HIV/AIDS Vaccines - National Institute of Health

by The NIH

HIV/AIDS Vaccines

NATIONAL INSTITUTES OF HEALTH

Despite education and treatment advances, experts project a worsening of the human immunodeficiency virus (HIV) crisis through the year 2000. HIV infection and AIDS death rates will continue to mount worldwide. In the United States, the tally of AIDS cases will escalate, particularly among women and minorities. If present trends continue, numbers of new infections will remain relatively stable in Europe and North America but will increase in parts of Latin America, Africa and, most markedly, in Asia.

Developing safe and effective vaccines to curb the human and economic costs of the HIV/AIDS pandemic has become an international health priority. To help accomplish this goal, the National Institute of Allergy and Infectious Diseases (NIAID), which spearheads federal funding for biomedical research on HIV/AIDS for the National Institutes of Health (NIH), has intensified its HIV vaccine research program.

NIAID'S HIV VACCINE PROGRAM - A BALANCED STRATEGY

The Institute's Division of AIDS (DAIDS) directs the HIV vaccine research program. Institute staff meet regularly with scientific, public health and community advisors to review the priorities and operation of the program.

To accelerate research progress, the program has two main thrusts: 1) foster basic research on the structure and function of HIV, vaccine formulations, vaccine delivery systems and laboratory studies of vaccine performance; 2) promptly evaluate promising candidate vaccines in animal models and, if warranted, in humans.

NIAID grantees and contractors around the country work closely with DAIDS staff to attain these goals. The Institute funds several collaborative ventures to enhance coordination of HIV vaccine research. These include the following:

þ National Cooperative Vaccine Development Groups for AIDS: Teams of scientists from academia, government and industry generating novel approaches to HIV vaccine design and evaluate these concepts in the laboratory and in animal models.

þ AIDS Cooperative Adjuvant Groups: Multidisciplinary groups of scientists developing new adjuvants, substances that can be combined with a vaccine to increase the type, strength or duration of immune responses elicited.

þ AIDS Vaccine Clinical Trials Network: Clinical researchers conducting Phase I and II human trials of experimental HIV vaccines. The network includes a specimen bank, immunology laboratories and data analysis center that support this research.

þ Primate research laboratories: Scientists investigating HIV-vaccine-related questions by testing HIV and HIV-like vaccines in chimpanzees and monkeys.

þ HIV Variation Project: Researchers examining the rates and magnitudes of genetic and immunologic changes in HIV and related retroviruses and their consequences for vaccine design.

In addition, NIAID's nationwide university- and community- based clinical trials programs are conducting trials of candidate therapeutic HIV vaccines.

Planning for Efficacy Trials

Inevitably, promising HIV candidate vaccines suitable for large-scale testing of their effectiveness will be identified. The Institute has begun laying the groundwork for such Phase III trials in the United States and abroad to ensure that no delay in starting these trials occurs.

Field data on virus strains being transmitted, rates of new infections and the prevalence of sexually transmitted disease and other potential co-factors of HIV transmission are being collected from various populations at high risk for HIV infection.

Institute staff assist public health and government officials, community members, scientists and others affiliated with potential trial sites to resolve numerous legal, practical and ethical issues that attend planning for efficacy trials. These concerns include vaccine cost, delivery and liability, training of medical personnel and conduct of the trial at potential overseas sites.

CHALLENGES IN DESIGNING HIV VACCINES

The ideal HIV vaccine would be inexpensive, easy to store and to administer, and elicit strong, appropriate immune responses that confer long-lasting protection against both bloodborne and mucosal (sexual) exposure to multiple HIV subtypes. What follows describes some reasons this ideal has not been easy to achieve.

What Constitutes Immune Protection?

Researchers face unprecedented scientific obstacles in trying to develop effective vaccines for HIV. First, exactly how the body can protect itself against HIV remains a mystery. Unlike most other viral diseases for which successful vaccines have been made, recovery from HIV infection has not been documented. HIV researchers have no human model of protection to guide them when constructing candidate vaccines.

Now that the pandemic has matured, however, long-term HIV survivors and others provide ample evidence that some people appear better able than others to resist HIV infection or the development of AIDS. Much of this information has come from protracted studies of people at high-risk for HIV. The "resisters" can be grouped as follows: 1) those who maintain healthy levels of CD4+ T cells, a crucial immune cell and HIV's main target, for seven to ten years or more after becoming infected; 2) individuals with HIV infection who lose a significant proportion of CD4+ T cells but seem to remain healthy in spite of this loss; and 3) people who appear to escape infection despite repeated exposure to the virus.

To determine if genetic or biologic factors affect the body's response to HIV exposure and infection, NIAID-funded investigators and others are comparing long-term HIV survivors with people who have become easily infected or sick. Leading areas of research include genetics, individual variations in the immune response, and exposure to or infection by less deadly variants of HIV. Any patterns found in the data may help investigators decode what contributes to protective immunity against HIV.

HIV Transmission Complicates Protection

Unlike most other viruses, HIV can be transmitted and can exist in the body not only as free virus but also in infected cells. Thus, a vaccine against HIV may be required to stimulate the two main types of immunity. Humoral (antibody-mediated) immunity defends against free virus when B immune cells produce custom-made proteins, called antibodies, including neutralizing antibodies that inactivate the virus. Cellular (cell-mediated) 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 to protection from HIV. Data on long-term HIV survivors and those generated from animal model and human clinical trials of experimental HIV vaccines may offer clues to the answer.

Another factor complicates the attempt to define HIV protection. Eighty percent of HIV transmission worldwide occurs sexually, according to the World Health Organization. Thus, an effective HIV vaccine also may have to stimulate mucosal immunity. Immune cells found in the lining of the respiratory, digestive and reproductive tracts and in nearby lymph nodes provide the first line of defense against HIV and other infectious organisms. Unfortunately, relatively little is known about how the mucosal immune system works. NIAID has increased its commitment to research on laboratory tools and animal models that will enable scientists to learn more about how HIV and other pathogens elude the defenses of mucosal cells and the immune- modulating proteins, called cytokines, that they stimulate.

Adjuvant Research Revived

One hopeful note is the renewed interest in adjuvants, substances formulated with vaccines to boost specific immune responses. Interest in adjuvants has revived because new- generation vaccine candidates containing only part of HIV and no live virus stimulate less potent immunity than traditional vaccines made from live-weakened or whole-inactivated viruses. Some adjuvants also stimulate mucosal immunity.

An adjuvant may work well with several different experimental vaccines. Thus the Food and Drug Administration (FDA) licenses the vaccine formulation, or the antigen-adjuvant combination, for human use rather than the adjuvant alone.

The activity of the adjuvant alum was first described in 1926, and alum remains the only adjuvant in use in FDA-licensed human vaccines. Alum increases the strength of antibody responses generated by the vaccine antigen. New, experimental adjuvants can increase the type, strength and durability of immune responses evoked by an experimental vaccine. For example, some vaccine antigen/adjuvant combinations can induce cell- mediated immune responses, even if the vaccine antigen by itself does not.

NIAID-funded scientists are evaluating a panel of promising adjuvants in monkeys to help identify the suitable candidates to incorporate in experimental human HIV vaccines. In 1993, NIAID began the first Phase I HIV vaccine adjuvant trials in humans. Various adjuvants paired with two different vaccine candidates are being compared to determine the best vaccine formulations to pursue.

Protection Against Genetic Diversity

Another unique problem confounding HIV vaccine development is the extensive genetic diversity among different HIV strains. Other successful virus vaccines have had to protect against only one or a limited number of virus strains. At least five genetic subtypes, or clades, of HIV exist, each of which includes many related but unique strains.

Strain diversity arises through genetic mutation or recombination. Because HIV genes mutate much faster than human genes, many variants of one HIV strain may arise within an infected person. Also, whenever a drug or immune response destroys one variant, a distinct but related variant can emerge. Moreover, variants may thrive in different tissues. Any of these changes may yield a variant that can escape immune detection.

Generally, an individual appears to be infected by only one HIV strain, but a preventive vaccine will need to generate immune responses that protect noninfected individuals from all different clades of HIV to which they may be exposed. Conserved regions of HIV genes that may exist in more than one clade would be desirable to find. A cocktail vaccine containing several proteins or peptides from different HIV strains may be the most effective way to invoke broad-based immunity.

Immune System Breakdown

Perhaps the most difficult challenge vaccine researchers face is that the major target organ of HIV is the immune system itself. HIV infects key 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. There the virus can hide indefinitely until the cell receives an activation signal 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 research area 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 by infecting the steady stream of CD4+ T cells that travel there in response to HIV infection.

Early HIV infection is an example of one area of investigation where basic research in immunology, epidemiology studies of long-term survivors, and animal model and human clinical trials all can 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.

Animals Model Studies - Imperfect But Important

Animal model studies can answer critical questions that may pose undue risk to humans or cannot be answered using computer modeling or laboratory tests. For example, animals can be inoculated with an experimental vaccine and then challenged with HIV to test the vaccine's effectiveness--a study that would be unethical to conduct in humans.

Although chimpanzees can be infected with HIV, they have not yet been observed to develop disease. Moreover, they are expensive to maintain.

Most large-animal AIDS research is conducted with macaque monkeys. They can be infected with simian immunodeficiency virus (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 extrapolating the results of SIV experiments to humans must be done carefully.

Despite the lack of an ideal animal model, important information has been obtained from both monkeys and chimpanzees. Experiments in both primates have demonstrated the feasibility of developing a protective vaccine. Moreover, two new animal models--infection of pigtail macaques with HIV and of rhesus macaques with a chimeric SIV-HIV virus--may become valuable alternatives to chimpanzees 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 different from that used in the vaccine. These findings provide hope that safe and effective human HIV vaccines can be developed.

CLINICAL RESEARCH

Important immunologic targets on HIV and on infected cells have been identified. For example, scientists now know that gp120, the principal envelope protein of HIV and the main target for antibodies and some cellular immune responses, contains the cell attachment site called CD4. For

these reasons, vaccines based on genetically engineered HIV envelope proteins--gp160 and one of its cleavage products, gp120- -have been the most well-studied to date.

As of May 1993, about 23 experimental HIV vaccines were in various stages of human testing around the world. Vaccine approaches in development or in clinical trials include:

þ subunit vaccine - a piece of HIV, such as the envelope proteins gp160 or gp120, produced by genetic engineering.

þ recombinant vectors - a live bacterium or virus such as vaccinia (used in the smallpox vaccine) that can transport into the body a gene that makes an HIV protein.

þ vaccine combinations - use of a recombinant vector vaccine to induce cellular immune responses followed by booster shots of a subunit vaccine to stimulate antibody production.

þ peptide vaccine - chemically synthesized portions of HIV proteins (peptides) known to stimulate immunity.

þ virus-like particle vaccine - a non-infectious HIV look- alike that retains all or part of the HIV envelope but only some of the interior components.

þ anti-idiotype vaccine - antibodies generated against antibodies to the virus.

þ naked DNA vaccine - direct injection of genes coding for HIV proteins.

þ whole-inactivated virus vaccine - HIV that has been inactivated by chemicals, irradiation or other means so it is not infectious.

þ live-attenuated virus vaccine - live HIV from which one or more apparent disease-promoting genes of the virus have been deleted.

Clinical Trials of Preventive HIV Vaccines

In August 1987, NIAID opened the first clinical trial of an experimental HIV vaccine at the NIH Clinical Center in Bethesda, Md. The trial eventually enrolled 138 noninfected healthy volunteers. The gp160 subunit candidate vaccine tested caused no serious adverse effects in this safety trial.

From the beginning of that first trial until May 1993, about two dozen preventive HIV vaccine trials have been initiated worldwide. These Phase I trials, which enroll noninfected participants, seek information on the vaccine's safety and preliminary information on its ability to stimulate immune responses.

NIAID's AIDS Vaccine Clinical Trials Network is the largest cooperative vaccine clinical trials group in the United States. Between 1988 and August 1993, more than 1,300 men and women have participated in HIV vaccine trials conducted at its five medical center sites located in Seattle, Baltimore, St. Louis, Nashville and Rochester, N.Y.

To date, all the vaccine candidates tested have been well- tolerated, generally producing only mild side effects typical of most vaccines. The most thoroughly tested candidates stimulate production of antibodies, although levels decrease within a relatively short period of time. Initial formulations and dosages of these vaccines produced few or low levels of neutralizing antibodies, and rarely elicited cytotoxic T cells, which are invoked through cell-mediated immunity to kill HIV- infected cells. With the newer protocols that have increased vaccine dosages, changed immunization schedules, tested experimental adjuvants, and used recombinant proteins shaped more like those of native HIV, more promising data have begun to emerge.

In December 1992, NIAID launched the first Phase II preventive HIV trial worldwide. Earlier trials enrolled noninfected people at low risk of HIV infection and primarily sought data on safety. The Phase II trial includes noninfected volunteers with a history of high-risk behavior--injection drug use, multiple sex partners or sexually transmitted diseases. Participants are counseled repeatedly to avoid any behavior that puts them at risk of HIV infection. The trial will help determine if these distinct populations, representative of people likely to be enrolled in large-scale efficacy trials, respond differently to the vaccines. The trial also will gather more detailed data on the safety and ability of the vaccines to stimulate immune responses.

As experimental HIV vaccines continue to grow in number and kind, clinical trials are expected to yield more valuable information about the relative effects of different vaccine formulations and different methods of delivery on the immune response.

Therapeutic Vaccines - A New Strategy

Traditionally, vaccines are used to stimulate immune responses that protect noninfected individuals from acquiring infection or disease upon subsequent exposure to the virus. For HIV infection, delaying or preventing the onset of AIDS symptoms in an infected individual through therapeutic immunization are desirable goals as well. Any agent that requires infrequent administration and might prolong the disease-free state of those infected would be beneficial to the public health. Also, if the agent reduces the amount of virus in an infected individual, the risk of HIV transmission to sexual partners or to a pregnant woman's fetus or newborn also might be decreased.

Can vaccines boost immune responses to HIV or reduce the amount of HIV in infected people? Experience with therapeutic vaccines is very limited. As of early 1993, NIAID and other sponsors had initiated more than a dozen therapeutic HIV vaccine trials worldwide, including some larger more advanced trials, to answer this question. So far, the vaccine candidates being tested seem to be well tolerated, but longer follow-up is needed to generate more data for interpretation.

Most therapeutic HIV vaccine trials have enrolled people who are HIV-infected but otherwise healthy and free of AIDS symptoms. In the first half of 1993, NIAID launched the first trials in the world to test therapeutic HIV vaccines in three additional populations: pregnant HIV-infected women and infants born to them, and asymtomatic HIV-infected infants and children. Early 1993 also marked the opening of NIAID's first therapeutic HIV vaccine trial to include people with more advanced disease.

FUTURE DIRECTIONS

Although the challenges are daunting, scientists remain optimistic that safe and effective HIV vaccines can be developed. Basic researchers have made tremendous strides in understanding how HIV causes disease, recently describing how throughout the long symptomless period of HIV infection, the virus gradually ravages the lymph nodes and related organs, a process imperceptible by the patient who generally feels well during this time.

Furthermore, novel ways to present HIV proteins to the immune system continue to be designed and tested, as do new antigen/adjuvant vaccine formulations. A growing number and variety of experimental vaccines are entering clinical tests in primates and humans, and more trials are exploring whether changing immunization schedules, increasing booster doses, or using a combination vaccine strategy can stimulate stronger, more durable immune responses. Together, progress in basic and clinical research is moving scientists closer toward identifying products suitable for large-scale HIV vaccine efficacy trials.

Prepared by:

Office of Communications <br> National Institute of Allergy and Infectious Diseases<br> National Institutes of Health<br> Bethesda, Maryland 20892<br>

Public Health Service<br> U.S. Department of Health and Human Services

October 1993