The search for a vaccine - AIDS research - includes related article

The development of a vaccine against HIV raises highly complex scientific and economic problems

The development of a vaccine to prevent infection with the Acquired Immunodeficiency Syndrome (Aids) presents biomedical research with an urgent and serious challenge.

Simple prophylactic measures that could prevent transmission of HIV, such as the screening of blood donations, the proper sterilization of surgical equipment and needles, or the use of condoms, are often not a practical proposition in developing countries because of their cost and/or because they meet with behavioural or cultural barriers that are very difficult to overcome. A vaccine against HIV is therefore badly needed. (Vaccines are the most efficient known way of dealing with virus diseases.)

However, in spite of almost ten years of intensive research, HIV vaccines still elude us. Nobody can be sure when a vaccine will be available, nor even if there ever will be a vaccine to cope with the seemingly endless variation of HIV and its ability to hide and persist in the body of infected individuals.

A persisting disease

Why can we not produce a vaccine against HIV by using the classical methods that have been so successful in developing vaccines against "classical" virus diseases? The answer to this question lies in the very properties of HIV and in the fact that Aids is a persisting disease. HIV is a retrovirus and as such inserts its genome into the chromosomes of the cell it infects, then transmits it as a piece of chromosome from one cell generation to the next.

The HIV virus actually does even "better" than most retroviruses. Classical retroviruses grow at low levels in infected cells, and cell growth is usually compatible with virus production: the virus does not kill the cells. HIV, however, has evolved a series of accessory genes that allow it to grow very rapidly once it is activated and to kill the cell after large numbers of progeny virus particles have been produced. It has been estimated that an asymptomatic HIV-positive individual can produce more than 2 billion HIV particles per day.

Another reason why HIV persists in the human body is that it can avoid the neutralizing antibody response of the host. The virus can persist in a latent state inside the infected cell, remaining dormant and escaping surveillance by the immune system. It can be transmitted directly from an infected cell to uninfected cells by a process known as cell fusion, in which the virus particles do not come into contact with circulating antibodies. HIV can also be transported by the infected cells to organs like the brain where immune surveillance is minimal.

Finally, the reason why HIV persists so well is that it attacks two of the major players of the immune system, the CD4+ T-lymphocyte (also known as the helper T-cell) and the macrophage. At the same time the virus perturbs the communication network between the different cells of the immune system, leading to profound dysregulation of the immune response.

The HIV virus has also developed a remarkable ability to change, both within infected individuals and from individual to individual. Intrinsically, it is no more variable than viruses such as the influenza virus or the polio virus. But whereas the influenza virus actively multiplies in the infected host for only a few days, HIV multiplies in its host for years, providing ample time for variants to emerge and be stabilized.

Prototype HIV-1 vaccines

Most of the potential vaccines against HIV- 1, the cause of the Aids pandemic, that have been tested in chimpanzees and human volunteers so far have been of what is known as the "sub-unit" type, consisting of purified viral proteins mixed with an adjuvant. Such protoype vaccines have demonstrated their protective efficacy in animal models such as chimpanzees. More recently it has been shown that immunization with antigens - substances that stimulate the production of antibodies from one virus strain (HIV-1 MN) could provide protection in chimpanzees from challenge with another virus strain (HIV-1 SF2). This opens the possibility that HIV-1 subunit vaccines may provide cross-protection from infection with different virus strains provided they belong to the same subtype.

Although extremely encouraging, these results are still only preliminary. First of all there has been no test for protection from infection by the sexual route in the animal models. Challenge of immunized chimpanzees has been by intravenous injection of the virus; whereas in nature HIV is essentially transmitted by sexual contact.

Secondly, it has been found that the HIV-1 strains used for challenging the animals are different from the wild HIV-1 strains that are isolated from human patients. The challenge strains have been selected to grow in the laboratory and are easily neutralized by neutralizing antibodies, whereas clinical isolates are not neutralized.

Thirdly, challenge of the animals is usually done very shortly after a booster immunization, i.e. at or very near the peak of the immune response. The fact that the antibody response elicited by HIV-1 vaccines appears to be transient in chimpanzees raises the question of whether the vaccines would induce sufficient immune memory to provide long-term protection in a natural setting.

Finally, it has not been possible from studies on animals to identify in a reproducible manner correlates of protection that could be used to predict vaccine efficacy. In other words, no yardsticks are available by which to measure potential vaccine efficacy.

Should prototype vaccines be tested on humans?

Before undertaking large-scale (Phase III) efficacy trials in populations at risk, in which a vaccine would be compared in a blind fashion with a placebo, trials must be conducted to assess the safety and immunogenicity (capacity to stimulate immunity) of candidate vaccine(s) in small numbers of human volunteers. Some subunit vaccines have been tested on human volunteers, and shown to be safe and immunogenic. This does not mean, however, that these vaccines would protect humans against infection. To find this out, an efficacy trial is needed.

The National Institutes of Health of the United States recently decided not to proceed in expanding efficacy trials of HIV-1 subunit vaccines, arguing that more predictive scientific data were needed that would make one reasonably confident that protection could be achieved by the administration of the vaccine. Furthermore, it was felt that vaccines based on more than one viral antigen might have a better chance of being effective. Finally, the fear was expressed that individuals taking part in an efficacy trial might perceive that they were protected, which could make them change their behaviour and be at higher risk of HIV infection.

At a recent WHO meeting, however, it was decided that "Phase III efficacy trials . . . could be conducted to obtain definite information on the ability of candidate vaccines to induce protective immunity in humans". This different attitude reflects the fact that public health needs may differ from country to country, resulting in different recommendations in different parts of the world. However, there should be no scientific or ethical shortcut in planning an efficacy trial in any country.

Vaccine testing in developing countries

The prospect of launching efficacy trials in developing countries is presently meeting many difficulties, some technical and others ethical.

One technical problem is the fact that it has not been possible so far, in spite of repeated attempts, to develop a multivalent, "universal" HIV-1 vaccine based on conserved antigenic determinants. It is therefore necessary that specific vaccines be developed to match the circulating HIV-1 isolates in the developing countries.

Another technical problem stems from the need to strengthen local infrastructures in these countries, i.e. hospitals and laboratories, and to train local personnel. It is impossible to plan an efficacy trial that would involve from several hundreds to a few thousand volunteers without appropriate logistical and professional support in the field.

Among the many ethical problems that may arise, that of the modification of sexual behaviour that might possibly be induced by a large-scale vaccine trial is of serious concern. Such a trial would be dangerous if the attitude of the volunteers towards prevention was significantly altered as a consequence of their enrollment in it. Educating the people is, therefore, one of the most important prerequisites to a large-scale trial. It is noteworthy that even some elites in developing countries confuse the use of vaccines in prevention and their use in immunotherapeutic interventions. Unreasonable expectancy of protection from highly exposed and poorly educated people is much to be feared. This could be overcome only by repeated counselling and education.

Another problem is that of the subsequent availability of the vaccine. Testing a vaccine in a developing country which would not be able to afford it later because of excessive pricing would be difficult to accept. It should also be made clear that the concept of developing a safe, sophisticated, but expensive vaccine for the industrialized countries and an unsafe, unsophisticated but cheap vaccine for the developing countries is ethically unacceptable.

Making HIV-1 vaccines available to developing countries

It is obvious that the success of vaccination against HIV will depend on the characteristics of the future HIV-1 vaccines - on their safety, efficacy, duration of protection, stability, the number of doses required for full immunization, and last but not least, their cost. There has been very strong political pressure to make HIV-1 vaccines available to developing countries at a marginal cost. Even though we are still years away from marketing such vaccines, it is appropriate for the public health community to set the stage for an effective global Aids-prevention effort. One should realize, however, that the cost of developing a new vaccine has reached fantastic heights due to the enforcement of stricter regulations, tighter quality controls, higher safety standards, and to the very high cost of clinical studies, not to mention the cost of research itself. Aids-vaccine research for the past ten years in the United States and Europe has already cost several billion dollars.

The financial returns to be expected by the vaccine manufacturers will obviously be low, vaccines being quite different in this respect from pharmaceutical drugs. How could a vaccine be made available to developing countries?

One possibility would be to sell the vaccine to these countries for a low price and for a compensatory high price on the Western world market. But how low is low? It has been estimated that an HIV-1 vaccine would be administered yearly to about 300,000 persons worldwide, which could involve 1,200,000,000 doses, not counting subsequent booster doses. Manufacturing, controlling and distributing such an enormous number of vaccine doses would cost several billions of dollars.

It is clear that we will have to invent a mechanism, such as direct payment from an international agency to the manufacturing companies, to provide the companies with sufficient reward while at the same time supplying the Aids vaccine to the developing world at a rock bottom price. This is basically what UNICEF (the United Nations Children's Fund) and the Pan-American Health Organization (PAHO) are trying to do for classical vaccines. But the chances of success of such an operation will depend strictly on the goodwill of the industrialized nations.

RELATED ARTICLE: Aids in a different light

by Marie-Therese Bocabeille

THE POSSIBILITIES OF TRADITIONAL MEDICINE

Modern medicine so far has nothing effective to offer to Aids patients, in spite of the massive technological, chemical, surgical and radiotherapeutic resources devoted to Aids research in recent years. At the same time, the principles of traditional forms of medicine have been ignored. And yet, while they make no claim to halt the epidemic, they can make a big contribution to the strengthening of the immune defences and to the prevention of opportunistic diseases.

According to Dr. Christian Tal Schaller(1), who has twenty-five years' experience as a practitioner of alternative medicine, there are two schools of thought. On the one hand there are those who believe that the virus is the sole or major cause of the immunodeficiency. On the other, there are practitioners who are in touch with natural medicine movements all over the world and who subscribe to the dictum of the great French physiologist Claude Bernard (1813-1878): "The virus is nothing, the terrain is everything".

The "terrain" comprises all the different parts of an individual that it would be too simple to limit to his or her physical body. In addition to the physical organs, which are themselves very complex, there are all kinds of complex forces and states of mind that play an essential role in any process of improvement.

Modern medicine, sophisticated though it may be, is almost exclusively concerned with physical illnesses which it regards as originating from outside - people are supposed to "catch" a disease - without the individual's having any particular responsibility for what happens to him or her.

It must be accepted, however, that this approach provides no explanation as to why, for example, not everyone who is HIV-positive develops Aids nor why some even return to being HIV-negative.

As things stand at present, the possibilities offered by traditional medicine cannot be ignored, much less snubbed or made fun of.

'HOW I BECAME HIV-NEGATIVE AGAIN'

Niro Markoff Asistent, a Belgian therapist living in the United States, was diagnosed HIV-positive in 1985. Some time went by before she accepted her condition and recognized her own responsibility for her rundown state. When her doctor admitted there was nothing he could do for her, she decided to take her life in her own hands. Using with the utmost care the 500-day reprieve she had been given, she embarked on a voyage of physical and mental self-discovery.

A year later, Niro Asistent became HIV-negative again. Inspired by her experience, she created a foundation, the Self Healing Aids-Related Experiment (S.H.A.R.E.), to which she now devotes her life. "I believe," she writes, "that Aids is the most powerful transformational tool that has ever been available to us on a mass level. It has detonated a bomb under the surface of society that is forcing us to reevaluate the entire foundation of life as we know it. It is shaking the medical community and its related industries, it is affecting the educational and judicial systems. It is forcing us to question our values, our morals and our identities.(2)

THE VIRUS, A NECESSARY BUT NOT A SUFFICIENT CONDITION

HIV alone is not enough to cause Aids, because not all HIV-positive people develop Aids. There are thus grounds for thinking that other factors, or co-factors, are involved.

A California research centre(3) has drawn up a list of co-factors which may contribute to the acceleration or slowdown of immunodeficiency. They include psychological factors such as stress, depression, pain and the conviction that one is dying. Others, such as nutrition, oxygenation, sleep or physical exercise, are related to life-style. Therapeutic treatment, relations with one's doctor, and the capacity to cure oneself are also involved.

'HIV IS NO DEATH SENTENCE'

Mark Griffiths(4), a British musician, was diagnosed HIV-positive in 1986. He immediately began improving his quality of life by learning to know himself and live at peace with himself. He sought to disintoxicate himself physically and mentally by natural methods, and gradually recreated the bond between his inner self and his body. By following his own evolution, without any miracle cure but with great confidence in his own intuition, he became his own doctor.

In the summer of 1990, Mark Griffiths came across a text entitled Is the Aids virus science fiction? by Peter Duesberg of the University of California, Berkeley, which echoed many of the doubts and questions that arose when he learned he was HIV-positive, especially about the opportunistic diseases that he was told he would encounter. In September of that year, he published a booklet entitled Healing into freedom: Aids, the apprenticeship, in which he reported the experiences of those he calls the long-term survivors.

Intent on encouraging the publication of alternative research which would be both scientific and rigorous, he has become the champion of a new way of looking at the question and a new debate. He believes that to be HIV-positive should not be regarded as a death sentence. He is fighting for patients to be free to choose their treatment. He has created a network which collects the testimony of people who have returned to good health after a serious illness, of scientists who support the theses of natural regeneration and therapists who teach self-healing. The Aids acronym for him has been reshuffled to read "Acquired Interior Development Source".

1 Dr. Christian Tal Schaller, 32 av. Petit Senn, 1225 CheneBourg, Geneva (Switzerland).

2. Niro Markoff Asistent, Why I survive Aids, Simon and Schuster/Fireside, New York, 1991, pp. 243-244.

3. LIFE (Learning Immune Function Enhancement), Aids Response programme, Center for Social Services, 3916 Normal Street, San Diego CA 92163, U.S.A.

4. Mark Griffiths, 87, chemin du Vellard, F-01710, Thoiry

MARIE-THERESE BOCABEILLE is a staff member of UNESCO's Promotion and Sales Division.

MARC GIRARD, a French biochemist, is Deputy Director and Head of the Molecular Virology Laboratory of Paris's Pasteur Institute, He is a member of the Steering Committees of WHO's Global Programme on Aids (GPA) and of its Global Programme for Vaccines and Immunization.

COPYRIGHT 1995 UNESCO
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