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As all of us know today, medical scientists have been able to combat a range of infections with the help of specially developed vaccines. At the same time there are still no reliable remedies from some such dangerous ailments. The problem of developing new and highly effective preparations has been and remains on the agenda of immune biotechnology. Progress and the latest achievements in this field have been described in an interview with our correspondent Sergei Popov by Acad. Rakhim Khaitov, Director of the State Research Center of the Russian Federation - the Institute of Immunology.

- Professor, why do you think it has now been necessary to revise vaccination methods which have basically remained unchanged since the 19th century and the time of the celebrated Louis Pasteur?

- Yes, his discovery was a great achievement of his time which helped save millions of lives. "Vaccinations as a method of prevention of infections have been doing their job. But science never stands still. Our knowledge of the physiological mechanisms of the immune system-one of the most complex in the organism-has changed. Detailed studies have been conducted of the functions of its components-bone marrow, the thymus, spleen, lymphatic nodes with their network of connecting vessels. Genetic studies have helped identify the functions and interactions of its elements: trunk cells*, T-and B-lymphocytes of different types, macrophages, "signal" molecules, etc. We now understand the process of their migration and quantity regulation and which parts of the coordinated mechanisms are "broken down" by pathologies. The cooperation of respective

* See: V. Yarygin, G. Sukhikh, "These Totipotent, Omnipotent Cells", Science in Russia, No. 1, 2004. - Ed.

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cells provides for the immune response-response to the penetration into the body of products of alien genetic "data"-antigenes.

But why after vaccination, and also after some ailments suffered by a patient, he acquires immunity to them for years to come? That is because, like the nervous system, our immune system has its memory. And it is this remarkable quality that provides the basis for the effect of vaccination. Singled out among the lymphocytes- these key elements of the immune system-is the category of what we call "memory" cells. After the organism of a patient has coped with an infection, these cells preserve data about the antigen and kind of "withdraw for rest" into the lymph nodes, spleen and other organs. And they "rest" there for decades until a new encounter with the familiar virus. And when that happens, they rush into action because they know all about the "enemy". The above cells rapidly proliferate and pass on information to B-lymphocytes. These, in their turn, start producing at a high rate antibodies-specific proteins circulating in the blood, lymph, tissue fluid and capable of linking with anti-genes and thus suppressing them and neutralizing toxins. A vaccinated organism is resistant to a virus, and either no infection takes place, or a person feels only slight indisposition.

Coming back to your question, let me point out that in classical vaccines, developed by the Pasteur method, we have long been observing appreciable drawbacks. They are produced from either killed viruses, or live ones, but weakened, and with the most toxic fragments removed. In any case they contain up to 99 percent of ballast substances which means that only one percent of the administered preparation participates in the formation of immunity. Thus the defense system of our body is forced to produce antibodies for "unrelated" antigenes-"runs idle". And these admixtures are far from being neutral and can cause some serious side effects: allergies, arthritis, nervous disorders, etc. That is why we now rely on vaccines of other kind. These are not simply "damaged" bacteria or viruses, but their strictly defined fragments which produce immunity. The task seems to be simple: to have a concrete antigen produced in a pure form and use it as vaccine. It turned out, however, that although harmless, this method is rather ineffective. And a different path was chosen which combined an antigen with an immunostimulator. This produced a powerful immune response.

- Work on this promising idea was mentioned by Acad. Rem Petrov (full member of the USSR Academy of Sciences since 1984) and yourself in our journal back in 1981.*

- And the first vaccine developed on the new principles appeared some 15 years later, in 1996. And during all of these years, and in fact even longer, intense theoretical and experimental research has been in progress in the labs of the Institute of Biophysics of the USSR Ministry of Health and later at the Institute of Immunology formed on their basis. The search went on, of course, not from a blank spot, so to say. It was back in the 1960s that Acad. Rem Petrov and members of his school began studies of immune response genes. And found out why individuals develop a different response to one and the same antigen: some people fall ill while others do not. The reason lies not in some casual factors, but in the body ability to produce an effective or ineffective response to intrusion of a virus-something which depends on inherited predisposition. So it was nec-

Functions of the immune system.

* See: R. Petrov, R. Khaitov, "Genetics of Immunity and Vaccines of the Future", Science in the USSR, No. 5, 1981. - Ed .

Pages. 26

essary to "sidestep" this genetic control, increase the response to a concrete antigen, overcoming the weak individual response. This path led to the substantiation of the principles of what we call phenotype correction of the genetic control of the immune response. We conducted our experiments on mice, and we learned how to turn those of the animals which had a weak response to an infection, or antigen into the category of individuals with a strong phenotype response. This was done with the help of substances from the category of synthetic polyelectrolytes: it turned out that they activate cells of the immune system-lymphocytes and phagocytes, increase the synthesis of antibodies in response to an alien antigen. Phagocytes more actively capture and digest microbe particles, produce oxidative radicals which help kill the microorganisms. It was also established that the effect of such artificially formed structures depends on the degree of polymerization of macromolecules: the greater it is - the stronger the effect. We knew the sizes of the lymphocytes and their receptors, as well as of antigenes and viruses, and we selected the polyelectrolyte of the required length. In fact it was specially "designed", and the work was conducted in conjunction with specialists of the Chair of High-Molecular Compounds of the Department of Chemistry of the Lomonosov Moscow State University, headed by Acad. Victor Kabanov. As a result we obtained a model vaccine. Thanks to that the mice used in our experiments survived even at the absolutely lethal doses of infection. Even in mice with a removed thymus the immune memory after injections appeared very rapidly and remained for a long time. What we needed, however, was a preparation harmless for human patients. With that aim in mind our institute researcher, Arkadiy Nekrasov, Dr. Sc. (Chem.) produced a remarkable polymer: it had immunostimulating properties, was absolutely non-toxic and, what was very important, - decomposed some time after the administration and was then discharged from the organism. What is more, it turned out to be a detoxicant, cleaning the body from toxins. We proved that in the conjugation in one structure of an antigen with a polyelectrolyte stimulator, the antibody and cell-produced immune response is increased by tens and hundreds of times.

So, for the first time in medical practice we introduced synthetic macromolecules whose biological effect is based upon their effective physico-chemical interaction with cells. Before, the range of related polymers was restricted to chemically neutral substances used as passive carriers of low-molecular medicines. We called the new preparation "Polyoxidonium". On its basis we produced antiflu vaccine called "Grippol"*. In 1996 it was registered by the Russian Ministry of Health and cleared for mass production and unrestricted medical uses. The preparation is used for disease prevention from the age of six months, can be used for adults of all ages and is effective for vaccination of high-risk groups. During the flu epidemics of 1997 - 2003 a total of over 40 mln people were vaccinated in this country.

- Did that number include some of your institute staff?

- Yes, all of us, including your humble servant and my whole family. Frankly speaking, before the introduction of GRIPPOL I often fell ill with severe fits of flu. But over the past few years I have practically forgotten all about this nagging ailment. What people call "five" vaccines against flu which, are, unfortunately, being

Organs and tissues of the immune system: B - B-cells; T - T-cells. M - macrophages, G - granulocytes, preT - precursors of T-cells.

* See: R. Khaitov, "Say No to Flu", Science in Russia, No. 2, 1997. - Ed.

Pages. 27

offered to the public, are effective against one single strain. And GRIP-POL is effective against three of the most common strains-A 1(H1N1), A2(H3N2) and B. This antigen "cocktail" has a minimum number of components: only two proteins interlinked with an immuno-modulator. This combination makes it possible to conduct vaccinations even during epidemics, since the resulting immunity comes in a week's time. And let me also stress that GRIPPOL is the only vaccine in the world with a "bmlt-in" immunostimu-lator (adjuvant). This feature guarantees its success even with patients with a weakened immune system. By its parameters GRIPPOL is on the par with the most advanced imported vaccines while being much less expensive.*

- But there is no denying the fact that with all of its hateful aspects, there are even more frightful infections than flu...

- Yes, and we are also coping with them, and on the basis of the same principles. Our "recipe" is an antigen plus immunostimulator (adjuvant). Our institute experts have developed and are successfully using in clinics the VIAN-VAK vaccine against typhoid fever. We are also testing preparations against brucellosis, dysentery and tuberculosis. At the development stage now are remedies against whooping cough, diphtheria and tetanus, Very dangerous today are varieties of hepatitis, especially hepatitis C. It does almost as much harm to one's health as AIDS and has comparable rates of mortality. As for HIV infections, we have already developed a preparation and submitted it to the RF Ministry of Health for tests. This is a liquid vaccine called VICHREPOL.

And it should be noted that specialists in different countries are working on similar remedies and have tested a number of them, but the results still leave much to be desired. The traditional methods of activation of the immune system are ineffective because the AIDS virus breaks down its mechanism doing most damage to the most important T-helper cells. With these cells "out of commission", there is no adequate immune response and with the virus proliferating at high rate the patient perishes from attending disorders. The way I see it, vaccine against AIDS and hepatitis С cannot be produced by the traditional Pasteurian method. The only effective vaccine will be that which "has no fear" of irnmuno-deficit. VICHREPOL is just that kind of structure because it is a combination of two HIV antigenes with an immunostimulator (adjuvant). And we are hopeful that the preparation can be used not only for disease prevention, but also for the treatment of people who have already fallen ill.

Paying due respect to the efforts of our own researchers, I must also mention the fact that we are conducting many of our studies in conjunction with other centers of the Academy of Sciences, the Academy of Medical Sciences and the RF Ministry of Health. Without this cooperation it would have been impossible to implement the Federal Program "Vaccines of the New Generation and Diagnostic Systems of the Future" and the program coordinates some 50 centers all over the country.

- Today about 30 percent of our population are suffering from allergies. Can your biotechnological methods be used for their treatment?

- Yes, they can. For example, they can completely heal bronchial asthma. Unfortunately, the available antihista-mine and other remedies can only slow down the allergic reaction for some time. But it is the result of the upsets of

Experiments with tests of artificial anti-flu vaccines, I - flu virus (1 - hemagglutinin, 2 - neurominidaze); II - conjugates of antigen-polymer (3 - hemagglutinin-polymer, twin conjugate); III - survival of mice vaccinated with hemagglutinin or conjugates (5 - administration ofisotonic solution of sodium chloride) with subsequent contamination with a flu virus; IV - number of antibody - forming cells in the spleen of mice of respective groups.

* For their cycle of studies "Conjugated Polymer-subunit immunogenes and vaccines", R. Petrov, V. Kabanov, R. Khaitov, A. Nekrasov and R. Ataullakhanov were awarded the 2001 RF State Prize for Science and Technology. - Ed.

Pages. 28

cell balances in the immune system. And helping to bring things back to normal are preparations of an entirely new class-allergotropines. The general idea is as follows. It turns out that vaccines, developed on the basis of a poly-electrolyte carrier, do not stimulate the synthesis of allergy antibodies and do not cause complications linked with this process. Wfe started experiments in which we combined the aforesaid poly-oxidonium with purified allergens. And we discovered that conjugates of this kind help boost considerably the production of defense antibodies which play a "blocking" role in this situation. Preliminary clinical tests have confirmed their effectiveness. The already patented preparations are BERPOL, TIMPOL and POLPOL produced on the basis of highly refined allergoids of birch, timothy and wormwood pollen. And that means that we can already speak of the promising nature of our "ideology of designing" such preparations which we have tested ourselves.

- As far as I know, vaccines of the new generation are part of the problems associated with the immune biotechnology investigated by your institute.

- Yes, important as they are, they are only part of our studies because there are also two more independent, although closely interlinked fields: development of immunomodulating preparations and what we call diagnostic systems of the future.

Now, what is biotechnology? It is using different strains of microorganisms for obtaining the required product. Introduced into these strains is an appropriate gene and the strains start producing proteins, enzymes, etc. And immunologists are using as biotechnologies their own specific methods, such as hybridomic technologies. These are also used for "designing" preparations for the restoration of affected body functions. And we find out which link of the "chain of defense" is damaged and choose the necessary immunomodulator. Among them there are some which "match" very definite cells. Development of such "addressed" remedies is a promising trend in pharmacology.

Our specialists have surveyed different population groups in many parts of this country. They established that a large percentage of people suffer from the acquired, or to be more exact, secondary immunodeficits-functional upsets caused by ecological factors, unbalanced food rations, etc. Such cases require preventive immunocor-rection with the use of curative preparations. The obtained data indicate that measures of this kind help sharply reduce the rate of infections.

And there is one more important part of our studies - the development of diagnostic systems for determining the immune, immunogenetic and allergic status of a person. In this case we have placed our accent on nano-technologies which make it possible to identify even few molecules which are of interest to us in any sample, such as serum, blood or water, wash off, etc. We have already developed the necessary equipment in labs and it will soon be available on a commercial basis. The consumption of reagents and the length of analyses will be reduced by orders of magnitude. Tangible progress has also been achieved in genodiagnostics: thanks to the chain polymerase reaction it is now possible to determine a concrete genome fragment. And many viruses are known to mutate and it is important to learn to identify them. For example, apart from flu there are more than one hundred different infections which affect respiratory organs. For their identification our institute experts have developed methods which make it possible, by using wash-offs and a DNA fragment, quickly identify any of these hundred of viruses, that is produce an exact diagnosis upon which the success of therapy depends.

Completely new possibilities in disease identification appeared a little more than a quarter of a century ago thanks to the advent of what we call hybridomic technique of synthesis of monoclonal antibodies. What is hybridom? This is a hybrid obtained by a fusion of normal lymphocytes of immunized animals with cancer cells cultivated in nutrient medium. From the former it acquires the ability to synthesize a certain antibody, and from the latter - the potential for endless multiplication. As a result the antibodies produced by the clone are absolutely identical and interact with one antigen only. The preparation obtained in the test-tube is an excellent diagnostic and curative substance. The future of our own and associated branches of medicine is largely associated with hybridomic technique and production of monoclonal antibodies.

- Immunology, like any developing branch of research, must have a host of unresolved problems?

- Of course it has. And it is necessary to identify concrete genes which are responsible for the development of allergies. We have to learn to synthesize peptides which are optimal for the production of vaccines. A vast number of infections still remain "unconquered". Say, veneric diseases like syphilis and gonorrhoea are healed by using drugs since there are no vaccines against them and such vaccines have to be developed. And there are still many "blank spots" in the field of organs transplantation.

- In conclusion, a very practical question. What would you suggest to our readers for strengthening their immunity?

- The list of preparations developed at our institute, patented and cleared for medical use and commercial production, includes a number of what we call immunomodulators. These have been successfully used for years for the treatment of ailments associated with conditions of immunodeficit. The high quality of our immunostimulants has been marked by two RF Government prizes for science and technology. But let me stress at this point that these are curative preparations, and a person in good health should avoid taking any medicines, even the best of them. To ensure the effective functioning of one's immune system it is quite enough to have an adequate and diverse diet with plenty of vitamins in it.


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