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.     

Practical management of rabies and the 1982 outbreak in Zorzor District, Liberia

A rabies outbreak in Zorzor District, Liberia, in 1982 resulted in 31 known bitten and 12 known exposed patients. Human diploid cell strain (HDCS) vaccine was used to vaccinate 40 patients. Of these, 34 were vaccinated at Curran Lutheran Hospital, Zorzor, Liberia, mostly by the intradermal (i.d.) route. Five of 28 bitten patients who started their vaccinations did not complete the 4-dose course, including a 16-year-old boy who did not return after the first injection and later died of rabies. There were also 2 deaths in 3 known bitten but unvaccinated patients. None of the 23 bitten who received 4 doses of HDCS vaccine contracted rabies. The i.d. route was also used for pre-exposure prophylaxis. This method of vaccination is less expensive than the intramuscular route and in our clinical setting we would not have been able to vaccinate all the patients without using it. A practical approach to rabies vaccination in a developing country and the technique of intradermal vaccination are discussed.     

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.     

Rabies pre-exposure prophylaxis using intradermal human diploid cell vaccine: immunologic efficacy and cost-effectiveness in a university medical center and a review of selected literature

The authors studied the antigenicity of intradermal human diploid cell rabies vaccine administered to 40 laboratory workers considered to be at-risk at the University of Virginia Medical Center. A 1-year postvaccination serology was determined for 20 of those 40, all of whom demonstrated an antirabies titer greater than or equal to 1:50 by the raped fluorescent focus inhibition test. By 2 years' postvaccination, 5 of 40 subjects had "unprotective levels" (less than 1:5), whereas 35 had titers greater than or equal to 1:5, and none had a titer greater than or equal to 1:50. Booster doses given to four subjects whose titers had declined produced a 1-month postvaccination antirabies titer greater than or equal to 1:50 in all cases. Vaccine administration by the intradermal rather than the intramuscular route resulted in a cost savings of $120 (U.S.) per employee. This data indicate that the intradermal administration of human diploid cell vaccine for rabies pre-exposure prophylaxis achieves an immunologic response thought to be protective while providing a substantial cost savings when compared with the intramuscular route of administration. Those who receive primary pre-exposure rabies vaccination should have serologic confirmation of immunologic protection every 2 years with a booster dose given to subjects demonstrating a titer less than 1:5.     

An important public health problem: rabies suspected bites and post-exposure prophylaxis in a health district in Turkey.

OBJECTIVE: The aim of this study was to describe rabies suspected animal bites and post-exposure prophylaxis (PEP) practices in Narlidere District in Turkey between 1999 and 2001. METHODS: One thousand five hundred and sixty-nine rabies suspected bite cases reported were identified from the District's rabies surveillance forms. RESULTS: Males comprised 66.7% of the cases, and 43.5% of the total were under 20 years old. In 74% of cases the animal involved in the bite was a dog. Only 70% of the animals had an owner, and only 17% of the animals had a rabies vaccination certificate. In terms of treatment, 68% of the human cases received PEP, and 21% of cases had an extra (sixth) vaccination dose, which is a substantial burden on the healthcare system, costing half a million US dollars per year. The place where the bite occurred (rural areas), the age of the recipient (more than 10 years old), the animal type (animals other than dogs and cats), lack of a vaccination certificate for the animal, and place of wound treatment (hospital) were significantly associated with PEP application. CONCLUSIONS: In addition to the currently recommended strategy of controlling the dog population and of vaccinating domesticated animals, adults and children should be educated about bite prevention to reduce the number of animal bites.     

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.     

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.     

Changes in Knowledge of Bat Rabies and Human Exposure among United States Cavers

The purpose of the study was to evaluate changes in the knowledge of bat rabies and human exposure among United States cavers during the last decade. A survey was distributed among cavers who attended the National Speleological Society convention in 2000 and those who attended in 2010. In 2000 and 2010, 392 and 108 cavers, respectively, responded to the questionnaire. Eighty-five per cent of respondents in 2000 indicated a bat bite as a risk for rabies compared with all respondents in 2010 (P < 0.0001 controlling for age). The proportion of respondents indicating that they were advised to receive rabies pre-exposure prophylaxis (PreEP) because of caving increased (17% and 29%; P = 0.03 controlling for age). Among these, PreEP was received by 56% and 45%. Although recognition of the risk of rabies exposure from bats is important, the proportion of cavers acting on current recommendations regarding PreEP does not appear to have improved in the past decade.     

The Route of Administration of Rabies Vaccines: Comparing the Data

Cell culture rabies vaccines were initially licensed in the 1980s and are essential in the prevention of human rabies. The first post-exposure prophylaxis (PEP) vaccination regimen recommended by the World Health Organization (WHO) was administered intramuscularly over a lengthy three-month period. In efforts to reduce the cost of PEP without impinging on safety, additional research on two strategies was encouraged by the WHO including the development of less expensive production methods for CCVs and the administration of reduced volumes of CCVs via the intradermal (ID) route. Numerous clinical trials have provided sufficient data to support a reduction in the number of doses, a shorter timeline required for PEP, and the approval of the intradermal route of administration for PEP and pre-exposure prophylaxis (PreP). However, the plethora of data that have been published since the development of CCVs can be overwhelming for public health officials wishing to review and make a decision as to the most appropriate PEP and PreP regimen for their region. In this review, we examine three critical benchmarks that can serve as guidance for health officials when reviewing data to implement new PEP and PreP regimens for their region including: evidence of immunogenicity after vaccination; proof of efficacy against development of disease; and confirmation that the regimen being considered elicits a rapid anamnestic response after booster vaccination.     

Rabies in a nine-year-old child: The myth of the bite

A nine-year-old boy died from rabies encephalitis caused by a rabies virus variant associated with insectivorous bats. The patient was most likely infected in the Laurentian Mountains of western Quebec, but neither the patient nor his parents remembered any direct contact with an animal. The diagnosis was made seven days after the start of symptoms. After examining the most recent cases of rabies in North America, it is obvious that rabies following bat exposure can occur without history of a documented bite. The present case report emphasizes that the general public and medical care providers need better information about the risks associated with exposure to bats.Key Words: Bat, Children, Encephalitis, Prophylaxis, RabiesRabies is a zoonosis responsible for more than 50,000 human deaths every year worldwide, as reported by the World Health Organization. In North America and Europe, human rabies has become a very rare disease, because of the systematic vaccination of domestic animals, massive vaccination campaigns of wild animals, efficacy of rabies postexposure prophylaxis (RPEP) and education programs (1,2). While knowledge about the risk of rabies associated with a bite from a terrestrial animal seems relatively adequate among the general public and medical care providers, a lack of information may exist regarding the risk of human rabies following contact with a bat. Between 1980 and 1996, 32 cases of human rabies were diagnosed in the United States, 17 of which occurred after a contact with an indigenous bat (of which only two patients had a definite bite), 14 cases after a dog bite and one after a skunk bite (3). In Canada, three of the four cases of human rabies that have occurred since 1970 followed exposure to bats, the last case dating to 1985 (4). Since September 2000, five cases of human rabies have been reported in the United States (5). One was consecutive to a dog bite contracted in Africa and four have been attributed to bats; in the latter cases, a definite history of a bite was noted in only one case. In 1996, the National Association of State Public Health Veterinarians of the United States stated that "since rabies is endemic in bats, bats should be excluded from houses and surrounding structures to prevent direct association with humans" (6). Possible measures to reduce the bat population to a critical threshold below which the virus might be unable to propagate or to induce immunity in the vector via vaccination seem physically, economically and ecologically impractical (7). The case that we report emphasizes that the bite or the scratch of a rabid bat can go unnoticed and may lead to the development of human rabies.     

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.     

Post exposure management of animal bite cases attending a primary health center of Delhi

Rabies is an ancient disease of mankind. Every year 4 million people are exposed worldwide after animal bite and around 60000 fell victim to the rabies of which more than 95% of cases are bitten by the dogs. Rabies is a disease associated with many myths. The present study was conducted to find out the clinical profile of the animal bite cases including the common practices, precautions adopted by them after animal bite and lastly the extent and completion of post exposure treatment. Total 147 cases of animal bites attended the OPD during the study. In present study, 123 (83.7%) cases were bitten by dogs, followed by monkey (8.2%) and cat (8.2%). Majority (54.4%) suffered class II bites followed by class I (31.3%) and class III bite (14.3%). Of the total 147 cases, 116 cases (78.9%) completed post exposure prophylaxis which was observed higher among male and in younger age group.     

安徽省70例狂犬病暴露后免疫失败流行病学分析

目的 分析狂犬病暴露后免疫失败个案,探讨免疫失败的原因。方法 收集整理安徽省2005-2016年70例狂犬病暴露后免疫失败个案资料,使用Epi Data3.1软件录入数据,用SPSS 22.0软件对数据进行统计分析。结果 65.71%病例暴露后均能在24 h内赴医疗机构进行伤口的冲洗和消毒。81.43%的病例未全程接种疫苗,其原因主要是存在侥幸心理,不愿继续接种疫苗,抗血清使用率2.86%。48.57%的病例在非暴露后门诊进行处置。潜伏期中位数40 d (最短9 d,最长10.5年),暴露于头颈部的病例潜伏期较短,不同咬伤部位之间的差异有统计学意义(χ²=25.01,P<0.01)。结论 建立狂犬病暴露后补偿机制,规范狂犬病疫苗流通渠道,打击非法及伪劣产品,加强狂犬病暴露后处置门诊医疗人员的技能培训,提高公众知信行,是预防人间狂犬病暴露后免疫失败的关键。     

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.     

Confirmed rabies exposure during pregnancy: treatment with human rabies immune globulin and human diploid cell vaccine

A review of the literature shows 24 cases of pregnant human exposure to rabies virus through confirmed rabid animal bites. Historically, these patients received passive immunization with equine rabies immunoglobulin and/or purified vero cell vaccine or duck embryo vaccine. With the recent development of human-derived rabies vaccines, we report an additional case of human gestational rabies exposure, which was treated with human rabies immune globulin and human diploid cell vaccine.     

Pre-exposure rabies immunization with human diploid cell vaccine: decreased antibody responses in persons immunized in developing countries

In November 1982, a U.S. Peace Corps volunteer in Kenya completed pre-exposure rabies prophylaxis with a standard 3 dose intradermal (ID) series of human diploid cell rabies vaccine (HDCV). In May 1983, she was bitten by a dog and died of rabies 3 months later. An initial investigation revealed that the patient, as well as 9 of 11 others immunized at the same time, had no rabies antibody titers (less than 1:5). We therefore instituted investigations into the immunogenicity of pre-exposure HDCV both in the United States and in developing countries. A serosurvey revealed unexpectedly low rabies titers in both Peace Corps volunteers and others immunized in developing countries. Antibody titers measured 2-3 weeks after ID immunization were compared in 9 groups totaling 271 persons in the United States and Kenya. There was no statistically significant difference in antibody titers in the 6 U.S. groups immunized from 1980-1984 (P greater than 0.15); however, groups immunized in the United States had significantly higher titers than a group of Kenyan nationals (P less than or equal to 0.0001), and the Kenyans had significantly higher titers than 2 Peace Corps groups immunized in Kenya (P less than or equal to 0.0001). No single hypothesis proposed (laboratory error, vaccine potency, vaccination technique, or specific immune suppression) accounted for the observed differences. Although we cannot fully explain the poor response to HDCV, it is probably due to multiple factors. We conclude that persons immunized with ID pre-exposure HDCV in developing countries should have rabies antibody titers determined to ensure their seroconversion; for persons immunized in the United States, such titers need not be routinely determined.     

History of Rabies Incidence and Rabies Control in Serbia in Support of the Zero by 2030 Campaign to Eliminate Dog-Mediated Human Rabies

Urban (principally canine-mediated) rabies has been a public health risk for people living in Serbia for centuries. The first legal act in urban rabies prevention in Serbia was established in 1834 by introducing high taxes for pet dog owners. Five years later in 1839, the first set of literature describing rabies prevention was issued by the health department from The Serbian Ministry of Interior. An overview of cauterization of rabies wounds was presented as the principal method of rabies post exposure prophylaxis. In 1890, a human rabies vaccination was introduced in Serbia with the royal government directive which ordered patients to be treated at the Pasteur Institute in Budapest in receipt of rabies vaccination. Urban (canine) rabies was eliminated during the 1980s, but sylvatic (principally fox-mediated) rabies still prevailed. The last human rabies case was recorded in the Province of Kosovo and Metohija in 1980. Sylvatic rabies in Serbia is in the final stages of elimination by orally vaccinating foxes (Vulpes vulpes). The only published finding of a lyssavirus among Serbian bats was made in 1954 by Dr Milan Nikolić in the vicinity of Novi Sad. In 2006, a comprehensive two-year active surveillance program of lyssaviruses in bats in Serbia was undertaken. In this single study, all of the bats from Serbia tested negative for a lyssavirus.     

Human rabies in the United States, 1960 to 1979: epidemiology, diagnosis, and prevention

Thirty-eight cases of human rabies occurred in the United States and its territories from 1960 to 1979. The major source of exposure to rabies has changed from indigenous dogs and cats in the 1940s and 1950s to wild carnivores and bats (11 of the 27 cases with known exposures); unusual exposures (3 cases) and exposures in a foreign country (7 cases) have also become more important. No exposure could be identified for 6 of the 38 cases. Two patients received optimal prophylaxis, 14 suboptimal, and 22 no prophylaxis after exposure. Some cases might have been prevented by an increased awareness of the risks and treatment for exposure to rabies, and use of the new rabies vaccines. The diagnosis was often made late in the clinical course including after death in 8 cases. This delay, in part, resulted from the diversity in the clinical presentation. Rabies should be considered in any case of encephalitis or myelitis. Laboratory confirmation of the diagnosis was often delayed. Testing for serum antibodies was the most reliable test in unvaccinated patients, and isolation of virus was the test most likely to be positive early in the illness.     

人用狂犬病疫苗肌肉注射免疫程序研究进展

狂犬病尚无有效治疗方法,其预防措施主要为暴露前或暴露后接种人用狂犬病疫苗。随着狂犬病疫苗生产工艺的发展,疫苗质量不断提高,其免疫程序也在不断改进。目前,国内普遍采用肌肉注射方法进行狂犬病疫苗接种,暴露前免疫程序为在第0、7、21或28天(0、7、21或28 d)各注射1剂疫苗;暴露后免疫程序为5针法和2-1-1法,再暴露免疫程序则根据第1次暴露后免疫后间隔时间的不同,接种不同剂次的疫苗。2018年《狂犬病疫苗:WHO立场文件》根据狂犬病研究的最新进展,对狂犬病暴露预防免疫程序进行了简化。本文将在新立场文件的基础上,对国内外狂犬病暴露预防处置程序研究进展进行总结,并就我国狂犬病疫苗免疫程序与新立场文件倡导的免疫程序间存在的差异及改进方案加以讨论。     

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.