceutical company Immuno AG, and an Italian pharmaceutical company, Castevecchio, which is working with researchers at the London Hospital Medical College. Other groups such as Acrogen, Inc. and the Salk Foundation are also seeking to develop whole-killed HIV vaccine products.
Live-attenuated vaccines are used to protect against a broad range of diseases, including measles and polio. In monkeys, live-attenuated SIV vaccines have provided the most consistent and impressive protection against simian AIDS. Harvard researcher Ron Desrosiers has tested a broad range of live-attenuated SIV vaccines with key genes deleted. Desrosiers demonstrated that monkeys injected with the live attenuated vaccines usually become infected with very low levels of SIV without developing disease for a long period of time, even when challenged with massive doses of pathogenic SIV. Other laboratories in the U.S. and Europe have replicated these results.
Despite these interesting results, human studies of live-attenuated AIDS vaccines appear unlikely at this time, primarily due to safety concerns. Researchers are concerned that live attenuated HIV, when given to humans, may revert to pathogenic virus at a later date. In fact, a few monkeys have recently developed simian AIDS from the live attenuated SIV vaccine.
A U.S.-based group, the International Physicians for AIDS Care, recently called for the initiation of a small and carefully monitored human study of a live-attenuated HIV vaccine. The group announced that 50 of its members would volunteer for such a trial. However, many researchers are of the opinion that given the evidence in monkeys, such a trial is premature at this time.
Virus-like particle vaccines (also known as VLP's) consist of non-infectious HIV look-alike particles that contain one or more, but not all, HIV proteins. The vaccines are produced by constructing a viral particle that is non-infectious, but contains enough of the viral structural proteins to make it immunogenic.
One type of virus-like particle vaccine, or "pseudovirion" vaccine, is being developed by Pasteur-Merieux-Connaught (PMC). The company is developing an HIV pseudovirion vaccine that contains gp160, gp120, p55 and p24, but lacks other essential HIV proteins. PMC hopes to initiate Phase I studies of their candidate vaccine in 1998.
Peptide vaccines consist of chemically synthesized pieces of HIV proteins (peptides) known to stimulate HIV-specific immunity. To date, peptide-based vaccines have shown less than impressive results in human studies, but some work is continuing.
Overall, a broad range of HIV vaccine approaches are being studied. Slow, but steady, progress is being made in developing candidate vaccines. However, none of these products appears ready for large-scale human trials at this time. Nevertheless, the growing realization that a vaccine is the only way to stop the global AIDS epidemic may translate into more substantial funding and greater future progress in the effort to develop a safe and protective anti-HIV vaccine.
The preceding article appeared in the Fall 1997 issue of The AmFAR Newsletter and is reprinted here with the permission of the American Foundation for AIDS Research (AmFAR). The premier issue of AmFAR's HIV Experimental Vaccine Directory is included in the newest edition of The AIDS/HIV Treatment Directory (Vol. 9, No. 1).
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