Geographically, Iran is the sixteenth-largest country in the world with an area of 1,648,195 square kilometers located in Southwest Asia (32.00˚ N and is 53.00° E). It shares borders with Iraq in the south, Afghanistan, and Pakistan in the east and Armenia, Azerbaijan, Turkmenistan, and Turkey in the north.
The geographical position and the distance from large seas are the main causes of the generally dry climate in Iran. In Iran, like many other countries of Asia and Africa, rabies is endemic and imposes large economic losses on the health systems. Despite free treatment and prevention measures, rabies still is detected in almost all regions especially in north, northwest, and northeast of the country. In Iran, the trend of animal bites is on the rise, with an increase in the number of bites from 180000 in 2017 to 200000 cases in 2019 that due to uncertainty of the animal safety and inadequate training for all of the people bitten by an animal. Of these, about 81 percent of them are bitten by dogs, and 89 percent of dog bites by dogs. Vaccination of people bitten by an animal would also be reduced if rabies was eliminated in stray dogs. One of the strategies used in the past to eliminate rabies was to kill stray dogs with this thinking that the transmission of the disease depends on the host population density, but studies have shown that this is ineffective. However, the targeted and humane removal of unvaccinated, ownerless dogs may be effective when used as a supplementary measure to mass vaccination. Therefore, in accordance with the consensus of the Global Conference held in Geneva in December 2015, a global framework for the elimination of dog-mediated human rabies of OIE and WHO (WHO 2016), to reach zero human deaths from dog-mediated rabies in Iran by 2030, a multi-disciplinary national committee on the elimination of dog-mediated rabies began to work in 2015.
Launching the World Rabies Day Celebration through webinar and free rabies vaccination
The pet-keeping trend is increasing in Iran as with other countries in the Middle East and Asia, therefore, about 200000 cases of biting are observed each year. All of whom receive post-exposure treatments due to the suspicions of the pets and inadequate educations. Of these, about 81% of subjects are bitten by dogs and 69.4% of dog bites are related to the owned dogs (1).
Figure 1: Comparison of the distribution of rabies in owned and stray dogs in Iran, 2000-2013 (n=1,186) (2).
Rabies is currently an economic health problem in Iran and almost all of the provinces are more or less involved in this. Most cases of the disease are observed on the edge of the Caspian Sea, northeast, and southwest of the country. According to the Ministry of Health and Medical Education, an annual of 180,000 individuals are treated by the Pre-exposure prophylaxis (PrEP) measurement (3). According to the antemortem diagnosis of rabies data of the National Center for Reference and Research on Rabies, the Pasteur Institute of Iran, 5-11 individuals die from rabies in Iran annually. Considering that the disease is spread throughout the country, preventive measures must be taken in all provinces.
1. The National Center for Reference and Research on Rabies, Pasteur Institute of Iran
The center after establishing in 1923 was selected as the collaborating center by the WHO from 1973 due to its intensive international cooperation in the field of rabies. The collaboration position is renewed every four years, according to the terms of reference submitted by the department to the EMRO (Eastern Mediterranean Office) and by completing the WHO collaborating centers questionnaires. Since 2014, the center has obtained the national rabies authority certificate after implementation of ISO 15189 and as a collaborating center for the health reference laboratory of the Iran Ministry of Health and Medical Education.
The establishment of antemortem rabies diagnostic laboratories in the country is also among the activities of this department. Missions of the department include the maintenance of scientific and technical achievements, the enhancement of quality and planning for sustainable development in the country and the region. In this regard, the quantitative and qualitative enhancement of the bilateral, or multilateral, educational, research, and technical cooperation of the center with relevant and international public agencies for controlling rabies and aiming at its elimination are long-term missions of the department.
1.1. Routine Rabies Diagnostic Laboratory
In the laboratory, the rabies-suspected brain samples of animals or humans are investigated by accurate and sensitive laboratory methods such as FAT and MIT, and the results are sent to the center requesting the test in a daily manner. In this unit, the annual rabies statistics, including the total number of subjects bitten by rabid animals, rabies-related fatalities, the prevalence of rabies in humans and animals in different parts of the country are discussed and analyzed. The Chief Executive Officer (CEO) of the laboratory prepares updated GIS maps on the prevalence of rabies.
1.2. Serological Laboratory (Rapid Fluorescent Focus Inhibition Test (RFFIT))
In this laboratory, the anti-rabies-specific antibody assay is performed by the RFFIT method on human or animal sera. Controlling of the antibody titers in imported immunoglobulin sera as well as the safe domestic sera are performed by the experts in this laboratory. In addition, the Ab-rabies titer is measured by the ELISA method, which is a quicker method than the RFFIT and is used for screening. The antiviral effects of some medicines, as well as the virucidal effect of some imported or domestic disinfectant substances, are also examined in this laboratory.
1.3. Laboratory for evaluating vaccines and biological products
In this laboratory, the potency of imported and domestic rabies vaccines for human and animal consumption is evaluated by the National Institutes of Health (NIH) method (recommended by the WHO). After confirming the immunization level of the tested vaccines in this laboratory, based on the capabilities and experience of the rabies reference center and due to its collaboration with other relevant governmental organizations, such as the Ministry of Health and Veterinary Organization, could allow the marketing of the vaccine in question. In the research and development (R&D) unit of the laboratory, research projects on the rabies vaccine and their immunization effect are being performed.
1.4. Molecular laboratory to the diagnosis of rabies
In this laboratory, molecular studies and diagnoses on the genome of isolated strains obtained from all over the country are performed such as RT-PCR, Real-Time PCR, and RT-LAMP. Other examinations performed in the department include the molecular analysis of infected brain, cerebrospinal fluid, skin, saliva, urine, and sera samples from antemortem and post-mortem rabies-suspected subjects.
5.5. Molecular epidemiology of rabies
In this unit, phylogenies and phylodynamic studies are conducted to monitor the distribution of wild rabies strains in different parts of Iran. According to the latest publication by Dr. Nadin-Davis in 2003 and by sequencing of a part of the virus genome (350 bp of a phosphoprotein gene), it cleared that the major variant of the rabies virus circulating in Iran is cosmopolitan lineage along with a few Arctic variants (4). In a recent cooperative study by the Pasteur Institute of Iran and Paris in 2017, a total of 150 samples were selected from different geographic regions and sequencing was performed for the total length of the viral genome. The preliminary results of this study indicate that the circulation variant has not changed in comparison with the Nadin-Davis study. Iran's Cosmopolitan variants are categorized into four different groups of Middle Eastern variants and Central Asian variants.
In addition to the increase in population, public awareness, as well as the number of health centers providing rabies prevention and treatment services, and increased access to these services by the individuals in Iran, the number of animal biting cases has also increased (5). The highest prevalence of animal bites is reported in the northern provinces, for example, Golestan and Ardebil due to the high number of owned dogs (2). Although there has been an increasing trend in animal bites during the past 28 years (1987-2015), such that the bitten cases have increased from 35 in 1987 to 198 per 100000 of the population in 2015, the rabies cases have been steadily decreasing (2).
Obtaining comprehensive and reliable information on animal bites is difficult because most biting cases are small that the individual feels no necessity to refer to medical centers. Therefore, such cases are never reported to medical centers.
- Vaccine Production
In Iran, the rabies vaccine has been manufactured on an industrial scale at the Pasteur Institute of Iran since 2011.
- Information, Education, and communication
Rabies is a vaccine-preventable disease. Knowledge, expertise, and experience present for rabies at Pasteur Institute of Iran are at disposal for every necessity related to the field of rabies diagnosis, PEP, surveillance, and control measures at the national level and regional countries in the frame of disease control and elimination or upon WHO request. In a situation where a significant proportion of the dog population is owned, increasing public awareness of the benefits of vaccination can also lead to improved compliance with national guidelines on vaccination.
Another step is the vaccination of domestic dogs and cats as they cause most rabies cases in humans and domestic animals. It is important to train livestock breeders and dog owners to cooperate with veterinary experts using collars and vaccinating dogs to control the disease.
• Minimization of human exposures to infected animals.
• To increase attention from the media and policymakers.
• Responsible pet ownership -Vaccinating pets
• Knows what to do if bitten
Activities on World Rabies Day:
• Webinar Training course for experts of Centers for Control and Prevention of rabies
• Launching first rabies and bite prevention training app in Persian
• Launching first rabies and animal bite prevention training site in Persian
- The free Rabies Vaccination Campaign
Free vaccination of livestock on-site, on World Rabies Day by the Veterinary Organization
History of the fight against rabies in contemporary Iran: people whose memories in the history of Iranian health will live forever in the control of rabies field
Professor Marcel Baltazard (1908–1971), Dr. Mehdi Ghodsi (1900-2000), Dr. Mahmoud Bahmaniyar (1919-2007), Dr. Hossein Mirshamsi (1919-2007), and Dr. Ahmad Fayaz (1936, today)
In Iran, rabies was known to peasants and shepherds from ancient times. They knew that the disease is transmitted to humans by rabid dogs and, sometimes, by wolves (6). Ibn Sina (980–1037 AD), the Iranian well-known scientist, introduced the disease as the fear of water (hydrophobia) and recommended that the bitten site is not covered for 40 days and blistering materials are used in the wound. He has explicitly stated that the blood from the rabid dog is an antibody of its bite. This treatment method, along with burning the wounds was the major treatment of animal bites up to the early twentieth century (6).
Up until the establishment of the rabies center in the Pasteur Institute of Iran, persons who were bitten by dogs, resorted to superstitious for the treatment and sometimes even lost their lives due to these activities. In 1923, two years after the establishment of the Pasteur Institute in Iran, a foreign ambassador's son in Tehran was injured by a suspected rabid dog and taken to the Pasteur Institute for treatment, while the institute still lacked anti-rabies services. They were forced to take the child out of Iran for treatment. This led to the decision of the authorities of the Pasteur Institute of Iran to establish an anti-rabies service and the service was launched in the institute in 1923 under the supervision of Dr. Mehdi Ghodsi (1900-2000). Gradually, other centers were established in other provinces and cities. According to geographic distributions, different animals could be a source of the disease. In Iran, rabies is more common in the fall and winter, in men than women and under 20-year-old subjects (7).
To date, Iran has played a major role in the new scientific advances in the rabies treatment field. For example, in 1954, Professor Marcel Baltazard (1908–1971), the director of the Pasteur Institute of Iran and his assistant Dr. Ghodsi, concluded that anti-rabies treatment was totally valid in its used form, but not sufficiently effective (8). The use of the vaccine obtained from the rabbit spinal cord continued until 1936, and then, Dr. Ghodsi developed the anti-rabies vaccine by the Fermi method using the rabbit’s brain. Fermi vaccine was used in Iran for ten years (9). Dr. Sabeti, the head of the vaccination center, who was in charge of treating the rabies-infected individuals for some 30 years, believed that due to the problems of breeding the rabbits, the Fermi anti-rabies vaccine could cause a nerve reaction called rabbit blow (10). So, in 1946, Dr. Ghodsi prepared the Semple rabies vaccine. He observed the behavior of rabies-infected subjects for years and followed closely the treatment results. In his 10-year observations, he found that the classic Pasteur treatment is not sufficient and effective in those with severe wounds due to the wolves’ bites and that some of those who were treated lost their lives due to rabies (11). He published two shocking articles, which became a milestone in the history of anti-rabies treatment. The first article was published in 1947 in the journal of the Pasteur Institute of Paris and the second in 1955 in the World Health Organization bulletin. In the two articles, Dr. Ghodsi evidenced the inadequacy of the anti-rabies vaccine when used alone for the treatment of rabies-infected individuals with deep and numerous wounds on the head and face (9). Publication of these articles by the Iranian scientist made the authorities of the World Health Organization (12) aware of the defects in the treatment of the rabies-infected individuals. Consequently, the WHO Experts Committee on rabies decided to provide the Pasteur Institute of Iran not only with the rabies vaccine but also with the anti-rabies serum obtained by immunizing a number of rabbits for the treatment of subjects who were bitten by wolves (9). The Iranian scientists at the Pasteur Institute sought the opportunity to treat those who were bitten by wolves with rabies vaccine and serum simultaneously. They waited four years for such an opportunity. In 1954, a wolf attacked residents in the Sahne county in the Kermanshah Province, wounding 29 people. The wolf was killed and the rabies virus was found in its brain and saliva. The injured subjects were transferred to the Pasteur Institute of Iran in Tehran for treatment. The director of the Pasteur Institute of Iran, Dr. Marcel Baltazar, along with Dr. Mahmoud Bahmaniyar (1919-2007), immediately used the anti-rabies vaccine and serum to save the injured subjects in two groups with the following methodology: the first group consisted of eighteen subjects with numerous and deep wounds on their head and face, 13 among whom received one or two rabies serums and a set of vaccination, and five only received the anti-rabies vaccine (9, 10). The second group included eleven injured subjects with weak wounds away from their head and face, who were divided into two groups. The first group was treated with the serum and vaccination and the second only with the vaccine. The result was very significant and successful. From among thirteen patients treated with a combination of serum and vaccine, despite their deep wounds on the head and face, only one caught rabies and was died and from among the five subjects who were treated with the vaccine, three died. Among the eleven subjects of the second group who had mild injuries, no one caught rabies. The results of the treatment of the injured subjects were reported to the WHO Expert Committee in Geneva (10). Subsequently, the Expert Committee suggested in 1955 that the combined anti-rabies serum and vaccine treatment method is the best way to save the rabies-infected subjects worldwide (10). This method is still used to treat rabies all over the world.
In Iran, the heterologous anti-rabies serum was being produced for years by Dr. Hossein Mirshamsi (1917-2008) and collogues at the Razi Institute. The serum was highly-graded and supplied in the lyophilized form; however, its consumption was halted due to its allergic complications. Instead, the use of the anti-rabies serum produced in humans or anti-rabies immunoglobulin was made common (13).
In 1964, researchers from the Wistar Institute in Philadelphia successfully proliferated the rabies virus on the human diploid cell and prepared the empirical human diploid cell rabies vaccine (HDCV) vaccine. They proved the immunogenicity power and harmlessness of the vaccine by injecting it to 16 of their colleagues (14). In 1975, the vaccine was built on a large scale in France and the manufacturers successfully obtained the license for its use in human beings. It was then applied to immunize the students of the Faculty of Veterinary Medicine in France (15). In 1976, the Pasteur Institute of Iran was assigned by the WHO to evaluate the HDCV vaccine. The Iranian researchers first used this vaccine to immunize five volunteer groups by various methods. After evaluating the antibody in the volunteers, they considered the method of injecting the vaccine on days 0, 3, 7, 14, and 30 and the injection of a booster dose on day 90 as the best prevention treatment method. Researchers at the Pasteur Institute of Iran used the method to treat 45 subjects who were severely injured by two rabid wolves and six rabid dogs. All of these subjects were rescued from the risk of rabies (16). At the same time, the results of their treatment, in addition to the results of the treatment of another group of rabies-infected subjects in the city of Essen, Germany, were examined by the WHO Expert Committee on rabies and was popularized around the world as the Essen method according to the recommendations of WHO (17).
During the past 40 years, due to the efforts of the Pasteur Institute of Iran and the Center for Reference and Research on rabies, Treatment, and Prevention of rabies have undergone a number of changes to save lives of those bitten by rabid animals in the country. Because of these efforts, Dr. Ahmad Fayaz (1936, today) was appointed as an expert on rabies by WHO Secretary-General in 1994. The prize of the French Academic Palms was awarded to him in 1998. He was chosen as a distinguished doctor due to his activities in the field of rabies by the Iranian Medical Council in 2005, and also was selected as one of the best physicians of 30 years of health activities, and a certificate was also awarded to him by the Presidency in 2008 (7).
Today, problems caused by the injection of heterologous serum have been resolved. The neurological complications of brain tissues which in some cases caused fatalities due to paralysis are no longer observed due to the use of cell vaccines. The number of doses from 14 to four times in the Zagreb regimen declined. Most importantly, the fatality rate of treated patients has decreased significantly (9). For example, in 1971, 1243 individuals bitten by rabid animals were treated and 13 were dead due to rabies. In 2010, however, more than 120000 bitten subjects received prevention-therapeutic treatments for rabies and the fatality rate was only 5 subjects (18).
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