Suckling Mouse Brain Vaccine Research Articles

Antibody Response to an Anti‐rabies Vaccine in a Dog Population under Field Conditions in Bolivia

Rabies remains an important public health issue in Bolivia, South America. Public concern and fears are most focussed on dogs as the source of rabies. The objective of the present study was to assess immunity of an inactivated suckling mouse brain vaccine against canine rabies used for the official vaccination campaigns under field conditions in an endemic area of rabies in Bolivia. A total of 236 vaccinated and 44 unvaccinated dogs in Santa Cruz de la Sierra, selected using stratified random sampling, were investigated in order to obtain owned dog characteristics and antibody titres against rabies in April 2007. The proportion of vaccinated dogs with an antibody titre exceeded the protection threshold value of 0.5 EU/ml was 58% [95% confidence intervals (CI): 52-65], indicating that vaccination is likely to elicit an antibody response (odds ratio 6.3, 95% CI: 1.2-11.5). The range of geometric mean of antibody titre for vaccinated dogs (0.89 EU/ml; 95% CI: 0.75-1.04) was considered to meet the minimal acceptable level indicating an adequate immune response to the vaccine. However, the titre level was not satisfactory in comparison with the results from other field investigations with inactivated tissue culture vaccines. It is recommended for public health authorities to (1) consider modernizing their vaccine manufacturing method because the level of immunity induced by the current vaccine is comparably low, (2) conduct frequent vaccination campaigns to maintain high levels of vaccination coverage, and (3) actively manage the domestic dog population in the study area, which is largely responsible for rabies maintenance.

Inactivated suckling mouse brain rabies vaccine provides short-term immunity in capuchin monkeys (Cebus apella).

Eight capuchin monkeys (Cebus apella) were vaccinated against rabies with an inactivated suckling mouse brain vaccine (SMBV). Three 1-ml doses of 2% brain tissue suspension were given by i.m. injection at 0, 30, and 60 days. Blood samples were collected at 0, 30, 60, 90, 150, 210, 240, 300, and 365 days and were tested by simplified fluorescence inhibition to titer-neutralizing antibodies. All of the animals developed neutralizing antibodies with titers >0.5 IU/ml after vaccination, but the immune response persisted for only 122.3 +/- 32.6 days. The SMBV was able to induce immune response in the capuchin monkeys, but protection was short-lived.

Rabies

Rabies

Humoral immune response of dogs to the inactivated suckling mouse brain vaccine used in anti-rabies campaigns in Brazil

An anti-rabies campaign is undertaken annually in Brazil with of the Fuenzalida & Palacios vaccine. The humoral immune response of dogs vaccinated during the campaigns was researched with the objective of evaluating whether the dogs presented a protective titer (0.5 UI/ml) 12 months after vaccination and how many of these achieved this titer 30 days after a buttressing vaccination. Three hundred and forty-one specimens of serum of dogs domicilied, 259 in the S. Paulo and 82 in the Paulinia counties, were analyzed utilizing the Rapid Fluorescence Focus Inhibition Test. The immune response was evaluated taking into consideration the nutritional state of the animal and the number of previous vaccinations. The larger number of the dogs had not achieved the 0.5 UI/ml titer after 12 months, independently of the nutritional state and the response to the buttressing vaccination was more apparent in dogs with two or more previous vaccinations. The cut off of 0.5 UI/ml as protective titer in dogs and the influence of the nutritional state and health conditions of the animals as responsible for humoral immune response are discussed.

Immune response to tissue culture rabies vaccine in subjects who had previous postexposure treatment with Semple or suckling mouse brain vaccine

Nerve tissue derived Semple and suckling mouse brain rabies vaccines are still widely used. Patients who experience a new rabies exposure and who were given such vaccines decades earlier are not uncommon in rabies endemic countries. The World Health Organization recommends that persons who have had a prevous course of a potent tissue or avian culture rabies vaccine and are reexposed, be given booster injections on days 0 and 3 without rabies immune globulin. Persons who have had previous pre- or postexposure vaccination with a vaccine of unproven potency, should receive a full course of tissue or avian cell vaccine and immune globulin in the event of a new exposure. This study evaluated the immune response in 98 Thai patients who gave a history of rabies postexposure treatment with Semple or suckling mouse brain vaccines 10–50 years previously. The majority (81) had an anamnestic response and developed neutralizing antibodies that were above the recommended minimal acceptable level (0.5 IU ml −1) on day 7. This suggests that they still had immunological memory. A minority of 18% had antibody titers below this level on day 7. However, they all developed titers above 0.5 IU ml −1 on days 14 and 30. Failure to have an accelerated response to revaccination by day 7 did not appear to be related to age or time elapsed since previous nerve tissue derived vaccine administration. It was not possible to predict which subject will or will not have an acceptable level of antibody before day 14. Rabies exposed patients who give a prior history of vaccination with an unknown or nerve tissue derived vaccine should therefore be treated as if they had never been vaccinated.

Measurement of rabies virus N protein in rabies vaccines

In this study, we designed a capture ELISA using a monoclonal antibody specific for the N protein, the major protein of the rabies virus nucleocapsid, to measure the N protein content in rabies vaccines. Free N protein content was compared in the two types of rabies vaccine currently used in humans: suckling mouse brain (SMB) vaccine prepared from rabies virus-infected brain tissue, and tissue culture (TC) vaccine prepared from supernatants of rabies virus-infected cells. It was found that SMB vaccines contained considerably higher amounts of N protein than most of the TC vaccines. Possible implications concerning the efficacy of rabies vaccines are discussed.

Immunogenicity of rabies vaccines used during an urban epizootic of rabies in Mexico

From 1 July 1987 to 31 December 1988, 30% of 247 rabid dogs in Hermosillo, Mexico had a positive history of rabies vaccination. Serosurveys suggested that inactivated suckling mouse brain vaccine (INACT-SMBV) and inactivated tissue culture vaccine (INACT-TC) used before and during the epizootic were poor immunogens. Prospective studies showed that only about one-third of dogs vaccinated with INACT-SMBV were seropositive 5 weeks after vaccination. Lack of vaccine potency was the most likely cause of poor immunogenicity. Rabies vaccines should be evaluated periodically by measuring antibody responses in animals. In some circumstances, minimum seroconversion rates and antibody titres in vaccinated animals may be better measures of immunogenicity than relative potency.

Nucleocapsid specific T and B cell responses in humans after rabies vaccination.

The importance of the immune response directed to the internal component of the rabies virus, the nucleocapsid (NC), was evaluated in humans after rabies vaccination. T cell activation was measured with a bulk proliferative assay and relative frequencies of circulating NC-specific PBL were calculated with the limiting dilution technique. Vaccinees were classified into two groups: NC responders and NC non-responders. In NC responders, the frequency of NC-specific circulating lymphocytes was up to 6 times higher than the frequency of virus-specific lymphocytes. In non-responders, NC-specific lymphocytes were up to 25 times less common than virus-specific ones. The NC capacity to induce a secondary antibody response was tested in vitro. After a stimulation with complete virus, lymphocytes originating from donors vaccinated with tissue culture vaccine produced a secondary antibody-response composed mainly of glycoprotein-specific neutralizing antibodies, whereas lymphocytes from suckling mouse brain vaccines produced essentially NC-specific antibodies. This result confirmed the serological status of suckling mouse brain vaccinees, who usually developed high titres of NC-specific antibodies. After an in vitro NC stimulation, lymphocytes collected from NC responders produced not only NC-specific antibodies, provided they have NC-specific B cells at the time of blood sampling, but most surprisingly, they also produce glycoprotein-specific neutralizing antibodies. This finding indicates that NC free of glycoprotein is capable, in some individuals, of boosting an heterologous glycoprotein response.

Rabies reference vaccine for use as a regional standard for Latin America and the Caribbean countries

A candidate rabies reference vaccine of suckling mouse brain (SMB) origin was prepared and standardized at the Pan American Zoonoses Center (PAHO/WHO) and evaluated in a collaborative study involving seven laboratories. On the basis of three different tests, its potency, immunogenicity, and stability were demonstrated to be satisfactory. The vaccine was proposed for consideration of the Latin American and Caribbean countries as a regional standard to determine the potency of SMB vaccines, the most widely used in the Region.

Effet inducteur de la 2-5A-synthétase par des vaccins antirabiques à destinée humaine dans des lymphocytes humains non sensibilisés

Summary The interferon response of non-sensitized human lymphocytes to 3 anti-rabies vaccines and to vesicular stomatitis virus (VSV) in vitro was studied using an assay of interferon-induced 2-5A-synthetase in lymphocyte extracts. Rabies vaccine prepared from foetal bovine kidney cells and a human diploid cell strain led to stimulation of enzymatic activity. The response to the two vaccines and to VSV showed a correlation in the lymphocytes of 72 % of subjects. In contrast, suckling mouse brain vaccine decreased the enzymatic activity, which was lower than the base level in lymphocytes of 67 % of subjects, probably due to an inhibitory substance in the brain from which this vaccine was prepared.

Antibody response to suckling mouse brain rabies vaccines for post exposure treatment

A new suckling mouse brain vaccine (SMBV) against rabies, produced by the Thai Red Cross Society, was compared with the well established Institut Pasteur SMBV in patients with very low risk rabies contact. The 4 regimens used were the standard daily injections with booster doses of Thai Red Cross vaccine (TRCV) and Institut Pasteur Vaccine (IPV), and a reduced dose scheme of 6 injections as used for tissue cuture vaccines. The effect of 20 IU/kg of human rabies immune globulin (HRIG) was tested on each regimen, making 8 groups, a total of 122 patients. Blood samples taken on days 0, 7, 14, 28 and 91 were tested for neutralizing antibody. Only the standard IPV regimen produced antibody in every patient; all had levels greater than 0·5 IU at some stage. Two people (13%) given the standard TRCV produced no detectable antibody (⩽ 0·1 IU) throughout the study. The reduced dose regimens gave very low antibody levels. 7% of the IPV and 76% of the TRCV groups failed to produce antibody on any occasion. The antibody response was significantly suppressed by the administration of HRIG. Compared to the original South American SMBV, the vaccines tested induced low levels of short lived antibody. No reduction in the dosage of SMBV should be considered unless the potency of the product is adequate.

Serologie and Immune Responses to Rabies Virus During Different Human Treatments with Tissue Culture and Suckling Mouse Brain Vaccines

The antibody response to rabies virus was studied in twenty volunteers immunized with different schemes of suckling mouse brain and human diploid cell culture rabies vaccines. Throughout the study period, titers in serum neutralization and indirect fluorescent antibody tests, as well as the class of immunoglobulins with antirabies activity, varied in different individuals with the treatment scheme and the antigenic potency of the vaccine. The results suggest that measurement of the IgG class of antirabies antibodies, and possibly IgA as well, may be a more adequate criterion to assess the immunogenicity of rabies vaccines than the determination of SN titers alone.

Schémas réduits de traitement antirabiqueavec les nouveaux vaccins de cultures cellulaires

Summary The original ≪Pasteur treatment≫ required long series of daily injections of rabbit medulla suspension of increasing virulence. Even with the Fermi and Semple types of inactivated sheep brain vaccines, these long series remained necessary, with a high risk of neuroparalytic accidents. The first possibility of using redu ced schedules of post-exposure vaccination appeared after 1955 with the sucklingmouse-brain vaccine. But it was only after 1965, with the newly developed cell culture vaccines, (mainly the human diploid cell vaccine), that a reduced schedule of rabies treatment of only 6 injections could be recommended by the WHO. This WHO scheme is now widely used with other cell culture vaccines in several countries. New reduced schedules of rabies post-exposure vaccination are presently under study with the aim of inducing an immune response as early as possible and, at the same time, reducing the amount of vaccine used (and thus the cost of vaccination) and the number of injections: the multi-site method and the intradermal route of injection have proven to be very efficient in this respect.

Anti-rabies treatment of dog-bite victims in Lagos, Nigeria: trial of suckling mouse brain and fetal bovine kidney cell rabies vaccines

Human rabies is common in Nigeria, a country known for rabies endemicity. Yet the supply of anti-rabies vaccines for human use (adult sheep brain origin, produced locally, and duck embryo and human diploid cell vaccines, imported) is grossly inadequate. This study involved controlled treatment of dog-bite victims with suckling mouse brain (SMBV) or fetal bovine kidney (FBKV) rabies vaccines in an effort to determine which type to recommend for production and use in Nigeria. Dog-bite victims treated were aged three to 74 years, with about equal numbers of males and females. Of the 136 patients, 116 (85.3%) completed at least the primo-series of vaccinations, and all have survived without any evidence of clinical rabies. Recipients of the SMBV showed local and generalized reactions in 11.1% and 2.5% of the cases, respectively. Recipients of the FBKV administered subcutaneously showed local and generalized reactions, in 12.5% and 9.4% of cases, respectively. There were no side effects attributable to the vaccine among patients who received the FBKV intramuscularly. By day 7, 26.7% of SMBV recipients and 28.6% of FBKV recipients showed antibody response, with titres of at least one Equivalent Unit ml −1. These percentages increased to 95.1 and 81.1, respectively, by day 14, and by day 20 (for SMBV recipients) or day 30 (FBKV recipients) the response was 100%. Titres dropped by day 90, but in no case to below 1 EU ml −1. We have concluded that both vaccines are equally efficacious and well tolerated. In view of the simple technology required, and the resultant lower cost, the SMBV is being recommended for production and use in Nigeria.

Pre-exposure rabies immunization of man with suckling mouse brain vaccine.

A case series study is reported which included serologic results obtained in 195 persons recruited from personnel and trainees of the Pan American Zoonoses Center in Buenos Aires, Argentina, and workers from other institutions. The individuals were vaccinated with three doses of suckling mouse brain vaccine administered on alternate days, and some of them were given a booster dose 30 or 365 days after the primary immunization. The sizeable percentage of reactors with a high neutralizing antibody response in a short period of time, the small number of persons requiring a booster dose 30 days after the first vaccine dose, the rapid and intense secondary immune response and the absence of serious post-vaccinal reactions justify encouraging the use of this abbreviated prophylactic course of suckling mouse brain vaccine.

Neuroparalytic accidents of antirabies vaccination with suckling mouse brain vaccine. Clinical and pathologic study of 21 cases.

Twenty-one cases of neuroparalytic accidents of rabies vaccination (with suckling mouse brain vaccine), 11 of them fatal, were observed, occurring predominantly in men; the mean age of the patients was 29 years. On the average, 13 doses of the vaccine were used. Only three patients received less than seven doses. The mean latent period was 14 days (range, 4 to 24 days). In 16 patients (76%), a Guillain-Barré syndrome occurred that was moderate in three, severe in seven, and fatal in six. Pathologically, this was shown to be a typical polyradiculoneuritis. Five patients had fatal involvement of the central nervous system. Three had an acute disseminated perivenous leukoencephalopathy, with concurrent rabies encephalitis in one case. One patient had a perivenous myeloradiculopathy and one a chronic encephalomyelopathy of six years' duration with demyelinating plaques in the periventricular white matter, cerebellum, and spinal cord. Since the reduction of postexposure rabies vaccination to seven doses, no new cases have been observed in Colombia.

Recovery from Rabies in Man

A 45-year-old woman from Mendoza, Argentina, was severely bitten by a dog that died 4 days later. Before death, the dog was nervous, aggressive, and had occasional seizures. Ten days after the woman had been bitten, rabies vaccine treatment was begun: 14 daily doses of suckling mouse brain vaccine followed by 2 booster doses. Twenty-one days after the biting episode, she developed a cerebellar striatal syndrome, which persisted throughout several months, and severe encephalitic symptoms, which persisted for 75 days. After 13 months, recovery was nearly complete. The patient's serum and cerebrospinal fluid contained rabies-neutralizing antibodies reaching maximum titers of 1:640 000 and 1:160 000, respectively. Titers of this magnitude have never been previusly recorded after suckling mouse brain vaccine treatment. This phenomenon, together with the epidemiologic, clinical, and laboratory data presented, supports the conclusion of a nonfatal case of rabies in man.

Comparative Immunogenicities of Chikungunya Vaccines Prepared in Avian and Mammalian Tissues

Summary The comparative immunogenicities of experimental formalin-inactivated chikungunya (CHIK) vaccines prepared in chick-embryo (CE), suckling-mouse-brain (SMB), and green-monkey kidney-cell (GMKC) tissue culture with the CHIK 168 virus have been described. Tests of protection in mice revealed that CE vaccine was markedly inferior to either SMB or GMKC vaccine. Both SMB and GMKC vaccine were highly effective in protecting mice against an intracerebral challenge. However, the potentially encephalitogenic properties of SMB vaccines seriously limit their use in practice, so further evaluation of this vaccine was not now pursued. Results of plaque-inhibition tests revealed that GMKC vaccine elicited significant levels of serum-neutralization (N) antibody in mice to heterologous African E-103, Asian BAH-306, and Indian C-266 strains as well as the homologous 168 strain of CHIK virus. To correlate these findings with actual protection a vaccine trial was performed in rhesus monkeys, with these strains of the CHIK virus in the challenge procedure. After three doses of GMKC vaccine, high levels of N antibody developed in monkeys, and in most instances, CF and HI antibody were present in low titers to the challenge viruses. The immunogenic potency of GMKC vaccine was clearly defined by the complete absence of viremia in the vaccinated monkeys and no appreciable stimulation of N, complement-fixation, or hemagglutination-inhibition antibody subsequent to challenge. In contrast, the control monkeys, with one exception, had viremia, and responded with high levels of N, CF, and HI antibody after challenge.