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.     

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.     

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.     

Descriptive analysis of malaria prophylaxis for travellers from Greece visiting malaria-endemic countries

International travel is changing the epidemiology of imported malaria. Our aim was to study malaria prophylaxis administered to travellers from Greece. The study was conducted during 2008-2009. Data were collected using a standardized form. A total of 2337 travellers were studied; prophylaxis was recommended to 60.2% of them. Of the 2337 travellers, 32.6% travelled to sub-Saharan Africa, 25.5% to South America, 11.8% to Indian subcontinent, 11.7% to Middle East, and 4.4% to Southeast Asia; prophylaxis was recommended to 77.4%, 64%, 80.6%, 4.8% and 73.5% of them, respectively. According to the purpose of travel, prophylaxis was recommended to 85.4% of those travelling for work, 75.2% of those visiting friends and relatives, and 62% of those travelling for recreation. Prophylaxis advised was provided to 68.5%, 66.2%, 61.5%, and 18.9% to those staying at a residence of local people, camping, hotels, and cruise ships, respectively. Regarding long-term travellers, malaria prophylaxis was recommended to 42.6%. Recommendation of malaria prophylaxis was significantly statistically in association with destination countries, purpose of travel, type of residence in endemic areas There is a need to improve recommendations for malaria prophylaxis for travellers from Greece, and to increase awareness and education of professionals providing travel health services in Greece.     

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.     

Feline and Canine Rabies in New York State,USA

In New York State, domestic animals are no longer considered rabies vector species, but given their ubiquity with humans, rabies cases in dogs and cats often result in multiple individuals requiring post-exposure prophylaxis. For over a decade, the New York State rabies laboratory has variant-typed these domestic animals to aid in epidemiological investigations, determine exposures, and generate demographic data. We produced a data set that outlined vaccination status, ownership, and rabies results. Our data demonstrate that a large percentage of felines submitted for rabies testing were not vaccinated or did not have a current rabies vaccination, while canines were largely vaccinated. Despite massive vaccination campaigns, free clinics, and education, these companion animals still occasionally contract rabies. Barring translocation events, we note that rabies-positive cats and dogs in New York State have exclusively contracted a raccoon variant. While the United States has made tremendous strides in reducing its rabies burden, we hope these data will encourage responsible pet ownership including rabies vaccinations to reduce unnecessary animal mortality, long quarantines, and post-exposure prophylaxis in humans.     

A spatial model to forecast raccoon rabies emergence

Although raccoons are widely distributed throughout North America, the raccoon rabies virus variant is enzootic only in the eastern United States, based on current surveillance data. This variant of rabies virus is now responsible for >60% of all cases of animal rabies reported in the United States each year. Ongoing national efforts via an oral rabies vaccination (ORV) program are aimed at preventing the spread of raccoon rabies. However, from an epidemiologic perspective, the relative susceptibility of na?ve geographic localities, adjacent to defined enzootic areas, to support an outbreak, is unknown. In the current study, we tested the ability of a spatial risk model to forecast raccoon rabies spread in presumably rabies-free and enzootic areas. Demographic, environmental, and geographical features of three adjacent states (Ohio, West Virginia, and Pennsylvania), which include distinct raccoon rabies free, as well as enzootic areas, were modeled by using a Poisson Regression Model, which had been developed from previous studies of enzootic raccoon rabies in New York State. We estimated susceptibility to raccoon rabies emergence at the census tract level and compared the results with historical surveillance data. Approximately 70% of the disease-free region had moderate to very high susceptibility, compared with 23% in the enzootic region. Areas of high susceptibility for raccoon rabies lie west of current ORV intervention areas, especially in southern Ohio and western West Virginia. Predicted high susceptibility areas matched historical surveillance data. We discuss model implications to the spatial dynamics and spread of raccoon rabies, and its application for designing more efficient disease control interventions.     

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.     

狂犬病病例暴露后发病风险及疫苗接种的判别分析

目的对狂犬病病例暴露后发病风险及是否接种疫苗进行判别分析。方法对2004-2009年河南省狂犬病例进行流行病学调查,用SPSS15.0建立数据库,对病例暴露后发病风险及疫苗接种进行判别分析。结果 Fisher线形判别函数判别结果显示,病例暴露后高发病风险判别正确率为51.0%,中发病风险判别正确率为34.2%,低发病风险判别正确率为67.7%。未接种疫苗者判别正确率为85.1%,接种疫苗者判别正确率为74.5%。结论狂犬病病例暴露后发病风险的判别分析符合率较低,暴露后是否接种疫苗判别符合率较高。     

Rabies in Europe: An epidemiological and clinical update

Rabies is a vaccine preventable zoonotic disease with a significant mortality burden worldwide. Several years of vaccination campaigns in wildlife animals have now achieved the control of rabies in Western Europe through a vaccination belt in front of endemic Eastern European countries. Nevertheless, rabies could be imported both by travellers from areas without an active public control of the disease or by animals coming from areas where the virus circulates in wildlife fauna. The knowledge of the current world epidemiology combined with a high index of clinical suspicion are needed to reach a diagnosis of rabies, especially in case of atypical presentation or without a history of animal exposure. The pre-travel counselling to people visiting highly endemic areas is essential to give information on how to reduce exposure to potential sources of infection and to select those subjects who could benefit from pre-travel vaccination. Rabies is almost invariably fatal, but the prompt administration of a vaccine course combined with anti-rabies immunoglobulins significantly reduces the probability to develop life-threatening consequences. In this review, we give a brief epidemiological and clinical update about rabies in Europe.     

狂犬病病毒感染免疫反应研究进展

狂犬病病毒感染机体后可引起严重的脑炎,病死率几乎为100%。暴露前预防免疫和及时的暴露后免疫可有效阻止脑炎的发生,一旦出现狂犬病临床症状后,几乎所有的治疗方法均无效。病毒感染机体后,激发机体产生先天性和获得性免疫应答,而在病毒进入中枢神经系统前,机体产生的免疫应答不足可能是免疫保护失败的原因之一。本文综述了机体对狂犬病病毒感染与疫苗免疫产生的免疫反应。     

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.     

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.     

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.     

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.     

Differential Willingness to Undergo Smallpox Vaccination Among African-American and White Individuals

OBJECTIVE:  To examine potential disparities in willingness to be vaccinated against smallpox among different U.S. racial/ethnic groups.
DESIGN:  Cross-sectional survey using an experimental design to assess willingness to be vaccinated among African Americans compared to whites according to 2 strategies: a post-exposure "ring vaccination" method and a pre-exposure national vaccination program.
SETTING:  Philadelphia County district courthouse.
PARTICIPANTS:  Individuals awaiting jury duty.
MEASUREMENTS:  We included 2 scenarios representing these strategies in 2 otherwise identical questionnaires and randomly assigned them to participants. We compared responses by African Americans and whites.
MAIN RESULTS:  In the pre-exposure scenario, 66% of 190 participants were willing to get vaccinated against smallpox. In contrast, 84% of 200 participants were willing to get vaccinated in the post-exposure scenario ( P  = .0001). African Americans were less willing than whites to get vaccinated in the pre-exposure scenario (54% vs 77%; P  = .004), but not in the post-exposure scenario (84% vs 88%; P  = .56). In multivariate analyses, overall willingness to undergo vaccination was associated with vaccination strategy (odds ratio, 3.29; 95% confidence interval, 1.8 to 6.1).
CONCLUSIONS:  Racial disparity in willingness to get vaccinated varies by the characteristics of the vaccination program. Overall willingness was highest in the context of a post-exposure scenario. These results highlight the importance of considering social issues when constructing bioterror attack response plans that adequately address the needs of all of society's members.     

减毒狂犬病病毒CTN181-3株免疫学特性研究

目的 对本室研发的1株狂犬病减毒株CTN181-3的免疫学特性进行研究。方法 以小鼠和金黄地鼠为模型,口腔或肌肉免疫1次后考查暴露前免疫;以金黄地鼠为模型,肌肉免疫考查暴露后免疫。结果 CTN181-3株经小鼠和金黄地鼠分别口腔或肌肉免疫1次均能产生高滴度的中和抗体和良好的攻击保护效果;经小鼠口腔和肌肉免疫早期即开始产生细胞因子IFN-γ和IL-2,诱发有效的细胞免疫。以金黄地鼠为模型的暴露后免疫结-果显示:肌肉免疫1次的保护率为50%,而免疫2次的保护率可达100%。结论 CTN181-3株具有良好的体液免疫和细胞免疫保护效果,而且暴露后2次免疫不必接种免疫球蛋白即可达到100%有效保护,其免疫性强、保护效果好,是一种很有应用前景的狂犬病动物用候选疫苗株。     

Immunogenicity and effectiveness of post-exposure rabies prophylaxis with a new chromatographically purified Vero-cell rabies vaccine (CPRV): a two-stage randomised clinical trial in the Philippines

Recent improvements in chromatographic purification procedures have made it possible to develop a new chromatographically purified rabies vaccine (CPRV) by further purifying the current rabies vaccine prepared from Vero-cell culture (PVRV) (Verorab; Pasteur Merieux Connaught). The immunogenicity and effectiveness of post-exposure rabies prophylaxis with this new vaccine were evaluated in a two-stage clinical trial conducted in the Philippines. In both study stages. post-exposure treatment consisted of five injections of vaccine [(D)ays 0, 3, 7, 14, 28], together with a dose of rabies immunoglobulin (RIG) of equine or human origin on D0. In stage 1, 231 subjects with low-risk rabies exposure (WHO category I or II), and who had a negative ERIG skin test, were treated with either CPRV (n = 114) or PVRV (n = 117). By D14, all subjects in each group had achieved rabies antibody titres over ten times that recommended by the WHO as indicating seroconversion (> or = 0.5 IU/ml). The kinetics of the immune response to vaccination were very similar in the two groups, and at D28, the immunogenicity of CPRV was equivalent to that of PVRV (one-sided equivalence test). Following these positive results, 132 subjects with severe rabies exposure were included in the second stage of this trial. All were scheduled to receive four vaccine doses with CPRV. After D14, only those 57 patients with confirmed rabies exposure (animal with positive FA test) and seven patients for whom rabies exposure could not be excluded (animal lost or not tested) completed the treatment and were followed for one year to assess survival. After 1 year, 62 patients treated for confirmed or possible severe rabies exposure had been examined and were still alive. Two patients contacted by letter and telephone confirmed good health 7 and 16 months after exposure. No severe local or systemic reactions were reported in either stage of the study, and no treatment-related serious adverse event occurred. This two-stage clinical trial attests to the safety and satisfactory immunogenicity of CPRV in post-exposure rabies treatment, and confirms the effectiveness of a new rabies vaccine in patients with severe confirmed exposure.     

Transmission dynamics of rabies virus in Thailand: Implications for disease control

Background  

In Thailand, rabies remains a neglected disease with authorities continuing to rely on human death statistics while ignoring the financial burden resulting from an enormous increase in post-exposure prophylaxis. Past attempts to conduct a mass dog vaccination and sterilization program have been limited to Bangkok city and have not been successful. We have used molecular epidemiology to define geographic localization of rabies virus phylogroups and their pattern of spread in Thailand.     

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.