Immunization against rabies with rabies immune globulin, human (RIGH) and a human diploid cell strain (HDCS) rabies vaccine.
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A collaborative study was carried out to establish a replacement for the International Standard for Rabies Vaccine, the stocks of which are exhausted. Three rabies vaccines for human use derived from different rabies virus strains and prepared on different cell culture substrates were compared with the International Standard for Rabies Vaccine using in vivo and in vitro assay methods in a collaborative study involving 14 participants. The proposed fifth International Standard (PISRAV) which was derived from the same virus strain as the present international standard preparation, the Pitman Moore (PM) strain, was found to be approximately twice as potent relative to the International Standard in immunogenicity assays as in antigenicity assays. On the other hand another vaccine, derived from the LEP strain, was considerably more potent in antigenicity assays than in immunogenicity assays. The glycoprotein of the proposed replacement standard measured in antigenicity assays appeared to be stable at +37 degrees C for 245 days, whereas the immunogenicity of the proposed replacement vaccine was sensitive to this heat treatment and the vaccine lost 66% of its immunogenic potency. The results of this study indicate that the NIH protection test should continue to form the primary basis for potency assay of rabies vaccine as glycoprotein content does not appear to correlate with immunogenic potency for different types of vaccine. The vaccine coded PISRAV has been established as the fifth International Standard for Rabies Vaccine and a potency of 16 International Units of Rabies Vaccine (based on the immunogenicity assays) assigned to the contents of each ampoule. Each ampoule has also been assigned a unitage of 10 IU of PM Rabies Virus Glycoprotein and 135 IU of PM Rabies Virus Ribonucleoprotein.
Of 79318 persons treated of rabies in the Uzbek SSR in 1968--1974 there were recorded 16 cases of death of clinically manifest rabies. The course of treatment included injection of rabies gamma-globulin in a dose of 0.5 ml per 1 kg of body weight and the maximal dose of rabies vaccine. The incubation period lasted from 44 to 833 days (229.6 on the average). The authors considered that irrational use of high doses of rabies preparations was the cause of unsuccessful treatment of rabies.
In an outbreak of bovine rabies in Argentina, a study was made of vampire bats (Desmodus rotundus) and wild carnivores. Rabies antibody rates of high prevalence were found in the bats, foxes (Dusicyon gymnocercus) and skunks (Conepatus chinga). The outbreak was part of an extensive continuing epizootic of vampire transmitted bovine rabies which may have also involved other vectors in the area of this study. Consumption of dead and dying bats by the carnivores is the suggested means of passage of rabies virus from vampire bats to foxes and skunks. Given optimum conditions it is conceivable that some outbreaks in carnivores may begin in this way.
Forty-five persons severely bitten by rabid dogs and wolves in Iran were treated after exposure with a new rabies vaccine produced in cultures of human diploid cells. All except one also received one injection of rabies immune serum. This treatment, in contrast to past experience with other vaccines, resulted in protection of all individuals against rabies. Thus, almost a century after the postexposure treatment of humans was initiated, an effective tool for protecting man against rabies has finally been developed.
Human anti-rabies immune sera enhanced the in vitro cytotoxicity of human lymphocytes against rabies virus-infected green-monkey kidney cells. The immune sera were collected from patients immunized with rabies vaccine produced either in human diploid cells or in nervous tissue. Significant cytotoxicity was observed even with high serum dilutions, indicating that the K-cell assay might be a sensitive tool for detection of anti-rabies antibodies.
The development of rabies immune globulin of human origin is discussed. Antirabies serum of equine origin when used in conjunction with rabies vaccine, enhances significantly the chances of survival after a severe bite by a rabid animal. However, those who receive the equine serum may develop serum sickness or even anaphylaxis. To circumvent this risk, while preserving the benefit, many workers have attempted to develop rabies immune globulin of human origin. Success was impeded by the difficulty in obtaining rabies immune plasma with the needed antibody level. Despite this and other obstacles, production of the human globulin on a scale sufficient to satisfy clinical needs has been finally realized. At the appropriate dosage, this globulin was demonstrated to interfere minimally, if at all, with the expression of active immunity induced by vaccination.
Five hundred and thirty-two rodents (10 species) and 112 other wild mammals (six species) were examined for rabies infections in Egypt. Rabies virus was isolated from the brains of three (1-2%) of 249 Gerbils, Gerbillus gerbillus and one (1-8%) of 56 foxes, Vulpes species. In neutralization tests these isolates were found to be identical to classical rabies virus. Significant numbers of rodent and other wild mammal species need to be examined before they may be excluded as possible reservoirs of rabies virus in Egypt. Based on initial findings it may be wise to reevaluate antirabies treatment for rodent bites occurring within the Arab Republic of Egypt.
Seroconversion and adverse reaction rates were studied in 92 persons given four or five doses in a two-week period of duck embryo rabies vaccine (DEV) or duck embryo rabies vaccine purified by ultracentrifugation (P-DEV). Mouse-neutralizing antibodies developed in 78 of 92 (84.8%) persons in these accelerated schedules. There were no significant differences in the frequency of antibody conversion or in geometric mean titers of antibody between persons given either vaccine. However, local and systemic adverse reactions were substantially less common with P-DEV. These data suggest that four of five doses of DEV or P-DEV given in a two-week course can be used for preexposure prophylaxis in situations where the more drawn-out regimens would result in continuation of a high-risk of rabies exposure. The antibody response of persons given this more accelerated regimen must be determined.
A murine model simulating human street rabies virus infection was used to evaluate the efficacy of polyriboinosinic-polyribocytidylic acid (poly I-poly C), three rabies vaccines, and combinations of these modes of therapy administered after exposure. One or two doses of 100 mug of poly I-poly C, injected into the same intramuscular site as the challenge virus, significantly reduced the mortality rate when therapy was initiated 3 hr after challenge; however, the same quantity of poly I-poly C injected into the opposite leg did not reduce the mortality rate. The muscle injected with poly I-poly C invariably contained four to eight times more interferon than a similar noninjected muscle from the same animal. Mice treated 3 hr after challenge with each of the three vaccines produced significant levels of antibody but were not protected, whereas treatment with combinations of poly I-poly C and vaccine resulted in significant protection. These results suggest that the combination of induction of local interferon and an immune response contributes to the protection of mice after exposure to street rabies virus infection.
Humoral antibody response to three types of rabies vaccines were assayed by the neutralization (NT), the mixed hemadsorption (MH), and the indirect immunofluorescence (IF) tests. The NT and MH tests were used to detect antibodies combining with antigens at the surface of virions and infected cells, whereas the indirect IF test measured antibodies mainly to the rabies nucleocapsid antigen. After immunization with a human diploid cell vaccine, antibodies were detected by both the NT and the MH test in the 14th- and 30th-day serum samples from each of eight vaccinated persons. There was a good correlation between titers obtained with the two tests in this group of vaccinees. Antibodies elicited by duck embryo and nervous tissue vaccines occurred less frequently and in lower titers. In these groups of vaccinees, 5 of 14 and 5 of 10, respectively, had antibodies detectable by the NT test in the 14th- and 30th-day sera but were negative by the MH test. It is suggested that this was due to the high levels of immunoglobulin M antibodies, which are known to be elicited by daily injections of vaccine. Since antibodies of the immunoglobulin M class are considered to be less important for protection against rabies, the MH test is recommended for immunity determinations. Compared with the NT test, this test also offers the advantage of being technically more convenient because of its capacity for testing numerous sera in a single run. Antibody titers obtained by the indirect IF test in the human diploid cell vaccine group were relatively low. Titers in the duck embryo and nervous tissue vaccine groups were higher but did not correlate with the results of the NT test.
To improve both safety and stability of the vaccines used in the field to vaccinate foxes against rabies by the oral route, a recombinant vaccinia virus, expressing the immunizing G protein of rabies virus (VVTGg RAB-26D3 187 X P strain) has been developed. The c-DNA corresponding to the glycoprotein of the ERA strain of rabies virus has been inserted into the thymidine kinase (TK) gene of the vaccinia virus (Copenhagen strain). The efficacy of this recombinant strain was tested by the oral route, primarily in foxes. The duration of immunity conferred by the VVTGg RAB, a minimum of 12 months in cubs and 18 months in adult animals, corresponds to the length of protection required for fox vaccination in the field. VVTGg RAB innocuity was tested in foxes and in domestic animals as well as in numerous wild animal species that could compete with the red fox in consuming vaccine baits in Europe. During a minimum of 28 days post vaccination, neither clinical signs nor lesions were observed in any of the vaccinated animals. Moreover no transmission of immunizing amounts of the recombinant occurred in the red fox or the other species tested. To study the stability of the vaccine strain, baits containing the vaccine were placed in the field. Despite considerable variations of environmental temperatures, the VVTGg RAB titre remained stable after one month in the field. Since all the baits are taken within one month, it can be assumed that most of the animals taking the baits are effectively vaccinated.(ABSTRACT TRUNCATED AT 250 WORDS)
During 1972-1976 46 persons in 9 foci were bitten by wolves. 39 of them were immunized with antirabies gammaglobulin and tissue culture rabies vaccine; 7 received culture vaccine only. Rabies in wolves was confirmed clinically or in the laboratory in 8 foci. Bites of dangerous localization: face, head or fingers of the hands, predominantly multiple, were noted in 25 humans; 5 of them were young, 7 to 16 years old. Antirabies gammaglobulin was given to 9 people, predominantly in the dose of 0,5 ml per kg of weight, once on the 1st day after exposure (381-538 IU per kg of weight) to 14 people, once on the 2nd day (706-773 IU) to 3 people, twice on the 2nd and 3rd to 3 people, once on the 3rd and 5th day to 10 people, twice on the 2nd and 3rd day or on the 5th day after exposure. Vaccination course was started 24 hours after administration of gammaglobulin and predominantly in the dose of 5 ml; it lasted for 25 days and was followed by 3 booster injections on the 10th, 20th and 30th day. Titres of virus neutralizing antibody were tested in dynamics in 39 people immunized with gammaglobulin and tissue culture vaccine. Antirabies gammaglobulin induced some inhibitory effect, but 2-3 booster injections of the tissue culture rabies vaccine completely compensated this effect. During the observation period of 10 months to 5 years all the exposed people remained healthy.
The structure of rabies virus and the importance of its glycoprotein in immunization are discussed. The improvement in vaccines for use in man, culminating in the production of the human diploid vaccine is described. Nevertheless problems remain, particularly with regard to post-exposure therapy. Possible disadvantages in the use of subunit vaccines are mentioned and attention is drawn to the discovery of the rabies-related viruses.
Rabies neutralizing antibody levels were determined before and after administration of a booster-dose of Wyeth rabies vaccine (WRV) in persons immunized earlier with either duck embryo vaccine (DEV) or with WRV. Virtually all those receiving an initial 3-dose regimen of WRV (0, 7 and 21--28 days) still had neutralizing antibody one year later, but there was a decline in titer from 10--50 IU per ml at 35 days to about 1--3 IU. Only one-half of those receiving DEV as the primary vaccine had even detectable antibody one year later. All volunteers responded anamnestically to a single WRV booster given 8--12 months after either primary vaccine. Those given WRV initially had much higher antibody levels than those given DEV, but after the WRV booster antibody levels in all vaccinees remained high, even one year later.
Infant cats were inoculated intracranially with rabies or feline leukemia viruses in an experimental study of wasting syndrome. The daily pre- and postinoculation body weights were recorded until kittens were moribund. Affected animals in both groups manifested growth failure or wasting syndrome. Immunodepression, manifested by a conspicuous depletion of thymic cortex, the thymus dependent areas of the spleen, and growth hormone producing-alpha adenopituicytes was significantly (p less than 0.01) related to the wasting status of the animals. The ability of pituitary glands from these animals to produce growth hormone was studied by in situ immunoperoxidase staining and showed a significant (p less than 0.01) difference between healthy and wasted animals. Rabies and feline leukemia viruses were each found responsible for the low immunoreactivity of growth hormone producing alpha adenopituicytes. Because the hypothalamus and the hypophysis were both found infected, it was concluded that regardless of the triggering agent in primary wasting, the hypothalamic-hypophyseal-thymic axis was always involved through a decrease in growth hormone production.
A veterinarian contracted rabies in the course of laboratory work with homogenates of rabid goat brain. Epidemiologic study determined a respiratory mode of transmission. After a fulminant encephalitic illness, formed rabies virions were identified in the synaptic zones of the olfactory glomeruli. Identification, isolation, experimental disease production, and tissue cytopathic effects of virus recovered from the brain fulfilled Koch's postulates in this unusual instance of virus disease of the nervous system.
Many thousands of people in France and abroad have already benefited from preventive rabies vaccination by means of a vaccine obtained from culture on human diploid cells, perfected ten years ago by R. Lang, the Institut Mérieux and the Wistar Institute. In addition to being well tolerated, the serological efficacy of this vaccine is such that 100% of the vaccines observed had a seroconversion after only two injections at an interval of one month. However, a booster dose should be given 6 to 12 months after the first injection, and a further booster 3 to 5 years later or on request in case of known contamination. These boosters, combined with an anti-tetanus booster, induce such high antibody titers--between 10-100 and even 1000 I.U./ml--that it is easy to obtain substantial batches of combined anti-rabies and anti-tetanus immunoglobulin from a small number of volunteers. The complete efficacy of this new vaccine reduces the number of systematic post-vaccinal serologic controls and its innocuity is such that an extended preventive vaccination programme may be carried out, for instance in the case of children living in areas known to be dangerous.