Fact Sheet: Number 7 (1996)
Controlling widespread infection with the human immunodeficiency virus (HIV) requires a multi-faceted approach including modification of complex behaviors, development of curative treatments and successful prevention strategies such as vaccination. A vaccine is a treatment given to uninfected individuals which elicits an immune response which protects the vaccinated individual from developing infection after exposure. Since the development of smallpox vaccine in the early 1800's, immunization has been one of the most successful means of preventing infectious diseases. The human immunodeficiency virus (HIV) has been the target of several vaccine preparations which have been immunogenic and well tolerated in human volunteers. Whether such vaccines can prevent HIV infection remains unknown.
How a Vaccine Works. A successful vaccine stimulates long range immunity by stimulating various components of the immune system and their associated memory cells. What component(s) of the immune system best neutralizes infection may vary from organism to organism. Many vaccines use live whole organisms which are less virulent; that is, less capable of inducing disease. These vaccines stimulate multiple immune functions which probably recognize multiple targets to bring about protection. However, making HIV less virulent is a dangerous task since infection is not curable; there is no true animal model for testing and there are justified concerns about reversion to a virulent form. For that reason, preparations are being developed that use portions of the virus to stimulate protection. Determining which portions of the virus to use and what immune functions to stimulate is difficult because there is little evidence to support that a protective immune response develops in humans. Major efforts are aimed at understanding the immune response to HIV and elements which are associated with a protective immune response. The goal is to produce a vaccine that is safe and produces long-term protection against all subtypes of virus. What follows is a discussion of the structure of the virus and the vaccine preparations being developed. (1)
The Structure of the Virus. HIV is a virus whose genes are carried on molecules of RNA. The center of the virus, or core, contains the RNA, some viral enzymes and other proteins which are surrounded by a protein coat. This coat is composed of at least 2 proteins, the p24 antigen and the p5 protein. The core is surrounded by a lipid envelope in which a number of proteins are embedded or attached. Two of these, gp120 and gp41 envelope proteins are derived from a precursor protein sp160 whose cleavage is essential for viral infectivity. It is gp120 which binds to human lymphocytes via a molecule called CD4 which results in infection. Variability in the enveloped proteins among different strains of HIV results in a moving target at which to aim a vaccine.
Animals. HIV only causes AIDS in humans. However, although no animal model mirrors the human infection, the chimpanzee has been used because chimps may be infected with the virus although they do not develop AIDS. Using proteins made in the laboratory, a vaccine composed of gp120 combined with internal HIV-1 proteins has been shown to protect against infection against intravenous HIV-1 viral challenge. Protection was observed at the time of the optimal immune response. Whether the vaccine would be protective at other times or with mucosal challenge (the usual route of infection) is unknown.
Another animal model uses a monkey called a macaque. Macaques can be infected with a retrovirus called SIV which is similar to HIV. A disease which resembles AIDS can be induced following SIV infection. The best macaque model has been one made up of a live but attenuated (weakened) form of the virus in which the nef regulatory gene has been deleted. Nef deficient strains are of interest because six blood or blood product recipients were accidentally infected by blood from a human donor infected with a strain of HIV-1 with a deletion of nef. The recipients have remained free of HIV-1 related disease with stable and normal CD4 counts 10-14 years after infection. (2) Unfortunately, in further experiments with macaques, the nef deletion mutant was found to cause AIDS in newborns raising serious concerns as to the safety of attenuated viral vaccines. Other trials in animals have been reviewed elsewhere. (3, 4)
Humans. Because of the concerns for safety in using an attenuated virus in an HIV vaccine and because it is difficult to demonstrate that an inactivated viral vaccines is non-infectious, most attention has been focused on developing a subunit vaccine. In this type of vaccine a component of the infectious agent (usually a protein) is used to stimulate immune responses. The most work has been done with gp160, the attachment protein and gp41, the part that traverses the viral membrane. Other proteins using p17 and p24 are also being studied.
Subunit vaccines have been studied in phase 1 trials which look at the safety of the vaccine preparation and in phase 2 trials which begin to look at efficacy. All preparations studied to date have been well-tolerated although mild local reactions are not unusual. Systemic symptoms have been seen predominantly with newer additive preparations, called adjuvants, which are designed to augment the immune response. In terms of generating an immune response, most promising have been 2gp120 vaccines. After 3 doses, these vaccines have generated antibodies which neutralize HIV almost all seronegative human volunteers.
The antibody responses generated were not as high as those induced by natural infection. The antibodies produced recognized the particular strain used in the vaccine prep; however, some cross neutralization, that is neutralization of other strains, was observed. In this, as in most vaccine trials, neutralizing antibodies were assayed at times when responses are optimal and were assayed using a strain of HIV adapted in the laboratory which appear to be more easily neutralized than virus obtained from infected individuals. In addition, the significance of neutralizing antibodies in preventing HIV infection is not a known logical first step in vaccine development. Envelope vaccines have also been shown to stimulate cellular immune responses such as lymphocyte proliferation and to generate cytotoxic T cells; that is, T cells which kill cells expressing HIV proteins on their surface. Despite progress, a number of questions remain before completion of large scale trials examining the efficacy of subunit vaccines. Among the most important unanswered questions is whether it is necessary to include proteins derived from multiple strains of HIV.
To increase vaccine efficacy, attempts have been made to improve the way the immune system "sees" HIV. The env gene of HIV has been incorporated into the genes of vaccinia virus or cowpox, the virus used in the vaccine which eradicated smallpox. The altered vaccinia virus replicated inside human cells and expressed HIV proteins. In human phase 1 trials, the antibody response was not as high as observed with subunit preparations and poor levels of neutralizing antibodies were generated. It appears that individuals developed immunity to the vaccinia virus after the initial dose which impaired the ability to develop augmented immune responses directed at HIV with booster doses. However, administration of booster immunizations composed of HIV protein may circumvent this problem and boosting with proteins of different strains of HIV may provide a means for immunizing against a variety of HIV. This method of immunization also results in the generation of cytotoxic lymphocytes.
Canarypox, a virus which does not replicate in mammals, is also being used in the development of a live vector vaccine. It is hoped that a canarypox vaccine would be safer to individuals who might be exposed to vaccinees. Even attenuated viruses capable of human replication may cause infection in persons with abnormal immune systems such as those observed in HIV infection.
Although a vaccine which is protective against HIV has not been fully developed, recent results are encouraging and attempts creative. Nevertheless, many issues remain. For example, who should be the first to test the vaccine? What if the immune response to the virus designates the individual as HIV+ when they are only having an immune response to the vaccine? What if someone actually does become infected but is not considered so because the immune response to the virus is attributed to the vaccine? What if individuals are less diligent in their "safe" sexual practices because they feel protected by the vaccine despite intensive counseling? Further progress will involve difficult decisions in addition to eloquent science. Meanwhile, prevention is the most effective means of avoiding HIV infection.
- Dolin, R. Human studies in the development of human immunodeficiency virus vaccines. J Infect Dis, 172:1175-1183, 1995.
- Deacon, NJ, Tsykin, A, Solomon A et al. Genomic Structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270:988-91, 1995.
- Graham BS and Wright PF. Candidate AIDS Vaccines. N Engl J Med 333:1331-1339, 1995.
- Letvin NL. Vaccines against human immunodeficiency virus- progress and prospects. N Engl J Med 329:1400-5, 1993.