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 infected by the virus is a high priority among 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 HIV infection by exposure to infected blood and by sexual contact. The vaccine would also protect against exposure to many different strains of HIV. Despite extraordinary advances in understanding both HIV and the human immune system, such an ideal vaccine continues to evade researchers.
(Scientific terms printed in bold-faced type are defined in the NIAID HIV Vaccine Glossary.)
What Constitutes Immune Protection?
The easiest way to design an effective vaccine is to know which immune responses protect against the specific infection and to 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, they have not precisely identified these factors.
Unlike other viral diseases for which investigators have made successful vaccines, there are no documented cases of complete recovery from HIV infection. 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.
Now that the pandemic has matured, however, 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 developing AIDS. Long-term survivors can be divided into two groups:
- Long-term nonprogressors who maintain healthy or steady levels of CD4+ T cells despite many years of infection
- HIV-infected individuals who lose a significant proportion of CD4+ T cells but remain healthy
Recently, researchers began studying individuals who remain uninfected despite repeated exposure to HIV. If researchers prove these multiply exposed but uninfected individuals have resisted HIV through active immune mechanisms, 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 cellular 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, CCR5, appear to be protected from infection with HIV strains using this co-receptor. 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.
Developing Immune Responses
Immunogenicity refers to the ability of a vaccine or a component of a microorganism to stimulate immune responses. Two main types of immune responses exist: humoral immunity and cellular immunity.
Humoral (antibody-mediated) immunity refers to protection provided by antibodies, the secreted products of one type of white blood cell called a B lymphocyte. Antibodies are custom-made proteins that circulate in body fluids (primarily blood and lymph), and they specifically recognize bacterial or viral components. B lymphocytes (B cells) produce antibodies in response to a specific foreign invader like HIV or a vaccine.
Antibodies can have different properties. So-called binding antibodies simply attach to part of HIV and may or may not have antiviral effects. Other antibodies 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. Multiple copies of a protein called gp160 form the HIV envelope. Gp 160 and gp120, which is a component of gp 160, have been used as the basis of many recombinant subunit vaccines, so called because they are genetically engineered to only contain copies of the envelope component 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 aare 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, is induced by first exposure to an invading organism. The name "memory" reflects their function, which is to create a criminal record 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 immunity at the mucous membranes that line the rectal and genital tract and induce what is called mucosal immunity. Scientists do not fully understand how immune cells lining the genital tract and other HIV portals into the body protect the body, but the cells may be important to blocking HIV transmission.
HIV Strain Variation
HIV continually evolves because of genetic mutation and recombination. Thus, researchers must estimate the significance of strain variation within individuals and among populations when developing HIV vaccines. Initially, a person does not appear to be infected with more than one HIV variant. Once HIV infection becomes established, however, 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 resistant variant can emerge. In addition, 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 elimination by the immune system.
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 three groups, M, N, 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 subtypes.
The first AIDS vaccines made were derived from laboratory-adapted versions of the LAI strain (also known as IIIB or LAV). Subsequently, LAI has been shown to differ from most strains found in infected people. Other 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.
Given that 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 common to all or most subtypes. If such common regions 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 need to stimulate the two main types of immune responses. Humoral immunity uses antibodies to defend against free virus while cellular immunity directly or indirectly results in the killing of infected 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.
According to the World Health Organization, 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 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.
Scientists at the National Institute of Allergy and Infectious Diseases (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, actually helps destroy the immune system. As CD4+ T cells travel to the lymph organs in response to HIV infection they are infected by the HIV that is harbored there.
Basic research in immunology, epidemiology, natural history and vaccine trials in animal models and humans all contribute to a greater understanding of the immune system breakdown and of how new 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 vaccines use one or more synthetic proteins of HIV, not the whole infectious virus. These new generation vaccines contain no intact live virus and thus, appear to stimulate less potent immune responses than traditional vaccines made from whole viruses that have been inactivated or attenuated.
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 adjuvant combinations can induce cellular 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, FDA licenses the 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.
An effective way to enhance immune responses to HIV is the combination approach. Researchers first prepare or prime the immune systems of volunteers with one vaccine, such as a live vector vaccine (a bacterium or virus genetically engineered to contain a synthetic HIV gene) and then boost these responses with a different vaccine, such as gp120 or gp160 subunits.
The best studied live vector vaccine is vaccinia virus, formerly used to immunize people against smallpox. Vaccinia is engineered to carry the foreign HIV gene(s) into the body. There, the vaccine directs cells to make the HIV protein, which in turn, stimulates production of protective antibodies and T cells. Later, the volunteers receive booster shots of a different vaccine containing the same HIV protein carried by the vaccinia vaccine.
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. Because of concerns that a vaccinia-based vaccine might cause serious vaccinia infection in some people with compromised immune systems, such as people already infected with HIV, researchers are developing and evaluating other more-attenuated vector vaccines.
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.
For the past 5 years, scientists have been evaluating DNA vaccines. DNA vaccines are direct injections of genes coding for specific HIV proteins and have been shown to induce cellular immune responses in animals. When the DNA is injected, the encoded viral proteins, such as HIV gp160, are produced, just as with live vectors. Scientists are actively pursuing the potential of this vaccine concept.
Animal 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 exposed to a virus to test the vaccine's effectiveness -- a study that would be unethical to conduct in humans. Although AIDS researchers lack an ideal animal model, several animal studies have provided relevant information.
Chimpanzees can be infected with HIV, but only a few chimpanzees have developed disease, making it difficult to extrapolate findings to humans. Moreover, chimpanzees are an endangered species and are difficult and expensive to maintain.
Investigators use macaque monkeys in most non-human primate AIDS research. Macaques can be infected with SIV, a virus 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 be fully applicable in humans. Nonetheless, investigators have obtained important information from studies involving monkeys and chimpanzees. Experiments in both species have demonstrated the feasibility of developing a protective vaccine.
Moreover, studies are now being conducted in macaques using a chimeric virus (SHIV) that is based on SIV but enclosed within an HIV envelope. Because SHIV mimics HIV infection and causes serious illness in macaque monkeys, it allows researchers to study the reactions of the immune system to the vaccines and the virus. These types of studies may become extremely valuable for evaluating candidate HIV vaccines.
More recently, another team of NIAID-funded investigators found that a new combination or "prime boost" HIV vaccine approach was effective when tested in monkeys. Although the vaccine did not prevent infection, it kept the virus at undetectable levels for several months after immunization. One of the vaccines contained a piece of DNA designed to carry genes for both HIV and SIV. The second vaccine added the same genes to a virus called MVA, a modified version of vaccinia virus. Both triggered an immune response against SHIV. These positive results led scientists to make HIV versions of the DNA and MVA vaccines to test this concept in human trials.
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
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