Human Rabies Immunoglobulin Research Articles

Rabies exposures in thai children.

To determine the epidemiology of potential rabies exposures in Thai children. The study was carried out at the Queen Saovabha Memorial Institute of the Thai Red Cross Society during I calendar year. All charts of victims aged 0 to 14 years with possible rabies exposures were retrospectively reviewed. Subjects were 2622 children, with a male to female ratio of 1.6:1 and a mean age of 6.7 years (range, 2 months to 14 years). Most exposures (86.3%) were related to dogs. The most common site of exposure was the lower extremity. The majority of exposures occurred in or around the home and as the consequence of unprovoked attacks rather than provoked attacks. Antirabies vaccines were given in all cases: 68.4% using the Thai Red Cross intradermal route, and 31.6% using the intramuscular route. Rabies immunoglobulin (RIG) was prescribed in 57.5% of children; 35.2% received human RIG (HRIG), and 22.3% received purified equine RIG (ERIG). This study confirms that rabies exposures, especially in children, are an important public health problem in Thailand. The reduced-dose, multiple-site intradermal rabies vaccine method and ERIG in place of HRIG reduce the cost of treatment.

Immunogenicity, safety and lot consistency in adults of a chromatographically purified Vero-cell rabies vaccine: a randomized, double-blind trial with human diploid cell rabies vaccine

The immunogenicity and safety of a chromatographically purified rabies vaccine (CPRV) was evaluated using US veterinary medical students. In the first study, 242 healthy adults were enrolled in a randomized, modified double-blind, multicenter trial and received five doses of either CPRV or human diploid cell vaccine (HDCV) by intramuscular injection on days 0, 3, 7, 14, and 28 concurrently with human rabies immunoglobulin in a simulated post-exposure prophylaxis regimen. Post-immunization titers in the CPRV and HDCV groups reached 0.5 IU/ml (the WHO-recommended minimally acceptable titer) or greater in all subjects in both vaccine groups by day 14 and remained above that level through day 90. In the second study, 438 healthy adults were enrolled in a randomized, double-blind, multicenter trial and assigned to receive five doses from one of three lots of CPRV by intramuscular injection on days 0, 3, 7, 14, and 28 in a simulated post-exposure prophylaxis regimen to evaluate lot consistency. Post-immunization titers rapidly increased to over 0.5 IU/ml by day 14 for all subjects and remained above that level through day 42 when the study was terminated. The three lots were considered equivalent. The percentage of subjects with at least one local reaction during the five-dose regimen was slightly lower in the CPRV group than in the HDCV group ( P=0.06). The most frequently reported local reaction for all doses of vaccine was pain at the injection site. Headache, myalgia, and malaise were the most frequently reported systemic events. The percentage of subjects with at least one systemic event was significantly lower for CPRV ( P=0.0084). No vaccine-related serious adverse reaction was reported in these studies. The results of these studies indicate that CPRV administered intramuscularly to healthy adults is immunogenic and is associated with fewer local and systemic reactions than HDCV.

Experimental utility of rabies virus-neutralizing human monoclonal antibodies in post-exposure prophylaxis

Rabies immune globulin (RIG) is essential for post-exposure prophylaxis but is expensive and not widely available. Rabies virus-neutralizing human monoclonal antibodies (Mabs) were evaluated in vitro and in a Syrian hamster model as a potential future alternative. Seven Mabs neutralized representative rabies virus variants. However, a European bat lyssavirus was not neutralized by either Mabs or RIG. Moreover, Duvenhage virus was neutralized by RIG, but not by Mabs, and Lagos bat and Mokola viruses were neutralized by one Mab but not by RIG. In hamsters, one Mab resulted in protection that was comparable to human RIG. These results suggest that Mabs may provide a promising alternative to RIG.

Exposure of hooded capuchin monkeys (Cebus apella cay) to a rabid bat at a zoological park.

On 27 May 1999, a big brown bat (Eptesicus fuscus) was discovered on an island exhibit at the Denver Zoo that contained a troop of 15 hooded capuchin monkeys (Cebus apella cay). The monkeys were attacking the bat when it was discovered. The bat was collected and humanely euthanatized without direct handling and submitted to the Colorado Department of Public Health and Environment Virology Laboratory for rabies evaluation. The monkeys had not been vaccinated against rabies virus. The next day, the laboratory confirmed that the bat was positive for rabies. The recommendations from the Colorado Department of Public Health and Environment and the Centers for Disease Control and Prevention were to euthanatize the monkeys or quarantine them and comply with the human nonvaccinated postexposure protocol. A 1-ml dose of a killed rabies vaccine was administered i.m. in the hip on each of days 2, 7, 12, 19, and 33 postexposure, and a single dose of human rabies immune globulin was administered i.m. 5 days postexposure. Blood was collected under anesthesia in order to evaluate the immune response after rabies vaccination from six monkeys 5 days postexposure, six monkeys 19 days postexposure (five of the six monkeys were the same monkeys bled 5 days postexposure), 15 monkeys 67 days postexposure, and 13 monkeys approximately 1 yr postexposure. All of the monkeys developed and maintained levels of rabies virus neutralizing antibody above 0.05 IU/ml by 67 days postexposure. Although a serologic titer of 0.05 IU/ml indicates an adequate human response after rabies vaccination, no similar information is available for nonhuman primates. To date, none of the monkeys has succumbed to rabies.

Proposal of abolition of the skin sensitivity test before equine rabies immune globulin application.

An epizootic outbreak of rabies occurred in 1995 in Ribeirão Preto, SP, with 58 cases of animal rabies (54 dogs, 3 cats and 1 bat) confirmed by the Pasteur Institute of São Paulo, and one human death. The need to provide care to a large number of people for the application of equine rabies immune globulin (ERIG) prevented the execution of the skin sensitivity test (SST) and often also the execution of desensitization, procedures routinely used up to that time at the Emergency Unit of the University Hospital of the Faculty of Medicine of Ribeirão Preto, University of São Paulo (EU-UHFMRP-USP), a reference hospital for the application of heterologous sera. In view of our positive experience of several years with the abolition of SST and of the use of premedication before the application of antivenom sera, we used a similar schedule for ERIG application. Of the 1489 victims of animal bites, 1054 (71%) received ERIG; no patient was submitted to SST and all received intravenously anti-histamines (anti-H1 + anti-H2) and corticosteroids before the procedure. The patients were kept under observation for 60 to 180 minutes and no adverse reaction was observed. On the basis of these results, since December 1995 ERIG application has been decentralized in Ribeirão Preto and has become the responsibility of the Emergency Unit of the University Hospital and the Central Basic Health Unit, where the same routine is used. Since then, 4216 patients have received ERIG (1818 at the Basic Health Unit and 2398 at the EU-UHFMRP), with no problems. The ideal would be the routine use of human rabies immune globulin (HRIG) in public health programs, but this is problematic, because of their high cost. However, while this does not occur, the use of SST is no longer justified at the time of application of ERIG, in view of the clinical evidence of low predictive value and low sensitivity of SST involving the application of heterologous sera. It is very important to point out that a negative SST result may lead the health team to a feeling of false safety that no adverse reaction will occur, but this is not true for the anaphylactoid reactions. The decision to use premedication, which is based on knowledge about anaphylaxis and on the pharmacology of the medication used, is left to the judgment of health professionals, who should always be prepared for eventual untoward events.

Rabies in Oman: Failed postexposure vaccination in a lactating woman bitten by a fox

Rabies was first detected in the Sultanate of Oman in 1990, when a child from Buraimi, northern Oman, on the border with the United Arab Emirates (U.A.E), died after being bitten by a fox.’ Subsequently, animal-bite surveillance revealed evidence of a country-wide epizootic of rabies in the common fox (Vulpes vulpes), which spread from the border of the U.A.E. to involve the whole of Oman, excepting Musandem Province in the northeast2s3 Shortly after the first case, postexposure prophylactic immunization for rabies (passive immunization with human rabies immune globulin [HRIG] and active immunization with human diploid cell vaccine [HDCV]), was made available in all Omani hospitals. Nevertheless, despite adequate postexposure prophylaxis, two more cases of rabies occurred in 1991 and 1992, following bites by a wolf and a fox, respectively.* This report presents another case of rabies that developed despite postexposure immunization in a lactating woman who was bitten by a fox. On April 20,1997, while sleeping in the desert, a 17year-old Bedouin woman was bitten on the upper lip by a fox. Her husband immediately drove her to the district hospital, where two deep lacerations on her upper lip were cleaned and dressed, but not stitched. Two 1-mL doses of inactivated Merieux rabies HDCV were administered by intramuscular injection into each deltoid, according to the Ministry of Health protocol. Antitetanus toxoid was given. At the time, HRIG was unavailable in the hospital, but the woman was ordered to go immediately to the regional hospital, a distance of several hours’ drive on a surfaced road, where HRIG was available. Unfortunately, she delayed attending the regional hospital until April 22, when, according to official guidelines for patients presenting more than 48 hours after injury,

Rabies.

Rabies is an important disease in wildlife in the United States and Canada, and dog rabies is still a major public health problem in many developing countries of the world. Rabies virus is transmitted in saliva by animal bites. Bats transmitted most recent cases of human rabies in the United States, often without known exposures. There have been recent developments in our understanding of rabies pathogenesis. Characteristic clinical features should raise the possibility of a diagnosis of rabies and initiation of appropriate diagnostic tests. Therapy of human rabies has been futile except in four patients who were immunized with rabies vaccine prior to the onset of their disease. Rabies can be prevented after an exposure in unimmunized patients with local wound cleansing and administration of rabies vaccine and human rabies immune globulin.

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.

Human rabies is fatal except in the small number of patients who received rabies immunization before the onset of clinical rabies. Therapy has been futile in all other cases once rabies has developed. Rabies is always preventable after an exposure if current recommendations are followed. After a potential rabies exposure, details about the contact, the animal, and the local epidemiologic situation are important in making a decision whether to initiate postexposure prophylaxis (PEP). Rabies PEP includes thorough local wound cleansing and both active and passive immunization. Five doses of rabies vaccine should be administered intramuscularly in the deltoid muscle on days 0, 3, 7, 14, and 28 in individuals previously unimmunized against rabies virus. Human rabies immune globulin (20 IU/kg) should be given on day 0 with administration into and around the wounds; the remaining volume is given intramuscularly at a site distant from the vaccine site. Certain individuals at high risk for rabies exposure are candidates for preexposure prophylaxis with three doses of rabies vaccine. Booster doses should be given as required.

The development of monoclonal human rabies virus-neutralizing antibodies as a substitute for pooled human immune globulin in the prophylactic treatment of rabies virus exposure

To provide a more defined and safer replacement for the human rabies immune globulin (HRIG) from pooled serum which is currently used for treatment of exposure to rabies virus we have developed a series of human rabies virus-specific monoclonal antibodies. Mouse–human heterohybrid myeloma cells producing rabies virus-specific human monoclonal antibodies were prepared using B cells obtained from volunteers recently-immunized with a commercial rabies virus vaccine (HDCV). Cell lines producing antibody which neutralized the Evelyn–Rokitnicki–Abelseth (ERA) rabies virus strain in vitro were cloned and the resulting monoclonal antibodies characterized for isotype, specificity against a variety of rabies virus isolates, and neutralization capacity. The ability of the monoclonal antibodies to neutralize a variety of rabies virus strains in vitro correlated with their binding specificity for these viruses in an enzyme-linked immunoadsorbant assay (ELISA). A number of these antibodies have proven suitable for the formulation of a prophylactic human monoclonal antibody-based reagent which would provide significant advantages to the HRIG in having defined, reproducible specificity, lessened possibility of contamination with viral pathogens, and consistent availability.

Decision-based evaluation of recommendations for preexposure rabies vaccination.

Preexposure rabies vaccination is recommended for individuals who are more likely to be exposed to rabies virus than the general public. 1 This vaccination series consists of 3 doses of vaccine administered IM or intradermally (ID), which permits postexposure vaccination to consist of 3 doses of vaccine rather than 5 and eliminates the need for postexposure administration of human rabies immune globulin. Preexposure vaccination may provide protection for persons with unrecognized exposures and those encountering a delay in receiving postexposure vaccination. 1

Veterinary surgeon's guide to Australian bat lyssavirus.

Veterinary surgeons in Australia must be aware of the emerging viral diseases and their potential effects on public health generally and, more specifically, on the veterinary profession. Australian bat lyssavirus was identified in 1996 and causes rabies-like disease in bats and humans. Two humans from Queensland have died of Australian bat lyssavirus encephalitis. Surveillance has shown that all Australian bats must be considered carriers of this new virus, therefore protective apparel should be used when handling bats. The pre-exposure regimen of inactivated rabies vaccine (Pasteur Mérieux) provides protection against infection. As part of the preventive regimen, at risk groups, such as veterinary surgeons, should seriously consider pre-exposure rabies vaccination. The post-exposure protocol involves administration of human rabies immunoglobulins and five intramuscular injections of the inactivated rabies vaccine.

Practical aspects of human rabies prevention

OBJECTIVE: To analyze the rabies situation in Brazil, and to study the indication and the most adequate postexposure therapy for human rabies prophylaxis according to the following factors: kind of accident; animal that causes the accident; rabies situation in the geographic area; possibility of observation or laboratorial analyses of the animal; availability of immunobiologics METHODS: Bibliographic review of the last years and analyses of the main technical official reports in the world, including those from the World Health Organization, from Brazil Health Ministry, the State Department of Health of São Paulo, and so on. CONCLUSIONS: The number of cases of human rabies in Brazil has been decreasing since the eighties; however the number of post exposure therapy is very high due to the inadequate program of rabies control in animals, mainly dogs and cats. The most common vaccine used is the Fuenzalida-Palácios. More modern and safe vaccines are only available in private clinics. In public health centers, it is available exclusively for special patients like the immunodeficient ones or those who present adverse reaction to the Fuenzalida- Palácios. The other drug used in preventive therapy is the equine rabies immunoglobulin which is presently a safe product. The option to this drug is the human rabies immunoglobulin - very expensive and not easily available. This drug is not indicated in Brazilian public health centers, unless there is risk of anaphylaxis for the patient with the use of the equine immunoglobulin

A study of human rabies immune globulin manufactured by the Thai Red Cross

This is a prospective post marketing study of 4496 patients presenting with severe animal bites in a canine rabies endemic region. They received human rabies immune globulin manufactured from volunteer blood donors at the National Blood Center of the Thai Red Cross Society at Bangkok. All patients also received a full course of tissue culture rabies vaccine. Only three subjects reported an adverse reaction (redness and itching at the immune globulin injection sites). None of the patients died during the subsequent 18 month follow up period.

Safety and efficacy of purified vero cell rabies vaccine given intramuscularly and intradermally. (Results of a prospective randomized trial)

Objectives: to determine adverse reactions as a result of pre- and post-exposure rabies vaccination, using the conventional intramuscular, and reduced dose intradermal regimens and purified Vero cell rabies vaccine. Design: a prospective and randomized study of patients exposed to rabies and of subjects in need of pre-exposure rabies vaccination. Setting: a metropolitan rabies control center in a canine rabies endemic country. Patients: 1198 subjects were recruited between May, 1994 and March, 1996. They were divided into four groups. Patients with suspected or proven rabies exposures were given the vaccine intramuscularly using the conventional regimen, or intradermally using the World Health Organization approved Thai Red Cross schedule. Human or equine rabies immune globulin was administered where indicated. Pre-exposure and post-exposure vaccine recipients were divided randomly into two groups each and given the vaccine either by the intramuscular or intradermal schedules. Measurements: all local and systemic adverse reactions were recorded and statistically analyzed. Results: pruritus at injection sites was the only significant local reaction. It was more common in the intradermal groups. Low-grade fever, the only significant adverse systemic event, was more common in the intramuscular groups and was noted in 8% of all subjects. Eighty-four patients bitten by proven rabid animals were found to be alive and well 3 years later. Forty-four of these had received the intramuscular and 40 the intradermal postexposure regimens with human or equine immune globulin injected into wounds on the first day of treatment. Conclusions: Purified Vero cell rabies vaccine is safe, carries a very low adverse reaction rate and is effective in preventing rabies in severely exposed subjects when used with human or equine rabies immune globulin.

RABIES POSTEXPOSURE PROPHYLAXIS

Using data from medical records, we evaluated the epidemiology and appropriateness of rabies postexposure prophylaxis in Massachusetts. The study sample consisted of 1151 patients seen between 1990 and 1995 in the Boston area with diagnoses or events of rabies preventive treatment, rabies vaccine administration and/or animal bite. Dogs and cats accounted 93% of exposure in patients who received prophylaxis. Forty-six percent of individual exposed to these animals started prophylaxis the same day the exposure occurred. In the case of 32% of patients who completed treatment the animal was documented as being available for quarantine and/or testing. Human rabies immunoglobulin eas not given to 18% of rabies vaccine recipients, despite a lack of history of rabies immunization. The study reveals that a large amount of rabies postexposure prophylaxis is administered to persons whose risk of exposure to the virus is very low or nonexistent. Much prophylaxis is administered when dog or cat quarantine or testing can be used to rule out rabies. Knowledge of the epidemiology of rabies in the area is frequently not applied when rabies postexposure prophylaxis is prescribed. Adherence to official recommendation for prophylaxis is often deficient and failure to follow full prophylaxis protocol consistently is inappropriate and potentially dangerous. In a small but significant proportion of individuals receiving rabies postexposure prophylaxis nonadherence to official recommendations occurs.

Evaluation of the Safety and Immunogenicity of a New, Heat-treated Human Rabies Immune Globulin Using a Sham, Post-exposure Prophylaxis of Rabies

A double-blind, controlled, randomized trial was conducted to evaluate the safety and immunogenicity of a new human rabies immune globulin (HTRIG). This product, manufactured by Pasteur Mérieux Connaught, PMC, has undergone a heat-treatment step (10 h at 60°C) and removal of mercurothiolate. The corresponding unheated product available from the same manufacturer (human rabies immune globulin, HRIG, IMOGAM RABIES®) was used for comparison.These two rabies immune globulins (RIGs) were administered either alone or in association with the human diploid cell rabies vaccine (HDCV, IMOVAX®RABIES, PMC) according to a standard, post-exposure rabies prophylaxis schedule. Sixty-four healthy adults were randomly assigned to four groups of 16 to receive either HRIG/placebo, HTRIG/placebo, HRIG/HDCV or HTRIG/HDCV. RIG was administered at the recommended dose of 20 IU/kg by three intramuscular (i.m.) injections in the gluteus. HDCV or placebo was given on day (D) 0, D3, D7, D14, and D28 into the detoid by the intramuscular (i.m.) route. Any local reaction from D0 to D3 at the immune globulin injection site, and any systemic reaction from D0 to D42, were monitored by subject diaries. Rabies-neutralizing serum antibody levels were assessed by the rapid fluorescent focus inhibition test (RFFIT) before treatment and on D3, D7, D14, D28, D35, and D42. No serious adverse reactions and, in particular, no allergic-type reactions were reported. The safety profiles of HTRIG and HRIG were similar, except that complaints of pain, or tenderness at the injection site were half as common in the HTRIG group. Most of the local reactions were mild or moderate.After the administration of HTRIG/placebo or HRIG/placebo, 60°C of subjects had detectable rabies antibodies levels, but by D42 all titres were below the seroprotective level (i.e. below 0.5 IU/ml). In the groups HTRIG/HDCV and HRIG/HDCV, the antibody titres rose markedly from D7, and reached a maximum value of 19 IU/ml (95% CI, 11 to 38 IU/ml) and 31 IU/ml (95% CI, 20 to 48 IU/ml), respectively, on day 14. All subjects who received RIG and vaccine maintained a protective antibody level from D14 to D42. No significant difference in immunogenicity results between these two groups (HTRIG/HDCV and HRIG/HDCV) was observed, and no interference of immune globulin with vaccine was reported.The safety and immunogenicity profiles of PMC HTRIG appear comparable with the current reference product. The heat-treatment step will enhance the safety by further reducing the probability of virus transmission through immune globulin treatment. The low levels of rabies antibodies obtained by intramuscular administration of either PMC HTRIG or of PMC HRIG support the recommendations that call for local infiltration of wounds with RIG.

An immunogenicity and efficacy study of purified chick embryo cell culture rabies vaccine manufactured in Japan

Purified chick embryo cell rabies vaccine manufactured by the Chemo-Sero-Therapeutic Institute(Kaketsuken) at Kumamoto, Japan (Kaketsuken) was submitted to an immunogenicity and efficacy study. 52 severely rabies exposed patients were treated with the conventional five doses intramuscular WHO approved (‘Essen’) postexposure schedule. This included the administration of 40 IU kg −1 of equine rabies immune globulin on Day 0. A control group of equally severely exposed subjects were treated with human diploid cell rabies vaccine manufactured by the Swiss Serum and Vaccine Institute as well as human rabies immune globulin. There were no deaths in either group in the more than 2 years follow-up period. Subjects treated with the chick embryo vaccine showed greater suppression of the neutralizing antibody response by the equine rabies immune globulin than those given the human diploid cell vaccine and human rabies immune globulin. A group of 20 less severely rabies exposed patients who received only the chick embryo vaccine without immune globulin all had antibody titers greater than the WHO minimal acceptable level on Day 14, 30, 90 and 180. Fourteen subjects among the severely exposed vaccine and immune globulin study group were given vaccine boosters on Day 180 because of low antibody titers. It is concluded that chick embryo rabies vaccine manufactured by Kaketsuken is an immunogenic and effective rabies vaccine, but that the potency of future batches must be increased to provide a greater safety margin.

Rabies

Rabies

Persistence of humoral immunity to rabies 1100 days after immunization and effect of a single booster dose of rabies vaccine

Forty-four vaccinees immunized with rabies vaccine and human rabies immunoglobulin according to the abbreviated intramuscular regimen (the 2-1-1 schedule) were followed-up after 1100 days and had their blood samples taken. The persistence of rabies neutralizing antibody was proven in the sera of all vaccinees, 56% of whom demonstrated titres ⩾0.5 IU ml −1. At the same day the vaccinees were given a single booster dose of vaccine whose effect was measured 2 weeks later. With the RFFI test on day 1114, sera revealed an extraordinarily high booster response in all 44 vaccinees. The study proved the anamnestic response after a full course of rabies vaccination to be a very stable one, and the capability of a single booster dose of vaccine to evoke high-titred rabies antibody response. Of the four vaccines used in the study, under comparable conditions, HDCV proved superior to PCECV, PDEV and PVRV on all 3 days of serology—35, 1100 and 1114, though this difference was statistically attested only on days 35 and 1114.