From Big Medical Encyclopedia

ANTIRABIC VACCINATIONS (grech, anti-against + lat. rabies rage; synonym pasterovsky inoculations) — administration of specific drugs (a vaccine, serum, gamma-globulin) for prevention of rage.

The method of treatment-and-prophylactic inoculations against rage (see) was offered in 1885 Mr. of Louis Pasteur (see), created the first antirabic vaccine. The principle of repeated repeated introduction of the vaccine prepared from a brain of a rabbit containing the increasing quantities of the live, so-called fixed rhabdovirus causing development of a disease in experimental animal (rabbits) through strictly certain time slice after their infection was the basis for a method.

The inactivation of a virus was reached by drying of pieces of a brain of the infected rabbits over caustic heat during various span (from 1 to 16 days). Inoculations began with administration of brain suspension of the virus which lost virulence and the subsequent daily introduction of the vaccine containing the increasing quantities of a live virus. Efficiency of a method was checked on dogs.

On July 6, 1885 Pasteur for the first time began a course of inoculations to the 9-year-old child bitten by a mad dog. Treatment was begun in 60 hours after stings and continued within 10 days, 13 vaccination are during this time done. Inoculations were begun with administration of suspension of a brain of a rabbit (16-day drying), free of a live virus, and finished with introduction of a virulent virus (a brain of one-day drying). The child survived. Soon pasterovsky inoculations gained wide recognition. In a year in Russia the second was open after French the pasterovsky station (see. Pasterovsky stations , points).

After Pasteur's opening various methods of inoculations differing from pasterovsky in more perfect technology of preparation of antirabic vaccines were offered. The shortest course of vaccination (no more than 6 days) within one day was connected with repeated injections of a vaccine using radio vaccines (Hempt's method, 1925).

Schemes A. items, and including at use of a vaccine of Pasteur, were repeatedly modified because of insufficiently high performance in cases of massive infection (multiple stings, especially in the head).

To increase efficiency And. the item worked well in the fifties 20 century when the method of the combined treatment was developed — administration of the purified and concentrated hyperimmune antirabic serum or its globulinovy fraction received from blood serum of animal different types (horses are more often) with the subsequent course of inoculations an antirabic vaccine. In the USSR the antirabic gamma-globulin prepared from serum of a horse is applied.

And. items in the presence of indications are appointed by the doctor to all persons irrespective of age and begin immediately. Duration of a course of inoculations, a daily dose of a vaccine are defined by set of a number of factors: a condition of the bitten animal, weight and localization of the put damage, age of the victim, an epizootic situation.

The full course of inoculations according to unconditional indications is appointed at stings, scratches, an oslyuneniya mucous and integuments an animal, and also externally healthy animals, obviously mad or suspicious on rage, who destiny cannot be tracked (wildings, stray dogs and cats). It is caused by the fact that in saliva of animals the rhabdovirus is found for 3 days before development of a disease. Inoculations carry out also at the oslyuneniya and damages put with the person suffering from hydrophobia at wound the objects contaminated by rabid saliva, cadaveric material of the animals who died from rage and people.

The main criterion during the definition of a course of inoculations in the specified cases is weight of a sting and its localization. At multiple stings of a body, at any stings of the most dangerous localization (a face, the head, a neck, fingers of hands), oslyuneniya of the injured mucous membranes, at any stings put with wild carnivores (wolves, foxes, jackals, etc.), appoint the combined inoculations — single administration of antirabic serum or gamma-globulin with the subsequent course of inoculations an antirabic vaccine. Antirabic gamma-globulin is entered into gluteuses after preliminary check of sensitivity of the victim to proteins of serum of a horse and desensitization of an organism. A dose of gamma-globulin of 0,25 — 0,5 ml on 1 kg of body weight. In the USSR the course providing daily inoculations of 5% a brain vaccine lasting no more than 25 days with 2 — 3 revaccinations at an interval of 10 days after the termination of a basic course is accepted. The daily dose of a vaccine for the adult makes 5 ml, it is entered into hypodermic cellulose of a stomach on 2,5 ml at an interval of 30 min. These complex And. items at massive infection are applied in all countries, with only that difference that the general duration of a basic course of inoculations and a daily dose of a vaccine at use of vaccines of different types vary. At easy single stings of any part of a body (except the person, the head, a neck, hands), at the oslyuneniya of the unimpaired mucous membranes damaged and the unimpaired skin only the course of vaccination lasting no more than 20 days with a daily dose of a vaccine equal of 2 — 3 ml is applied.

At multiple stings, stings in the head, a face, fingers of hands externally healthy known animals appoint a conditional course of inoculations, enter only antirabic gamma-globulin (0,25 ml on 1 kg of body weight) or an antirabic vaccine (5 ml within 3 — 4 days). For an animal establish 10-day veterinary observation. At obviously adverse situation (the sting is not provoked, the animal is not imparted, the area epizootic is unsuccessful on rage) a conditional course of inoculations can be conducted also at easier stings. If the animal remains healthy within 10 days, then the course of inoculations is not continued. If the animal gets sick with rage, will disappear or will die from the unknown reasons, inoculations continue, and in cases where their appointment was not provided in the moment of contact with an animal, the full course is immediately appointed.

To children it is appointed smaller, than the adult, a dose of a vaccine. A course of inoculations according to unconditional indications to persons with heavy stings, to persons with allergic diseases and diseases of c. N of page, to babies, pregnant women will see off in the conditions of a hospital.

During inoculations and after their termination it is necessary to observe a certain mode: it is strictly forbidden to take alcoholic drinks, it is necessary to avoid overfatigue, overheating, cooling; medical serums (except antitetanic) can be appointed only according to vital indications.

At introduction of antirabic vaccines along with local inflammatory skin reaction shock, a neyropa ralitichesky complications in rare instances can develop (see. Postvaccinal complications ). At the first signs of defeat of c. the N of the page imparted immediately hospitalize. At administration of heterological antirabic serumal drugs anaphylactoid reactions are observed in 15 — 20% of cases. In the USSR and the USA areaktogenny drug — antirabic immunoglobulin from human serum which is in a stage of testing is developed.

And. items are carried out to the USSR according to the existing manual but to use of an antirabic vaccine and antirabic gamma-globulin where are provided as a course of inoculations at defeats of various weight, and methods of treatment of postvaccinal complications.

Preventive inoculations to dogs and cats are carried out by employees of veterinary service; for maintenance of hyperimmunity of animals impart annually single introduction of a vaccine. Such inoculations are one of effective measures against a drift of rage from the natural centers of an infection (from wildings).

For the purpose of individual protection are recommended preventive And. the item to the laboratory workers working with a street rhabdovirus, to veterinary workers, persons, conducting catching of stray dogs and cats, etc.

Antirabic vaccines

In 1885 Mr. Louis Pasteur and his employees Shamberlan, Ru and Tyuye (C.Chamberland, E. Roux, L. F. Thuillier) suggested to use the version of the causative agent of rage (adapted to c as a vaccinal strain. N of page of rabbits by carrying out 90 successive intracerebral passages) which was called the fixed virus.

Unlike a street rhabdovirus, the fixed virus with big constancy caused a disease in rabbits at intratserebralny introduction after a short incubation interval (7 days), bred in a brain more actively, almost lost the pathogenic properties at hypodermic introduction. Pasteur's strain was provided to various countries for production of antirabic vaccines. In a crust, time the original strain and especially its branches (substrains) passed numerous passages on rabbits. Subvirus strains of Pasteur underwent some changes of biological properties, the incubation interval of a disease at rabbits was reduced to 4 days, in the antigenic relation the unity with the street virus circulating in the nature remained. For the purpose of preservation of stable properties of a strain of Pasteur it is recommended to reduce number of successive passages as much as possible.

Apply an original strain of Pasteur and strains, similar to it, fixed and supported by intracerebral passages on rabbits to production of modern brain vaccines. The fixed virus can be stored in vitro in 50% neutral glycerin or in the form of the frozen or dried up suspension.

Vaccines are prepared from a brain of rabbits, young sheep, goats, from a brain of newborn white mice and rabbits. Was considered that vaccines from a brain of newborn animals do not contain the so-called entsefalitogenny factor which is one of the reasons of development of postvaccinal neurologic complications. A vaccine less reaktogenna, but their use does not exclude from a brain of newborn animals completely a possibility of development of postvaccinal complications.

Koprovsky and Cox (H. Koprowski, N. Sokh) in 1948 offered the new vaccinal strain of Flyuri («Flury») fixed on one-day chickens and adapted and modified on fabrics of the developing chicken embryo. There are two modifications of a strain of Flyuri — a strain 40 — the 50th passage and the strain which passed 180 passages. Later the second embryonal strain — Kelev («Kelev») was offered. Strains support on the chicken embryos infected in a vitellicle with a suspension from fabric of a chicken germ and use for preparation of live vaccines for preventive vaccination of animals.

Powell and Kalbertson (N. of Powell, S. of Culbertson, 1950) adapted the fixed rhabdovirus to fabrics of the developing duck embryo infection in a vitellicle.

Fenye (R. of Fenje, 1960) by the alternating passages of a pas white mice and culture of cells of a kidney of the Syrian hamster adapted to this culture the option of the fixed virus received by it — a strain «Garden» («Sad»), offered it as a vaccinal virus and showed a possibility of receiving a cultural vaccine. In the subsequent a strain «Garden» was adapted to culture of cells of kidneys of a pig; he received the name — a strain of AYR («ERA»). «Garden» is the second option of a strain a strain of Vnukovo-32 which was received as a result of carrying out additional passages in primary culture of cells of a kidney of the Syrian hamster at the lowered temperature of cultivation — 32 °. It is known several vaccinal strains received on various fabric cultures of animal origin which are used for receiving the cultural vaccines which are applied in veterinary practice. The most effective consider the vaccine prepared from a strain of AYR. In recent years the fixed virus is adapted to culture of diploid cells of the person (WI-38).

Cultural vaccines for immunization of people are developed and are in a stage of implementation. The USSR prepares a vaccine in primary culture of cells of the kidney of the Syrian hamster infected with a strain of Vnukovo-32. The most perspective consider the cleared and concentrated cultural vaccines prepared on diploid cells of the person.

All vaccines divide into two main types: live and inactivated. Any vaccine can be prepared in the lyophilized form that provides stability of properties of drug at long-term storage. In medical practice the inactivated drugs in connection with bigger safety of their use practically forced out live vaccines.

Live vaccines

Original vaccine of Pasteur. The vaccine is prepared from a spinal cord of the rabbit slaughtered in an agonal state. The spinal cord is taken entirely in strictly aseptic conditions, cut on several parts and suspended in the closed bottles at the bottom of which the caustic potassium absorbing moisture contains. Drying in these conditions within 2 — 14 days is followed by progressively decreasing maintenance of a live virus to its full inactivation. In 1891 the method is modified by A. Calmette. After 3 — 4-day drying the brain was placed in vessels from 20 ml of neutral glycerin and sterilized in the autoclave at t ° 120 °, kept in glycerin no more than 40 days and used for preparation of a vaccine. This modification was applied at Pasteur's institute from 1911 to 1952.

Hedyesh's vaccine [E. (And.) Högyes, 1887]. As inoculative drug entered the suspension of a virussoderzhashchy brain of a rabbit prepared for ex tempore on normal saline solution in the increasing concentration from 1: 10 000 to 1: 100 (so-called dilyutsionny method). The author considered advantage of a method more exact dosage of a virus in the entered material.

The inactivated vaccines

the Antirabic vaccines inactivated by action of chemical agents. Phenolic vaccines. Fermi (S. of Fermi, 1908) suggested to use phenol with the purpose of an inactivation of the fixed virus. The author showed that influence of small concentration of phenol at different temperature schedules during various time for brain suspension can inactivate the fixed virus, without changing significantly its immunogene activity. In a crust, time apply vaccines which differ on a temperature schedule of an inactivation and quantitative content of phenol.

1. Fermi's vaccine. Prepare carefully homogenized suspension of a brain of a sheep, rabbit on the normal saline solution containing 1% of phenol and stand her in the thermostat at t ° 22 ° during the 24th hour. The end product contains 5% of a brain suspension and 0,5% of phenol. In the USSR the phenolic Fermi vaccines prepared from a brain of sheep are applied. The virus is inactivated by 1% phenol at ta 22 ° within 14 days. Produce only the lyophilized drugs. Before the use the vaccine is parted in 3 ml of solvent. Ready drug contains 5% of suspension of marrow with a small amount of phenol (no more than 0,25%), sucrose, to-ruyu add as the stabilizer. The vaccine contains a small amount of a live virus. Also completely inaktirovanny fenolvaktsina from a brain of sheep and a fenolvaktsin received in primary culture of cells of a kidney of the Syrian hamster is applied.

2. Vaccine of the Sample (D. Semple, 1917). By an original method 8% suspension of a brain of a rabbit the content of 1% of phenol prepared, to-ruyu maintained in the thermostat 24 hours at t ° 37σ. Before the use parted twice with normal saline solution. The end product contained 4% of marrow and 0,5% of phenol.

In a crust, time release the vaccines prepared from a brain of a rabbit, sheep, goats containing various amount of marrow and smaller (in comparison with an original method) amount of phenol. The full inactivation of a virus is reached by longer incubation of brain suspension in the presence of phenol at ta 20 — 30 °. Add 0,01% of a tiomerzal to a vaccine. At immunization enter not less than 2 ml of 5% of brain suspension.

Eterizovainy, or radio, vaccines. Remlenzhe (R. Remlinger, 1919) for the first time used ether for an inactivation of the fixed virus. Hempt (And. Hempt, 1925) modified a method and offered partially and completely inactivated vaccine. The brain of a rabbit was kept at first in ether during 90 hours, back — 72 hours, and then in feno-lizirovanny glycerin (33% of glycerin, 1% of phenol) within 20 days.

In a crust, time eterizovanny vaccines are prepared from a brain of sheep. The pieces of a brain processed by ether keep in fenolizirovanny glycerin not less than one and a half months. On Nikolic's modification (M. of Nikolic) the brain is in addition inactivated by 48 hours in 1%formaline. The vaccine is prepared on a distilled water, usually in the form of 9 — 10% of the suspension containing 0,5% of phenol.

Avain embryo vaccine. Prepare 33% suspension from fabric of the developing duck embryo infected in a vitellicle inactivate beta propiolactone. A vaccine less reaktogenn, but also less immunogen compared with brain vaccines. Beta propiolactone is used also for an inactivation of brain vaccines.

The antirabic vaccines inactivated by physical impacts. Babesh and Pushkariu (V. Babes, E. Puscariu) for the first time offered a vaccine of various degree of an inactivation that was reached by warming up of 1% of a brain suspension at t ° 65 — 45 °.

In a crust, time for the purpose of receiving the inactivated vaccine apply uv radiation, a cut causes an instant inactivation of a virus. Special devices which provide a continuous stream of virussoderzhashchy material in the form of a pellicle and an exact dosage of radiation are developed for the production purposes. The suspension containing no more than 10% of fabric, which is previously filtered through several layers of a gauze or a wire screen can be subjected to an inactivation. If before the use the vaccine is stored in liquid state, then add preservative (tiomerzat in cultivation 1: 8000 or 0,25% phenol). The irradiated vaccines with various content of marrow are applied (1% of a vaccine from a brain of newborn mice, 5% — from a brain of animal other types).

Evaluation test of vaccines

All released series of vaccines undergo obligatory control on sterility, harmlessness, the maintenance of a live virus and an immunogenicity. Dry antirabic vaccines are controlled on residual humidity and solubility.

There are three main standard methods of definition of an immunogenicity of vaccines: two tests of K. Habel and method (NH) of national institutes of health care of the USA; the last is the most exact, is applied in the USSR. Definition of an immunogenicity of vaccines by the NH method is made in comparison to a reference national or international vaccine.

In veterinary practice the live avain, live cultural embryo vaccines, brain vaccines inactivated by phenol, beta propiolactone, uv radiation are widely applied to preventive immunization of animals.

Bibliography: The committee of WHO experts on rage, lane with English, Is gray. tekhn. dokl., No. 321, WHO, Geneva, 1967; P and with t of e r L. The chosen works, the lane with fr., t. 2, page 690, M., 1960; Shen R. M. Antirabic vaccines, in book: Prevention of infections live vaccines, under the editorship of M. I. Sokolov, page 103, M., 1960; Abelseth M. To. An attenuated rabies vaccine for domestic animals produced in tissue culture, Canad. vet. J., v. 5, p. 279, 1964; it, Propagation of rabies virus in pig kidney cell culture, ibid., p. 84; F e n j e P. A rabies vaccine from hamster kidney^tissue cultures, Canad. J. Microbiol., v. 6, p. 605, 1960; Laboratory techniques in rabies, ed. by M. M. Kaplan a. H. Kop-rowski, WHO, Geneva, 1973.

L. P. Gorshunova.