Challenges in Designing HIV Vaccines

Designing an effective vaccine to protect people from infection with the human immunodeficiency virus (HIV) or from becoming ill if already exposed to the virus is a high priority of worldwide efforts to control the epidemic.

The ideal HIV vaccine would be inexpensive, easy to store and administer and would elicit strong, appropriate immune responses that confer long-lasting protection against both bloodborne and mucosal (sexual) exposure to many HIV subtypes. The following describes why this ideal has not been easily achieved.

(Throughout the fact sheet scientific terms common to vaccine research have been printed in bold-faced type and defined.)

What Constitutes Immune Protection?

Researchers face unprecedented scientific challenges in trying to develop vaccines for HIV. The easiest way to design an effective vaccine is to know what immune responses protect against the specific infection and construct a vaccine that stimulates those responses. Although scientists have found clues about these so-called correlates of immunity or correlates of protection for HIV, these factors have not been precisely identified.

Unlike other viral diseases for which successful vaccines have been made, complete recovery from HIV infection has not been documented. Therefore, HIV vaccine researchers have no human model of protection to guide them. Indeed, whether a natural protective state against HIV can exist remains unknown.

However, now that the pandemic has matured, long-term survivors--those who remain clinically asymptomatic and maintain a CD4+ T cell count greater than 200 for at least 10 years following infection--provide ample evidence that some people appear better able than others to resist progression of HIV infection or the development of AIDS. Long-term survivors can be divided into two groups: (1) long-term nonprogressors, those who maintain healthy or steady levels of CD4+ T cells despite many years of infection, and (2) HIV-infected individuals who lose a significant proportion of CD4+ T cells but still remain healthy.

Recent attention also has been directed to those people who remain uninfected despite repeated exposure to HIV. If these multiply exposed but uninfected individuals can be proven to have resisted HIV by an active immune mechanism, they would represent the natural protective state upon which a vaccine could be modeled.

Another clue to why some people resist HIV infection has come from studies of recently identified co-receptors for HIV. Scientists have found that individuals who have inherited two copies of a mutated gene coding for one of these co-receptors, CCKR5, appear to be protected from HIV infection. This suggests that a single targeted intervention may be capable of preventing HIV infection.

To determine the factors that influence the body's response to HIV exposure and infection, investigators are comparing long-term HIV survivors with people who quickly became infected or sick. Leading areas of research include genetics, individual variations in the immune response and exposure to or infection by less deadly HIV variants. Such studies will help clarify what contributes to protective immunity against HIV.

Immune Responses

The ability to stimulate immune responses is called immunogenicity. Two main types of immunity exist: humoral immunity and cellular immunity. Humoral (antibody-mediated) immunity refers to protection provided by the secreted products of one type of white blood cell called a B lymphocyte. These products, custom-made proteins known as antibodies, circulate in body fluids, primarily blood and lymph. B lymphocytes (B cells) produce antibodies in response to a specific foreign invader like HIV or a vaccine.

Several different antibodies can be generated. So-called binding antibodies simply attach to part of HIV and may or may not have antiviral effects. Functional antibodies are binding antibodies that actually do something more. For example--neutralizing antibodies--inactivate HIV or prevent it from infecting cells.

Scientists have identified the outer envelope of HIV as important for stimulating neutralizing antibodies. A major protein, gp120 (glycoprotein 120), is found on the surface or envelope of HIV. Together with its parent protein gp160, gp120 forms the basis of many recombinant subunit vaccines, so-called because each is genetically engineered to contain only one small piece of the virus.

The second type of immunity, cellular (cell-mediated) immunity, refers to activities of T lymphocytes. Cytotoxic T lymphocytes (CTLs), nicknamed killer T cells, directly destroy HIV-infected cells. A subset called CD8+ CTLs (CD8+ T cells) bear CD8 receptors on their surfaces and kill cells that are producing HIV. Other CD8+ T cells can suppress HIV replication without necessarily killing the infected cell. CD8+ T cells may be critical to resisting HIV infection.

Regulatory T cells, another component of cellular immunity, direct antibody- and cell-mediated immune responses, like a conductor leading a symphony orchestra. The chief regulatory T cell, the helper T cell, also is HIV's main target. The virus attaches to the cell through a receptor on the cell's surface called CD4. Hence, helper T cells are called CD4+ T cells.

A subset of helper T cells, memory T cells, are evoked on first exposure to an invading organism. The name "memory" reflects their function, which is to create a criminal record file on that virus or microorganism. If the virus enters the body again, memory T cells will quickly stir the immune system into action. The most common way to measure memory T cells is by a test called the T lymphocyte proliferation assay, which indicates the strength of such cellular responses to HIV.

To be effective, an HIV vaccine may have to stimulate a third type of immunity, mucosal immunity. Immune cells lining the mucous membranes of the genital tract and other HIV portals into the body produce different responses that are not well understood.

HIV Strain Variation

HIV continually evolves as a result of genetic mutation and recombination. Thus, researchers must estimate the significance of strain variation within individuals and among populations when developing AIDS vaccines. Usually a person does not appear to be infected with more than one HIV variant. But once HIV infection becomes established, the virus continually undergoes changes, and many variants may arise within an infected person.

Whenever a drug or immune response destroys one variant, a distinct but related one can emerge. Also, certain variants may thrive in specific tissues or become dominant in an individual because they replicate faster than others. Any of these changes may yield a virus that can escape immune detection.

The envelope and core genes of many HIV isolates, the viruses taken from patients, have been analyzed and compared. On this basis, scientists have grouped HIV isolates worldwide into two groups, M and O. At least nine subtypes or clades have been identified in group M, and only a few in group O. Each subtype within a group is about 30 percent different from any of the others. In contrast, successful vaccines for other viruses have only had to protect against one or a limited number of virus strains.

The first AIDS vaccines made were based on the LAI strain (also known as IIIB and LAV). Subsequently, LAI has been shown to differ from most strains found in infected people. Newer vaccines have been based on the SF-2 and MN isolates, which belong to the same subtype as LAI but better represent HIV strains isolated from North Americans and Europeans.

A preventive vaccine will need to generate immune responses that protect uninfected individuals from all the different HIV subtypes to which they may be exposed.

Scientists are looking for conserved regions of HIV genes, those that produce proteins common to all or most subtypes. If such common proteins are not found, a cocktail vaccine comprising several proteins or peptides from different HIV strains may be necessary to invoke broad-based immunity.

HIV Transmission is Complex

Unlike some other viruses, HIV can be transmitted and can exist in the body not only as free virus but also within infected cells. Thus, a vaccine against HIV may be required to stimulate the two main types of immunity. Humoral immunity uses antibodies to defend against free virus. Cellular immunity directly or indirectly results in the killing of infected cells by immune cells. A major unanswered question is how important each type of immunity is for protection from HIV. Data from animal models and long-term HIV survivors, and human clinical trials of experimental HIV vaccines, may offer clues to the answer.

Another factor complicates the attempt to define HIV protection. According to WHO, 80 percent of all HIV transmission worldwide occurs sexually. Thus, to be effective, an HIV vaccine also may need to stimulate mucosal immunity. Mucosal immune cells that line the respiratory, digestive and reproductive tracts and those found in nearby lymph nodes are the first line of defense against infectious organisms. Unfortunately, relatively little is known about how the mucosal immune system protects against viral infection.

Immune System Breakdown

Perhaps the most difficult challenge for vaccine researchers is that the major target of HIV is the immune system itself. HIV infects the key CD4+ T cells that regulate the immune response, modifying or destroying their ability to function.

After infection, HIV incorporates its genetic material into that of the host cell. If the cell reproduces itself, each new cell also contains the HIV genes. There the virus can hide its genetic material for prolonged periods of time until the cell is activated and makes new viruses. Other cells act as HIV reservoirs, harboring intact viruses that may remain undetected by the immune system.

Understanding how HIV disease evolves, especially during early infection, is a high priority for the Institute. Scientists at NIAID and elsewhere have shown that no true period of biological latency exists in HIV infection. After entering the body, the virus rapidly disseminates, homing to the lymph nodes and related organs where it replicates and accumulates in large quantities. Paradoxically, the filtering system in these lymphoid organs, so effective at trapping pathogens and initiating an immune response, may help destroy the immune system: HIV infects the steady stream of CD4+ T cells that travel to the lymph organs in response to HIV infection.

Basic research in immunology, epidemiology studies of long-term survivors, and vaccine trials in animal models and humans all contribute to a greater understanding of the immune system breakdown and ways vaccines may be designed to prevent or slow down the progress of HIV disease.

Adjuvants, Other Immune Enhancers

Because of safety concerns, most candidate HIV/AIDS vaccines use one or more proteins of HIV, not the whole infectious virus. These new generation vaccines contain no intact live virus and thus stimulate less potent immune responses than traditional vaccines made from whole viruses that have been inactivated or attenuated (weakened).

To augment the immune responses elicited by these and other vaccines, scientists use immunologic adjuvants, which can increase the type, strength and durability of immune responses evoked by a vaccine. Some vaccine antigen/adjuvant combinations can induce cell-mediated immune responses in animals, even if the vaccine antigen by itself does not. Some adjuvants also stimulate mucosal immunity.

Currently, only one adjuvant--alum, first discovered in 1926--is incorporated into vaccines licensed for human use by the U.S. Food and Drug Administration (FDA). An adjuvant may work well with one experimental vaccine but not another. Therefore, the FDA licenses the vaccine formulation, or the antigen-adjuvant combination, rather than the adjuvant alone. Alum primarily increases the strength of antibody responses generated by the vaccine antigen. Because of alum's limited activity, other adjuvants now being evaluated in animal models and human studies may be better suited for the newer candidate HIV vaccines.

A different way to enhance immune responses to HIV is the prime-boost vaccine strategy. Researchers first prepare or prime the immune systems of volunteers with a live vector vaccine, a bacterium or virus that has been genetically engineered to contain a gene for an HIV protein such as gp160 but that cannot infect the person with HIV or cause disease.

The best studied vector is vaccinia virus, formerly used to immunize against smallpox. Vaccinia carries the foreign HIV gene into the body. There, the vaccine directs cells to make the HIV protein that the body perceives as foreign, stimulating production of protective antibodies. Later, the volunteers receive booster shots of a different vaccine made from the same HIV protein.

By itself, a gp160-containing vaccinia virus vaccine stimulates production of memory T cells but few antibodies. The prime-boost combination, however, can stimulate a strong cellular immune response--including persistent killer CD8+ T cells--as well as antibodies that neutralize the virus or inhibit formation of syncytia, giant cells formed when HIV-infected cells fuse with cells that are not infected.

Because of concerns that a vaccinia-based vaccine might cause serious vaccinia infection in some people with compromised immune systems, such as people with HIV who have not been exposed to either smallpox or the vaccine, other vector vaccines are being developed and evaluated.

Several experimental vector vaccines made from a canarypox virus, which closely resembles vaccinia, are in clinical trials. Canarypox virus infects but does not reproduce in human cells and therefore should be much safer. Another example of a vector under development for HIV vaccines is Salmonella, bacteria that infect the human gut.

Plasmid DNA vaccines, direct injections of genes coding for HIV proteins, are a recent innovation that have shown good ability to induce cellular immune responses. When the DNA is injected, the encoded viral proteins, e.g., HIV gp160, are produced, just as with live vectors. The potential of this vaccine concept is actively being pursued.

Animal Model Studies

Animal model studies can answer critical questions that cannot be answered either in humans, because of undue risk, or by using computer modeling or laboratory tests. For example, animals can be inoculated with an experimental vaccine and then challenged with virus to test the vaccine's effectiveness--a study that would be unethical to conduct in humans. However, AIDS researchers lack an ideal animal model.

Although chimpanzees can be infected with HIV, only one chimpanzee has been observed to develop disease, making it difficult to extrapolate findings to humans. Moreover, chimpanzees are an endangered species and both difficult and expensive to maintain.

Most non-human primate AIDS research is conducted with macaque monkeys. They can be infected with SIV, a retrovirus similar to HIV that causes an AIDS-like disease. The genetic and physical structures of SIV differ enough from those of HIV, however, that the results of SIV experiments may not wholly apply to humans.

Nonetheless, important information has been obtained from both monkeys and chimpanzees. Experiments in both species have demonstrated the feasibility of developing a protective vaccine. Moreover, a new animal model--infection of macaques with a chimeric virus (SHIV) based on SIV but including the HIV envelope, with subsequent development of disease--may become extremely valuable for evaluating candidate HIV vaccines.

In late 1992, NIAID-funded investigators first reported results from their experiments with a live-attenuated SIV vaccine made by deleting the SIV nef gene. The vaccine demonstrated durable protection against high intravenous doses of a lethal SIV strain different from that used in the vaccine. These findings provide hope that safe and effective human HIV vaccines can be developed. Optimism for the live-attenuated approach itself, however, is tempered by concerns about its safety.

NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology.

Prepared by:
Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services
January 1997

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