A new case of bat rabies in France

INTRODUCTION: Bat rabies represents an emerging zoonosis in Europe and the only endemic cause of rabies in France. CASE RECORD: A 29 year-old woman was bitten at the hand by a bat. The diagnosis of bat rabies was positive and the viral strain was an European Bat Lyssavirus 1a. A combination of rabies vaccine and human rabies immune globulin was provided to the patient. DISCUSSION: Any direct contact with a bat must be avoided. In case of exposure to bats, the postexposure treatment must associate the rabies vaccine and human rabies immune globulin because of antigenic diversity of Lyssavirus circulating in bat species.     

The primary hamster kidney cell rabies vaccine: adaptation of viral strain, production of vaccine, and pre- and postexposure treatment

The hamster kidney cell rabies vaccine was investigated as a substitute for classical nervous tissue rabies vaccine. The Beijing strain of fixed rabies virus was adapted to primary hamster kidney cells (PHKCs), and four types of rabies vaccine (plain, adjuvant, concentrated, and concentrated adjuvant vaccines) were developed for human use. The potencies of the vaccines met the requirements of the World Health Organization, and these vaccines elicited rather satisfactory antibody responses in volunteers. The postexposure use of vaccine was evaluated in 301 individuals, 97 of whom had been bitten by proven rabid animals. None of the individuals contracted rabies during the observation period. After several years of field trials with both pre- and postexposure vaccines, the evidence indicates that the PHKC rabies vaccines are effective and safe for human use.     

Rabies control in Japan

In 1957 Japan succeeded in eradicating rabies, which had been endemic since the 18th century, due to the registration and confinement of family dogs, the elimination of stray dogs, and the compulsory vaccination of dogs. At present, however, vaccination coverage of family dogs is far lower than the required level of 70%. The facilities that are presently able to investigate rabies are limited in number. In addition, few medical institutions keep rabies vaccine in stock or offer postexposure vaccination to travelers bitten by animals in rabies endemic areas. Moreover, rabies immunoglobulin (RIG) cannot be given to such individuals because RIG is not produced at present in Japan, nor is it authorized to be imported. To keep Japan free from any rabies deaths, an improvement in vaccination coverage among dogs and in the supply of postexposure prophylaxis is required, and the establishment of a rabies surveillance system is also considered to be essential.     

Failure of pre- and postexposure rabies vaccinations in a child infected with HIV.

We report the case of a 6-y-old HIV-infected girl with severe immune deficiency who failed to respond to intramuscular pre-exposure rabies vaccination using human diploid cell rabies vaccine on days 0, 7 and 28. She also failed to respond to an intradermal postexposure rabies regimen using purified verocell rabies vaccine at 4 sites on days 0, 3 and 7 and at 2 sites on days 30 and 90 (double the usual regimen). Sequentially monitored rabies neutralizing antibody titers were below the WHO minimum acceptable level (> 0.15 IU/ml) in all specimens. Rabies prevention in HIV-infected persons with severe immune suppression requires further study.     

Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus

Rabies remains an important public health problem with more than 95% of all human rabies cases caused by exposure to rabid dogs in areas where effective, inexpensive vaccines are unavailable. Because of their ability to induce strong innate and adaptive immune responses capable of clearing the infection from the CNS after a single immunization, live-attenuated rabies virus (RV) vaccines could be particularly useful not only for the global eradication of canine rabies but also for late-stage rabies postexposure prophylaxis of humans. To overcome concerns regarding the safety of live-attenuated RV vaccines, we developed the highly attenuated triple RV G variant, SPBAANGAS-GAS-GAS. In contrast to most attenuated recombinant RVs generated thus far, SPBAANGAS-GAS-GAS is completely nonpathogenic after intracranial infection of mice that are either developmentally immunocompromised (e.g., 5-day-old mice) or have inherited deficits in immune function (e.g., antibody production or type I IFN signaling), as well as normal adult animals. In addition, SPBAANGAS-GAS-GAS induces immune mechanisms capable of containing a CNS infection with pathogenic RV, thereby preventing lethal rabies encephalopathy. The lack of pathogenicity together with excellent immunogenicity and the capacity to deliver immune effectors to CNS tissues makes SPBAANGAS-GAS-GAS a promising vaccine candidate for both the preexposure and postexposure prophylaxis of rabies.     

Rhesus diploid rabies vaccine (adsorbed): a new rabies vaccine using FRhL-2 cells

The FRhL-2 cell line, a diploid line derived from the lung of a fetal rhesus monkey, was used to prepare a potent rabies vaccine by adapting the Kissling strain of rabies virus to FRhL-2 cells, growing the virus in quantity, inactivating the virus with beta-propiolactone, and concentrating the virus by adsorption to aluminum phosphate. High levels of antibody to rabies virus, induced by the vaccine in both guinea pigs and humans at 14 days after immunization, were determined to be IgG. Data from postexposure protocols with guinea pigs and simulated postexposure protocols in humans showed protection and antibody response even when rabies immune globulin was administered at the time of vaccination.     

Antibody response after a four-site intradermal booster vaccination with cell-culture rabies vaccine.

The current World Health Organization recommendation for booster vaccination of previously immunized individuals with potential exposure to rabies is two doses of vaccine intramuscularly or intradermally on days 0 and 3. We report responses to two types of postexposure treatment of healthy individuals who had received preexposure rabies vaccination 1 year previously. Group A individuals received four intradermal doses (one-fifth of the diluent volume of vaccine per dose) on day 0, and group B individuals received two intramuscular doses on days 0 and 3. Immunogenicity of the two booster regimens was assessed by titrating the amount of neutralizing antibody (Nab). We found that the booster doses of vaccine produced remarkable responses in all subjects. Nab titers of > or = 0.5 IU/mL (acceptable antibody level for protection against rabies) were detected in all subjects on day 14, and they were shown to be consistently high 1 year after the booster vaccination. We also found that the Nab titers for group A were significantly higher (two- to eightfold) than those for group B on days 5, 14, 150, and 360 after the initial booster vaccination (P < .05). Our study shows that the four-site intradermal booster regimen with use of one-fifth of the diluent volume of cell-culture rabies vaccine on day 0 is associated with a significantly higher antibody response than is the conventional booster regimen for subsequent postexposure rabies treatment of individuals who have received preexposure rabies vaccination with cell-culture rabies vaccine 1 year previously.     

Simulated post-exposure rabies vaccination with purified chick embryo cell vaccine using a modified Thai Red Cross regimen.

OBJECTIVES: Currently, two intradermal regimens for the administration of cell culture rabies vaccines are approved by the WHO for rabies post-exposure prophylaxis: the two site Thai Red Cross regimen (TRC) and the eight site regimen. For the TRC regimen the volume of vaccine recommended per dose is 0.1 ml of purified Vero cell rabies vaccine (PVRV) and 0.2 ml of purified chick embryo cell vaccine (PCEC). The objective of the present study was to evaluate comparatively the immune response to PCEC and PVRV vaccines administered by the TRC regimen using a uniform dose of 0.1 ml of vaccine. METHODS: Forty-two subjects received TRC regimen (2-2-2-0-1-1) with 0.1 ml of PCEC vaccine and 38 subjects received the same regimen with PVRV. The rabies neutralizing antibody response in these subjects on days 10, 28, 90 and 180 was determined by the standard mouse neutralization test (MNT). RESULTS: There was adequate antibody response with both the vaccines and 100% seroconversion was observed by day 10. Furthermore, the antibody titers obtained with PCEC did not differ significantly from those obtained with PVRV on all days tested (p > 0.05). CONCLUSIONS: It can be concluded from the results that an adequate antibody response can be obtained with PCEC vaccine when administered by the TRC regimen even after reducing the quantity of vaccine from 0.2 ml to 0.1 ml per intradermal dose. The feasibility of using this regimen in true post-exposure cases needs to be further evaluated.     

Post-exposure intradermal antirabies vaccine: a cheaper alternative for developing countries

Intradermal (i.d.) human diploid-cell vaccine (HDCV) has been routinely used for post-exposure treatment of rabies at a rural mission hospital in central Thailand since 1979. Four 0.1 ml doses have been given over a fortnight, reconstituted vaccine being regularly stored for repeated use. No significant side effects have been encountered. Consistent antibody formation has been shown. In patients followed up for one year no case of rabies has been observed. Post-exposure intradermal HDCV is safer and more effective than nervous tissue vaccine and is of moderate cost. It should be more widely employed within the Third World.     

Comparison of an anti-rabies human monoclonal antibody combination with human polyclonal anti-rabies immune globulin

The World Health Organization estimates human mortality from endemic canine rabies to be 55,000 deaths/year. Limited supply hampers the accessibility of appropriate lifesaving treatment, particularly in areas where rabies is endemic. Anti-rabies antibodies are key to protection against lethal rabies. Currently, only human and equine polyclonal anti-rabies immune globulin (HRIG and ERIG) is available. Replacement of HRIG and ERIG with a safer and more widely available product is recommended. We have recently identified a combination of 2 human monoclonal antibodies (MAbs), CR57 and CR4098, that has high potential. We here describe a head-to-head comparison between an CR57/CR4098 MAb cocktail and HRIG. The MAb cocktail neutralized all viruses from a panel of 26 representative street rabies virus isolates. In combination with vaccine, the MAb cocktail protected Syrian hamsters against lethal rabies when administered 24 h after exposure, comparable with the results obtained with HRIG. Furthermore, the MAb cocktail did not interfere with rabies vaccine differently from HRIG. These results demonstrate that the human MAb cocktail of CR57 and CR4098 is a safe and efficacious alternative to RIG in rabies postexposure prophylaxis.     

Diffusion and fate of intramuscularly injected human rabies immune globulin

The importance of rabies immune globulin (RIG) in postexposure rabies treatment is well known and it has been emphasized that the local injection into the animal bite sites is crucial. This preliminary study used a radioisotope tracer that allows following the fate of human rabies immune globulin (HRIG) injected intramuscularly. There was significant retention and local diffusion of the immune globulin at the injection site and significant radiotracer could still be detected at the site 24 h later.     

Rabies vaccine prepared in human cell cultures: progress and perspectives

Rabies vaccine prepared in human diploid cell strains is a replacement for the previously available vaccines that are prepared in animal tissues and are less immunogenic and more reactogenic. The human cel-grown vaccine made in the United States is a split-product vaccine, whereas the vaccines made in Europe are whole-virion vaccines. Both types of vaccine contain concentrated and inactivated "fixed" rabies virus. When used before exposure to rabies virus, the vaccine should be given intramuscularly in three 1-ml doses on days 0, 7, and 21. Immediately after exposure to rabies virus, a person should be given human rabies immune globulin (20 international units/kg). This treatment should be followed by five intramuscular doses of vaccine given on days 0, 3, 7, 14, and 28. For maintenance of long-term immunity in persons continously exposed to the risk of rabies, booster doses of the vaccine should be given at two-year intervals.     

Human rabies in India: epidemiological features, management and current methods of prevention

In most endemic countries stray dogs are the main source of rabies infection in humans. In India 95-97% of rabies patients are infected by dogs. Most pet dogs do not regularly receive booster doses of vaccine. In Thailand, most rabies patients develop the disease within 1 month of exposure. Rabies immunoglobulin is costly and usually not available. So in India nervous tissue vaccine is commonly used--it is inexpensive and freely available despite frequent neurological complications. The cost of immunization by tissue culture vaccines may be reduced by nearly 60% by intradermal vaccination.     

Clinical knowledge and attitudes of Turkish physicians toward rabies caused by animal bites

Rabies is an endemic infectious disease and one of the most important causes of human mortality in both underdeveloped and developing countries. In Turkey, 167,000 individuals are believed to be victims of animal bites annually. In this study, we investigated Turkish physicians' knowledge and clinical awareness of rabies caused by animal bites. This was a cross-sectional, analytical study. We used questionnaires that collected demographic information and assessed the physicians' basic knowledge of rabies as well as the management of animal bites suspected of causing rabies. The questionnaires were completed in person with physicians who work in Istanbul. A total of 890 physicians responded to our cross-sectional questionnaires. The maximum possible scores for basic and clinical rabies- related knowledge was 100 points each. The average score for basic rabies knowledge was 64.5 ± 16, while the average score for clinical rabies knowledge was 62.8 ± 12. However, 68% of the physicians in the study were not aware of the proper method for cleaning wounds as a first-line treatment in postexposure prophylaxis. In addition, 38.4% of the physicians in the study did not understand the administration of vaccines together with immunoglobulin as part of postexposure prophylaxis. We also found that 79% of the physicians did not know the correct doses of vaccines, while 37.6% did not know the correct sites and routes of vaccine administration. Finally, 30% of the physicians were not aware of the correct vaccine schedules in postexposure prophylaxis. Our data indicate that Turkish physicians' basic and clinical knowledge of rabies was insufficient. Rabies prophylaxis educational programs should be designed to educate physicians on the guidelines provided by the World Health Organization and the Advisory Committee on Immunization Practices for the treatment of rabies caused by animal bites.     

Antibody responses to human diploid cell vaccine for rabies with and without human rabies immune globulin

One hundred one volunteers with no exposure to rabies were given human diploid cell vaccine (HDCV) for rabies with or without 20 international units of human rabies immune globulin (HRIG)/kg of body weight to evaluate schedules for therapy with HDCV and HRIG after exposure. All of the volunteers who received three or more doses of HDCV alone or four or more doses of HDCV with HRIG developed high titers of neutralizing antibodies by day 35, which persisted for at least 60 days. By day 7, of the 61 volunteers given HRIG and HDCV, 53% had neutralizing antibodies by a mouse neutralization test and 67% had neutralizing antibodies by a rapid fluorescent focus inhibition test. Similar antibody levels were found in volunteers given HRIG alone, a finding which suggests that low or undetectable early titers after administration of HDCV and HRIG were due to inadequate HRIG dosage rather than any interaction between the passive antibody (HRIG) and the vaccine antigen. These results suggest that trials with 30 or 40 international units of HRIG/kg in combination with HDCV are warranted.     

Preventing rabies with the Verorab vaccine: 1985-2005 Twenty years of clinical experience

Purified rabies vaccine cultured on Vero cells (Verorab, sanofi pasteur) is WHO-approved for pre- and post-exposure prophylaxis by intradermal and intramuscular routes. During 20 years of use, over 40 million doses of Verorab have been administered in more than 100 countries. No serious adverse event due to Verorab has been reported in clinical trials involving 3937 persons, and Verorab is better tolerated than human diploid cell vaccine (HDCV). Pre-exposure prophylaxis is confirmed immunogenic in 1437 subjects by all routes, with prompt responses following boosting; Verorab boosts effectively subjects pre-immunized with HDCV. Unlike HDCV, Verorab is not associated with post-boosting serum sickness. In the absence of data in immunodeficient/HIV-positive individuals, pre-exposure immunization is urged as early as possible. Essen, Zagreb, Thai Red Cross Intradermal (TRC-ID) and other post-exposure intramuscular and intradermal regimens are documented. Two thousand one hundred and eighty-three subjects received post-exposure prophylaxis, including 874 high risk, severe or confirmed rabid attacks. Co-administration of rabies immune globulin (RIG) does not affect neutralizing antibody levels when Essen or TRC-ID regimens are employed; levels are lower with the Zagreb regimen. Verorab has been administered safely and effectively post-exposure to 251 pregnant women, without any increase in congenital malformations or spontaneous abortions. From a pediatric perspective, safety and efficacy have been demonstrated in 759 children (0-15 years). Intradermal post-exposure Verorab is an effective and inexpensive option for developing countries. Inadvertent subcutaneous administration does not reduce immunogenicity. WHO already strongly recommends the replacement of nerve tissue vaccines with modern vaccines. Extensive clinical experience supports the use of Verorab for intramuscular and intradermal pre- and post-exposure prophylaxis, including in special situations.     

A study on the seroconversion in dogs vaccinated with cell culture rabies vaccine

Seroconversion studies were conducted in dogs vaccinated with rabies vaccine, of different age group, sex and breed, with a single and booster doses of cell culture Rabies vaccine. The results of the present study revealed that (i) Maternal antibodies were detected in 40% to 80% of 60 selected pet dogs. However 20% to 60% of the pet dogs did not have protective levels of antibody (<0.5IU). (ii) A single dose of vaccine resulted in appreciable levels of protective antibody in 100% of pet dogs both in seronegetive and in dogs with low levels of antibody. (iii) When a booster dose was administered at twelve months period, considerable levels of antibody persisted upto twenty-four months. It can be concluded from the present study that a single dose of potent tissue culture vaccine resulted protective levels of antibody in the seronegetive dogs (<0.5IU). In an Rabies endemic country like INDIA, annual booster dose of vaccine would enhance the immune response and help in the persistence of protective levels of antibody in the immunized dogs.     

Emerging aspects of rabies infection: with a special emphasis on children

PURPOSE OF REVIEW: Increased awareness of the long-neglected rabies virus could promote the highly effective methods of preventing human deaths. Rabies and rabies-related lyssaviruses have recently been appearing in unexpected places, sometimes with dire consequences. Although rabies of canine origin remains 100% fatal in human beings, should the surprising recovery of a single unvaccinated child influence treatment now? RECENT FINDINGS: Evidence of rabies-related lyssavirus infection of bats is increasing across continents and with new virus types. Human rabies has been misdiagnosed as cerebral malaria, or even drug abuse. Organ transplant recipients have been infected. The first unvaccinated patient, a teenager, bitten by a bat, recovered from rabies encephalitis, but why might this be? Highly effective control and prevention of infection is possible. Preexposure prophylaxis for schoolchildren could now become routine. Improved economical intradermal postexposure vaccine regimens could increase the availability of affordable treatment in developing countries. Controlling dog rabies could prevent 95% of human deaths, but education and resources are lacking. SUMMARY: The risks and problems of rabies and other lyssaviruses vary greatly across the world. Knowledge of epidemiology and prevention could save the lives of victims of animal bites and promote efforts to control and even eliminate dog rabies.     

Retrospective: animal attacks and rabies exposures in Thai children

Over 50% of animal bites and potential rabies exposures in Thailand are in children and they also have the more severe injuries due to inexperience, smaller size and less ability to fend off attacks. Potential rabies exposures and animal bites are common in Thailand. Majority of these are in children where the extent of the injuries is also much more severe. The bitten areas correlate to the age of the children and level of the bitten animal head. These are areas noted for a higher risk of infection with rabies virus and shorter incubation periods. The vast majority of bites are due to dogs (86%) of which 74.6% are stray or community-owned animals. The prevalence of dog bites shows no seasonal variation in adults but there are two peaks during school vacation period for children. Extensive educational efforts directed at the Thai public are responsible for the rapid presentation of victims for post-exposure treatment. The dramatic reduction of human rabies deaths in Thailand during the last decades was achieved largely by the provision of expensive WHO standard post-exposure treatment, utilizing modern tissue culture vaccines and immunoglobulins. Canine and feline rabies is nevertheless still endemic and not likely to be controlled or eliminated till sustainable humane methods of dog population control and comprehensive countrywide canine rabies vaccination become possible through government policy.     

Effectiveness of immune globulins in preventing infectious hepatitis and hepatitis A: a systematic review

OBJECTIVE: To assess the effectiveness and safety of immune globulins in preventing infectious hepatitis and hepatitis A. STUDY DESIGN: Systematic review with meta-analysis. DATA SOURCES: We searched the Cochrane Library, MEDLINE, EMBASE, Biological Abstracts and Science Citation Index to December 2002. Vaccine manufacturers were contacted for additional data. REVIEW METHODS: We included randomised controlled trials comparing effectiveness of hepatitis A immune globulins with no intervention or placebo, and carried out a meta-analysis. RESULTS: We included six studies (two in Russian). Tested immune globulins show higher effectiveness than placebo or do-nothing against infectious hepatitis both in primary prevention and in prevention after exposure (effectiveness 83%; RR: 0.17; 95% CI: 0.15-0.19; and effectiveness 69%; RR: 0.31; 95% CI: 0.20-0.47, respectively). We found considerable heterogeneity among studies, possibly due to different methodology, background rates of disease and immune globulins dosage and concentrations. No safety data were reported in the studies. CONCLUSIONS: Immune globulins are efficacious in preventing infectious hepatitis and hepatitis A, but included studies do not report data about their safety. Average length of passive protection was three months. Given the notable heterogeneity of performance of immune globulins, short protection conferred and absence of trial safety data, the only indications for the use of immune globulins may be in situations in which inadequate supplies of vaccine are available or when the eight-day window of opportunity for vaccine use is past.