Rabies is one of the most terrible zoonotic diseases known to humans (Alan C. Jackson, 2016). Although the disease can be prevented by vaccination, it kills about 59,000 people each year, mainly in low to middle-income countries (Singh et al., 2017). The domestic dog is responsible for 99% of human death worldwide and, approximately 40% of the victims are children under the age of 15 (K. Hampson et al., 2015; Liu & Cahill, 2020). The fatality rate is nearly 100%, once the clinical signs begin to develop in the infected host. Virus main transmission is via animal bites, but transmission through close contact with broken skin, a mucous membrane with the saliva of rabid animals, and organ transplantation is also reported (Lu et al., 2018; C. E. Rupprecht et al., 2002; Harun et al., 2022).

The etiological agent belongs to the genus Lyssavirus, family Rhabdoviridae and order Mononegavirals (C. Rupprecht et al., 2017). The genus comprises a grow-ing number of viral genotypes and so far, 17 officially classified genotypes have been characterized. The Rabies virus is the prototype of lyssavirus (Calvelage et al., 2021). All lyssaviruses are capable of causing lethal encephalitis in susceptible animals. Iran is an an-cient country located in the Middle East, a region bet-ween Asia, Europe, and Africa (Mehrdad). All neigh-boring counties suffer from rabies health problems in Fig. 1 (Ahmad et al., 2021; Atıcı & Oğuzoğlu, 2022; Hasanov et al., 2017). Rabies is a significant health problem in Iran and the disease is reported in all 31 provinces of the country (Simani et al., 2004). Due to high habitat diversity in Iran (Farashi & Shariati, 2017), a wide range of wildlife animals are found in the country, and the rabies virus is isolated from wolfs, jackals, foxes, and other wild animals (Bannazadeh Baghi et al., 2018). Epidemiological studies show that domestic dog is responsible for most of the animal bites in Iran and is considered the main reservoir of the virus (Gholami et al., 2017; Rahpeyma et al., 2015). In Iran, animal bite statistics have increased over the past three decades, from 35 cases per 100,000 populations in 1987 to 177 cases per 100,000 in 2016 (Bay et al., 2021). Therefore, the rabies elimination campaign is considered a complex task (Miao et al., 2021) and req-uires strict intersectoral collaboration between human and veterinary authorities and policymakers. 

Dogs play as the main vectors of human rabies (Bourhy et al., 2010) and are responsible for more than 99% of human cases, Therefore, controlling rabies in dog population through mass vaccination campaigns, particularly in stray dogs, are the priority for human rabies prevention (Ceballos et al., 2014; Denduangbo-ripant et al., 2005; Pastoret et al., 2014). In this regard, zero by 2030 was launched in 2015 by the World Health Organization (WHO), the United Nations Food & Agriculture Organization (FAO), the World Organ-ization for Animal Health (OIE), and the Global Alli-ance for Rabies Control (GARC) to help countries speed up their efforts to end human rabies by 2030 (Organization, 2018b). The main objective of this study was a systemic review of information and exis-ting platforms towards this WHO mission. 

World Epidemiology 

While rabies is prevalent all around the world, except Antarctica (Malerczyk et al., 2010), approximately 95% of human death is reported in Asia and Africa (Katie Hampson et al., 2015). Around 15 million hu-man exposures to rabies are estimated, which causes a significant economic loss of 8.6 billion US dollars (USD) annually and it is associated with a loss of 3.7 million disease-associated life years (DALY) (Beyene et al., 2018). 

On the other hand, rabies is considered one of the neg-lected tropical diseases, and it is assumed that rabies is underreported and the estimated burden is higher than of registered numbers in endemic regions (Taylor et al., 2017).  

Treatment

Although rabies has been around for a long time (L. H. Nel, 2013), and considerable advances have been made in the scientific knowledge of the etiology and patho-genesis of the disease, the disease is considered non-curable when the clinical outcome appears (Dacheux et al., 2011; Tarantola, 2017). In addition, the sporadic occurrence of human cases makes systematic clinical research therapies even more difficult. So far, only about 30 human cases have been well documented for survival that the majority of these survivors experi-enced severe neurological effects (de Souza & Madhu-sudana, 2014; Wilde & Hemachudha, 2015; Willou-ghby et al., 2005). On the other hand, in rabies-ende-mic areas, patients access to intensive critical care may be restricted, because of the cost and lack of clin-ical expertise (Baron et al., 2022; Darryn L Knobel et al., 2022). As the pathological processes of the rabies virus are complex and the outcome of infection is severe, a combination therapy approach is required for the successful treatment of rabies in the future (Banyard et al., 2019; Alan C Jackson, 2005). This combination therapy briefly can be classified into four categories: 1- inhibition of viral propagation by using specific antiviral drugs or monoclonal antibodies.  2- Prevention of neuronal degeneration. 3- Modification of host inflammatory response in later stages of in-fection, as the studies show that host immune respon-ses may be damaging in later stages of CNS infection.  4- Managing severe systemic compromise of patients in late-stage of disease. The treatment process for the four categories should be initiated as soon as possible and expected results will be improved in the early initiation of treatment (D. L. Knobel et al., 2022).

Post- exposure prophylaxis (PEP)

WHO-recommended PEP for unvaccinated individuals exposed to rabid animals should be started with imme-diate washing or cleaning out the wound, adminis-tration of a rabies vaccine, and if Category III exposure is detected, an additional injection of rabies immu-noglobulin (RIG) is required (World Health, 2018). Currently different PEP vaccination (with intramusc-ular or intradermal routes) is authorized for people who have not previously been vaccinated against rabies. Immunosuppressed persons should receive rabies PEP in a 5-dose vaccine regimen (i.e., 1 dose of vaccine on days 0, 3, 7, 14, and 28) and it is recommended that rabies serum antibodies should be checked 1 to 2 weeks after the fifth dose of vaccine in this group (Gongal & Sampath, 2019; Kessels et al., 2019; Liu & Cahill, 2020). Unfortunately, studies have shown that low education level and unawareness about timely PEP, and lack of RIG administration on the day (D0) were substantially associated with high risk of non-compliant PEP schedule and fatal outcomes in rabies endemic areas (Joseph et al., 2013).

Vaccine

Vaccines against rabies virus are among the oldest antiviral interventions. The first vaccine against RABV was developed in 1885 by Louis Pasteur and was based on neuron-derived vaccines (Borutzki et al., 2022; Dreesen, 1997). Despite having low immune-genicity and adverse side effects, neuron-derived RABV vaccines have been in widespread use for over a century but they have now been largely discontinued (Ertl, 2019; Wu et al., 2011). Advances in cell culture technologies enabled the creation of rabies cell- culture -based vaccines. Currently licensed rabies vaccines in comparison with nerve-tissue-derived vaccines have many advantages. First, they are safe and have been administered to millions of people over the decades. Second, they are highly effective (high immunegeni-city) when administered correctly. Third, the vaccines induce long-lasting immunity in recipients. The serum antibody titer of 0.5 IU/ml defined by the WHO is considered to measure adequate seroconversion after vaccination.

Fig. 1: Map of Iran showing the two highlighted provinces with high animal bites (Dehghani et al., 2016). The      icon    indicates rabies prevalence in all 31 provinces of country. The     icon indicates rabies prevalence in neighbors countries of Iran. Blank map from d-maps.com

Mass vaccination of dogs

Animal bites especially dogs, cause tens of millions of injuries each year and are a major public health prob-lem for children and adults worldwide (Desai, 2020; Patel et al., 2017). Dog bite death rates are higher in low- and middle-income countries because many of these countries have rabies problems and post-expo-sure treatment and adequate health care may be lacking (Duperrex et al., 2009). It is estimated that 180000 animal bites are recorded each year in Iran (Sarbazi et al., 2020). According to data published by the Center for Disease Control, Ardabil and Golestan provinces have the highest number of animal bites (450 in 100,000) in Fig. 1, followed by the Chaharmahal - Bakhtiari provinces (300- 450 in 100,000). The lowest rates are reported from Tehran (< 100 in 100,000) (Dehghani et al., 2016). Dogs are responsible for most (99%) human cases of rabies, and controlling the disease in these animals is the priority for preventing human rabies (Bourhy et al., 2010). 

Most importantly Dog vaccination reduces necessity for PEP and the death from dog mediated rabies (Lechenne et al., 2017). There are successful models of human rabies control through the mass vaccination of dogs in the world. For example, in Central and South America, strict dog population control measures and coordinated mass vaccinations have resulted in rabies control. In Japan, and many island nations or regions in Asia, rabies has been controlled or the eliminated for decades (Belotto et al., 2005; Davlin & VonVille, 2012; Lembo et al., 2011; Louis H. Nel et al., 2017; Organization, 2018a). 

Rabies elimination needs a global response to rabies on a sustainable base. It requires close coordination and intersectoral collaborations between human and veteri-nary departments in all affected countries. In Iran, public health authorities identified rabies as a health problem during the early-mid 20th century, as the national center for reference on rabies was established at the Pasteur institute of Iran. However, the pathway to ending rabies requires aggressive implementation of WHO guidelines. 

The authors received no financial support for the rese-arch of this article.

We have no Conflicts of interest in this research.