WHO recommended pre-exposure prophylaxis for rabies using Japanese rabies vaccine

After severe exposure to suspected rabid animal, WHO recommends a complete vaccine series using a potent effective vaccine that meets WHO criteria, and administration of rabies immunoglobulin (RIG). RIG is not available globally, and is not marketed in Japan. If pre-exposure prophylaxis for rabies is given, RIG is unnecessary even after severe exposure. It is thus important to give pre-exposure prophylaxis for rabies to people who plan to go to rabies-endemic areas. In Japan, pre-exposure prophylaxis for rabies consists of 3 doses of cell-culture rabies vaccine. The first two doses are given 4 weeks apart, and the third dose is given 6-12 months after the first dose, all of which are injected subcutaneously (standard regimen). People who plan to travel abroad to rabies-endemic areas may know of their destinations only 1 or 2 months in advance at best. Therefore, it is virtually impossible to complete the 3 dose regimen for rabies in Japan. Pre-exposure prophylaxis recommended by WHO consists of 3 doses given intramuscularly on days 0, 7, and 28, making it possible to complete pre-exposure prophylaxis in one month. This WHO recommended pre-exposure prophylaxis using Japanese cell-cultured rabies vaccine (PCEC-K) has not been studied, so we elected to fill the gap using PCEC-K, administered based on the WHO recommendation and examined its efficacy and safety. Subjects were 26 healthy volunteers with no previous rabies vaccination giving oral and written consent. Vaccine was administered on days 0, 7, and 28, and rabies antibody levels were tested on days 7, 28, and 42. On day 7, every antibody level was negative. On day 28, antibody levels were between 0.7-3.5 EU/ mL, with the exception of 3 cases still negative. On day 42, all cases, including the 3 negative cases, exceeded 1.6 EU/mL, providing sufficient protection against rabies. This result was not inferior compared to the standard regimen. Local adverse effects such as erythema and pain were noted, but none were serious. In conclusion, WHO recommended pre-exposure prophylaxis for rabies using PCEC-K is considered effective and safe.     

Knowledge and practices about rabies among travel medicine consultants in Greece

The number of travellers returning with animal bites from rabies enzootic areas has increased in Greece. The aim of this study was to assess the knowledge of travel-associated risk and preventive measures for rabies. A questionnaire was sent to Travel Medicine consultants in all prefectures. Of 100 Travel Medicine consultants, advice about rabies was given to long-term travellers, business travellers, travellers to rural areas, and travellers engaged in animal activities in rabies enzootic countries by 44%, 22%, 58%, and 75% of them respectively. Avoidance of animals, post-exposure medical assistance, return back to their country, and special caution about children was recommended by 89%, 95%, 8%, and 65% of them, respectively. Rabies pre-exposure vaccination was recommended for travellers to rural areas, long-term travellers, and travellers engaged in animal activities by 61%, 35%, and 81% of them, respectively. Regarding post-exposure vaccination, 78% and 37% answered correctly with regards to travellers with no pre-exposure prophylaxis and travellers with pre-exposure prophylaxis, respectively. Counselling about rabies and management of risk exposure needs to be improved. Our findings indicate the need to promote continuous training in Travel Medicine in Greece and provide practical information about rabies prophylaxis.     

Fatal case of human rabies infection: A case report

Rationale: Rabies, as an acute viral disease of the mammal's central nervous system(CNS), with a high mortality rate, is transmitted to humans through the bite of a rabid animals, especially canine and feline. Patient concerns: An Afghan man, aged 50 years was bitten by a fox in a farm around the Qom-Tehran road, Central Iran in 2018. The patient visited the doctor after the bite, however the period between incidence and hospital visit was not established and no indication was given whether the bite site injury was thoroughly washed. The patient was neither referred to the health center for vaccination(post-exposure prophylaxis) nor an effective therapeutic measures was applied. Forty-five days post-exposure, the patient presented with symptoms such as headache, fever, tingling and burning sensation and was referred to the Centers for Disease Control and Prevention(CDC) unit of Qom Provincial Health Center. Diagnosis: Rabies infection. Interventions: Forty-five days after the animal bite, in CDC of Qom Health Center, he received rabies post-exposure prophylaxis treatment and was referred to an infectious diseases physician. Based on the history of animal bites, the patient was classified as probable case of rabies. The clinical symptoms of rabies appeared in patient after hospitalization. Outcomes: Ultimately the patient died in hospital 4 days after hospitalization(50 days after the occurrence of animal bite). After referring the patient to the CDC, the patient's saliva(0.5-1 mL) was sampled three times every 3-6 hours and tested by PCR. Human rabies was confirmed by Department of Virology in the Pasteur Institute of Iran. Lessons: Physicians and clinicians have responsibilities to be critical in observations and take prompt actions in case of animal bites, as rabies usually develops within 7 to 14 days, and delayed intervention after the onset of symptoms, vaccine and serum injections cannot lead to the survival of the patient.     

Antemortem diagnosis of human rabies in a veterinarian infected when handling a herbivore in Minas Gerais, Brazil

The Ministry of Health's National Human Rabies Control Program advocates pre-exposure prophylaxis (PEP) for professionals involved with animals that are at risk of contracting rabies. We report an antemortem and postmortem diagnosis of rabies in a veterinarian who became infected when handling herbivores with rabies. The antemortem diagnosis was carried out with a saliva sample and a biopsy of hair follicles using molecular biology techniques, while the postmortem diagnosis used a brain sample and conventional techniques. The veterinarian had collected samples to diagnose rabies in suspect herbivores (bovines and caprines) that were subsequently confirmed to be positive in laboratory tests. After onset of classic rabies symptoms, saliva and hair follicles were collected and used for antemortem diagnostic tests and found to be positive by RT-PCR. Genetic sequencing showed that the infection was caused by variant 3 (Desmodus rotundus), a finding confirmed by tests on the brain sample. It is essential that professionals who are at risk of infection by the rabies virus undergo pre-exposure prophylaxis. This study also confirms that molecular biology techniques were used successfully for antemortem diagnosis and therefore not only allow therapeutic methods to be developed, but also enable the source of infection in human rabies cases to be identified accurately and quickly.     

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.     

Assessment of rabies exposure risk among Israeli travelers

BACKGROUND: The decision whether or not to administer rabies pre-exposure prophylaxis (PEP) to travelers visiting endemic areas is a complex one. Paramount for making that decision is knowledge of the risk of animal bites during travel. This study attempts to estimate the risk of bites in travelers, and study the action they took before and after the incident. METHODS: Travelers presenting for pre-travel immunizations during the period of August through December 2004, who planned a travel of >or= 1 month's duration were retrospectively identified, contacted and interviewed by a structured questionnaire. These travelers did not receive specific advice concerning rabies. RESULTS: The study cohort comprised of 815 travelers (median age=25), of who 13 (1.6%) were injured by a potentially rabid animal (mainly, dog=6; monkey=4). The incidence of potential rabies exposure was found to be of 2.66 per 1000 travelers per month. Those injured had significantly longer trips than the non-injured (6.9+/-3.8 vs. 4+/-5.0 months, p=0.037); notably, the injuries occurred after a median of 5 weeks from departure. Although seven travelers noted blood at the site of injury, only four (31%) of the injured sought medical attention following the exposure, and all four received post-exposure prophylaxis. CONCLUSIONS: An injury by potentially rabid animals is not rare among long-term travelers. As the injury may occur early in the itinerary, rabies PEP should be considered for this population. Educational efforts are required in light of the lack of understanding of the dismal consequences of rabies among travelers.     

Current rabies vaccines and prophylaxis schedules: preventing rabies before and after exposure

Travellers are probably the largest group in the general population to receive rabies pre-exposure prophylaxis. The dangerous consequences of the unavailability of rabies immune globulin in many countries could be ameliorated if pre-exposure rabies vaccination were practised more widely, especially in children, living in dog rabies enzootic countries. The WHO has recommended several different regimens for post-exposure prophylaxis, while individual countries decide on protocols for local use. Intramuscular regimens are expensive and waste vaccine. Although failure to receive vaccine is usually the due to the cost, the economical potential of intradermal vaccination has still not been realised 19 years after its introduction. The currently recommended 2-site intradermal post-exposure regimen is not economical for use in rural areas where 80% of Indian rabies deaths occur. Most countries using it demand higher potency vaccine, indicating that they do not have complete confidence in the method. This intradermal regimen has only been used where immunoglobulin is likely to be available for severely bitten patients. Increased intradermal doses are sometimes used for selected patients. Provision of economical rabies prophylaxis can be improved. Decisions to change recommendations should take account of the immunological, financial, practical and logistical aspects of dog bite treatment in remote areas.     

Epidemiological investigations of human rabies in China

Background  

The epidemic of rabies showed a rising trend in China in recent years. To identify the potential factors involved in the emergence, we investigated and analyzed the status and characteristics of human rabies between 1996 and 2008. Moreover, the status of rabies infection and vaccination in dogs, and prophylaxis of humans after rabies exposure were analyzed.     

Epidemiology and prevention of animal bite and human rabies in a rural community-One health experiment

ObjectiveTo estimate the incidence of human rabies and animal bite/exposure; to describe the post exposure prophylaxis received by animal bite/exposure cases; to assess the safety and immunogenicity of rabies vaccine (purified chick embryo cell vaccine) administered as pre-exposure vaccination for school children and risk groups by intradermal route in the rural community and to demonstrate a decrease in the incidence of human rabies and animal bite/exposures through implementation of one health experiment.MethodsThis prospective interventional study was conducted over a period of 2 years (December 2009-November 2011) in a rural area near Bangalore, Karnataka, South India and consisted of six villages (project villages), three villages were identified as study villages with active interventions (Implementation of rabies awareness activities, post exposure prophylaxis, pre-exposure intradermal rabies vaccine) and three villages as control villages without any active interventions.ResultsA majority of the animal bite cases were category III exposures and all of them had received rabies immunoglobulin and anti-rabies vaccine as per WHO recommendation. A majority received 3 to 5 doses of vaccine. Three hundred and sixty eight subjects had received pre-exposure intradermal rabies vaccination thrice on days 0, 7 and 28 d.ConclusionsNo human rabies case was reported during the study period and there was 30% decrease in animal bite/exposure cases in study villages after the one health experiment project was implemented. Pre-exposure vaccination was safe and immunogenic.     

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.     

Anti-rabies antibody titers among subjects who received rabies post-exposure prophylaxis with foreign-made rabies vaccines at the beginning and followed with Japanese rabies vaccine

Recently travelers who were bitten by possibly rabid animals in rabies endemic regions and returned to Japan have increased in number. About half of them received rabies post-exposure prophylaxis (RPEP) with one or more doses of foreign-made rabies vaccines (FRV) in the local medical institutions. FRV, however, are not available in Japan so we have to continue the RPEP with Japanese rabies vaccine (JRV). It has not been demonstrated that an anti-rabies antibody induced with JRV following Vero cell rabies vaccine (PVRV) or chick embryo cell rabies vaccine (PCEC) could be high enough to prevent clinical rabies. We examined anti-rabies antibody (ARA) titers among the subjects visited our vaccine clinic to receive RPEP and obtained results as follows: the ARA titers after a total of 5 doses of PCEC or PVRV and JRV were high enough to prevent clinical rabies as after 5 doses of JRV. However, ARA titers obtained after receiving one dose of PVRV and 2 doses of JRV seemed lower than those produced after one dose of PCEC and 2 doses of JRV or 3 doses of JRV. To accelerate antibody production, consequently, the simultaneous intradermal and subcutaneous injection method of rabies vaccine may be applied to those who were bitten in their hands or head by possibly rabid animals and received only one dose of PVRV in rabies endemic regions.     

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.     

Is there a risk to contacts of patients with rabies?

The number of persons in the United States potentially in contact with rabid humans has increased in recent years because of labor-intensive medical care, longer survival times, and care in two or more hospitals. Many of these persons request rabies prophylaxis, and their physicians prescribe it because of their insecurity, a situation that is expensive and often unnecessary. Records of the Centers for Disease Control and the literature were reviewed to examine the current practice of prophylaxis of contacts and the actual need for it. Rabies virus is present in a variety of human fluids and tissues during the first five weeks of illness, but there are only four well-documented reports of human-to-human transmission--all in corneal transplant recipients. Prophylaxis of contacts of 14 rabid patients was predominantly for saliva exposure to open wounds or mucous membranes and was given most often to medical personnel having the greatest contact with the patient. Although it has never been documented, human-to-human transmission of rabies following saliva exposure remains a theoretical possibility. Virus shedding by rabid patients should be studied thoroughly in the future. Recommendations for managing contacts of rabid patients are presented.     

Evaluation of cases admitted to a center in Istanbul, Turkey in 2003 for rabies vaccination and three rabies cases followed up in the last 15 years

We evaluated the cases of 7,266 individuals who applied to our hospital's Center for Rabies Vaccination between January and December 2003. Among 1,831 female and 5,435 male cases, 37% were given 3 doses of vaccination, 14% were given 5 doses, and in 24% of cases a 2-1-1 vaccination schedule was applied. Antirabies serum of horse origin was given in 179 cases. Regarding the wounds, 83% were superficial and 17% were deep. Most of the cases involved dog bites (74%). Of the dogs involved, 30% were pets (with owners). Only a few (6%) of those pets had been vaccinated. Of the 2 dogs investigated for rabies in Pendik Veterinarian Research Institute, none were found to harbor the disease. In the last 15 years, 3 cases were followed up with a diagnosis of human rabies in our clinic. Domestic animals (without owners, living a somewhat wild life in cities) are still the cause of many rabies cases. As rabies carries a very high fatality risk, public health precautions and education are important as well as post-exposure prophylaxis.     

Risk factors for human exposure to raccoon rabies during an epizootic in Connecticut

The emergence of rabies among terrestrial wildlife poses increasing but poorly defined risks to people. In particular, events leading to human exposure to rabies virus via mammalian reservoirs remain elusive. Thus, we determined those risk factors associated with human exposure to rabies-positive animals during a raccoon rabies epizootic in Connecticut. Existing passive surveillance data on animal rabies tests in Connecticut from 1991 through 1994 were evaluated for demographic, ecological, and behavioral characteristics of human exposure. Of 2,525 rabies-positive terrestrial animals identified, human contact was reported on 556 occasions (22%) and involved at least 939 individuals. The annual incidence of exposure rose from none during 1985-1990 to 66 in 1991 and then averaged 291 during 1992-1994. Exposure was most often indirect in nature, involved a rabies-positive raccoon, was mediated through a domestic animal, and occurred most frequently either near or inside the home. These results suggest that human exposure to rabid animals represents a significant, reemerging public health concern in the United States. Analysis of the epizootiology of rabies infection and of individual exposure risks could reduce inappropriate administration of rabies postexposure prophylaxis, as well as inform other proposed interventions.     

Cryptogenic rabies, bats, and the question of aerosol transmission

Human rabies is rare in the United States; however, an estimated 40,000 patients receive rabies postexposure prophylaxis each year. Misconceptions about the transmission of rabies are plentiful, particularly regarding bats. Most cases of human rabies caused by bat variants have no definitive history of animal bite. Three hypotheses are proposed and reviewed for the transmission of rabies from bats to human beings. They include nonbite transmission (including aerosol transmission), the alternate host hypothesis (an intermediate animal host that acquires rabies from a bat and then transmits rabies to human beings), and minimized or unrecognized bat bites. Nonbite transmission of rabies is very rare, and aerosol transmission has never been well documented in the natural environment. The known pathogenesis of rabies and available data suggest that all or nearly all cases of human rabies attributable to bats were transmitted by bat bites that were minimized or unrecognized by the patients.     

Development of a cocktail of recombinant-expressed human rabies virus-neutralizing monoclonal antibodies for postexposure prophylaxis of rabies

To provide a cost-effective and safe replacement for human rabies immunoglobulin (HRIG), we used DNA recombinant technology to express 3 human rabies virus-neutralizing human monoclonal antibodies (huMAbs) in a rhabdovirus vector (RhV). Infection of either baby hamster kidney cells or CHO cells, with the resulting RhV-huMAb recombinant viruses, yielded high-level production (< or =40 micro g/mL/48 h) of RhV recombinant-expressed huMAbs (rhuMAbs) that differ in both isotype and epitope-recognition specificity. A cocktail of these rhuMAbs neutralizes several fixed and street wild-type rabies viruses (RVs). Mice and hamsters treated only once with this rhuMAb cocktail after infection with a lethal dose of RV were protected. In the mouse models, the postexposure prophylaxis (PEP) efficacy obtained with the rhuMAb cocktail was comparable to that obtained with HRIG, a finding strongly suggesting that rhuMAbs should be given serious consideration for use in future PEP of humans.     

一例暴露因素不明的狂犬病病例的分子流行病学溯源

目的 对一例暴露因素不明的人狂犬病病例进行实验室确诊,通过分子流行病学分析探索其可能的感染来源。方法 通过对存活疑似人狂犬病病例的唾液、脑脊液、血清标本采用直接免疫荧光试验、反转录-聚合酶链式反应和快速荧光灶抑制试验进行实验室确诊;通过时空进化分析探索该病例可能的感染来源。结果 病例唾液标本直接免疫荧光试验结果呈阳性,病例血清标本经快速荧光灶抑制试验检测抗狂犬病病毒中和抗体呈阳性。病例唾液标本经反转录-聚合酶链式反应获得狂犬病病毒核蛋白基因预期扩增片段,序列测定进一步证实为狂犬病病毒。该狂犬病病毒株与2011年安徽省一株犬源狂犬病病毒株核苷酸序列同源性最高,为98.4%。结论 该疑似狂犬病病例可确诊为狂犬病病例。其发病源于至少2011年以来的某次不自觉的狂犬病病毒感染。     

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.     

Caring for patients with rabies in developing countries – the neglected importance of palliative care

Although limited publications address clinical management of symptomatic patients with rabies in intensive care units, the overwhelming majority of human rabies cases occur in the rural setting of developing countries where healthcare workers are few, lack training and drugs. Based on our experience, we suggest how clinicians in resource‐limited settings can make best use of essential drugs to provide assistance to patients with rabies and their families, at no risk to themselves. Comprehensive and compassionate patient management of furious rabies should aim to alleviate thirst, anxiety and epileptic fits using infusions, diazepam or midazolam and antipyretic drugs via intravenous or intrarectal routes. Although the patient is dying, respiratory failure must be avoided especially if the family, after being informed, wish to take the patient home alive for funereal rites to be observed. Healthcare staff should be trained and clinical guidelines should be updated to include palliative care for rabies in endemic countries.