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Current Situation of Avian Influenza in Iran and around the World

Zoonotic avian influenza is an important disease in Asia and Middle East countries since 1997, when H5N1 and H9N2 subtypes of avian influenza viruses (AIV) were transmitted to human being by breaking specific barriers. Both H5N1 and H9N2 subtypes caused severe influenza and influenza like symptoms in infected peoples respectively. These subtypes became enzootic in some South Eastern countries of Asia such as Vietnam, China and Indonesia as well as Near Meddle East countries like Egypt. The H9N2 subtype of AIV was detected firstly in 1998 in poultry industry of Iran and several outbreaks has been reported till now. The H5N1 subtype was detected in migratory swans in 2005, backyard chickens in 2006 and commercial ducks in 2011 in winter residence of migratory birds in north of Iran. Based on the information of Ministries of Agriculture and Health, no H5N1 bird flu case was detected in both human or poultry industry of Iran. At present, the all grant parent and breeder flocks of Iran follow a vaccination schedule, programmed by veterinary organization of Iran. Unfortunately, despite of massive vaccination of breeder flocks, the H9N2 strains continues to circulate about in all province of Iran . The vaccines used for H9N2 infections in poultry industry of Iran are produced by locally or imported from international vaccine companies. There is not any special regulation for application, production and/or importation of inactivated or recombinant live vaccines of H5 or H7 subtypes in Iran. Based on the detection of H5N1 subtype of AIV in north of Iran, Iranian poultry industry are presently in risk of HPAI outbreaks.
Keywords: Avian influenza virus, bio-security, diagnosis; Eradication; vaccination
Avian influenza virus (AIV) infections can be a devastating viral disease causing enormous losses in the poultry industry worldwide. Since the re-emergence of the H5N1 subtype of AIV in 2003 in Asia, Africa, the Pacific Region, Europe and the Middle East, the H5N1 virus has become endemic in some countries and continues to cause outbreaks in poultry. More importantly, it is now causing sporadic human infections that are associated with high morbidity and mortality rates (4). Conventional control strategies are based mainly on surveillance, stamping out of infected flocks, movement restriction, and enforcement of biosecurity measures (18). However, in developed countries there was not any big worry in their infrastructure. Nevertheless, in developing countries with their poor infrastructure, there were losses due to spread of the infection estimated by several billions of culled birds, and the disease become endemic in many infected countries. Vaccination as a supportive tool in AIV control strategies was implemented to limit the spread of H5N1 in some Far East countries such as China and Pakistan and to reduce the losses (8,10). Different types of vaccines are already in use that decrease shedding of the virus, morbidity, mortality, transmissibility; increase flock resistance and decrease egg production (18,23).
The World Health Organization (WHO) is coordinating the global response to human cases of H5N1 avian influenza and monitoring the corresponding threat of an influenza pandemic. The cumulative number of cases of H5N1 virus infections reported to WHO until 29 January 2012, was 566 with 304 subsequent deaths, accounting for 60% mortality rate (34). The 2006 was the year with the highest number of reported cases and a case fatality ratio of 63% (33). The reported number of cases declined after that, probably reflecting the successful monitoring and detection of infections in poultry and humans. Fatality rates were high in all age of human being, but were the highest in persons between 10 and 39 years of age, regardless of their sex.
Avian influenza disease due to H9N2 subtype in poultry during later part of the 1990s has been noticeably increased worldwide. The H9N2 subtype outbreaks occurred in domestic ducks, chickens and turkeys in Germany during 1995 and 1998; chickens in Italy in 1994 and 1996; pheasants in Ireland in 1997; ostriches in South Africa in 1995; turkeys in USA in 1995 and 1996; and chickens in Korea and China in 1996-2006. More recently, H9N2 viruses have been reported in middle eastern countries and have been responsible for widespread and serious disease problems in commercial chickens in Iran, Pakistan, United Arab Emirates, occupied Palestine (Israel) and Saudi Arabia (16,26). The H9N2 subtype virus has been broken the human barrier by causing influenza like symptoms in infected peoples. This review paper specially focus in genetic determinants of H5N1 and H9N2 subtypes of AIVs, and role of vaccine antiviral drugs in control of Avian influenza diseases (24).
The H9N2 subtype has been isolated by Vasfi Marandi and Bozorgmehri fard in 1998 and H5N1 viruses have been reported in 2005 in swans, 2006 in backyard chickens, and 2011 commercial ducks in north of Iran by veterinary organization of Iran (24).
The interested clinicians and researches have been invited to address new avian influenza book authored by Mehdi Vasfi Marandi that published by University of Tehran press in 2012. 
Genetic characterization of circulating H5N1 viruses
The hem agglutinin sequences of circulating influenza A (H5N1) viruses are classified into distinct clades. Recent human clade 1 infections, have been limited to Cambodia, Thailand and Viet Nam. Clade 2.1 viruses, have continued to circulate in poultry and have caused human infections in Indonesia. While clade 2.2 viruses, have the most diverse distribution, with outbreaks in birds in over 60 countries in Africa, Asia and Europe and human infections in Azerbaijan, Bangladesh, China, Djibouti, Egypt, Iraq, Nigeria, Pakistan and Turkey. Clade 2.3.4 viruses, have been responsible for human infections in China, Laos Myanmar and Viet Nam. Since September 2008, human infections have been limited to China, Viet Nam, Cambodia, Egypt and Indonesia (1).
A number of recent reports highlight the importance of mutations in H5N1 subtype of AIVs, indicating that these genetic variations may increase the possibility of a new pandemic. Influenza viruses are inherently unstable, due to their segmented RNA genome and the lack of a genetic proofreading mechanism that allows undetected errors that occur during replication. Since the first documentation of human infection with H5N1 subtype AIVs in 1997, the virus has undergone several changes. These changes have influenced the patterns of virus transmission and have spread amongst domestic and wild birds. Human infections are still considered a relatively uncommon event as the virus does not spread easily from birds to humans or from human to human. (20).
The H5N1 viruses have not yet demonstrated the capacity for efficient and sustained human-tohuman transmission, although limited transmission is believed to be the cause of some family clusters of cases (110). Since those sporadic family clusters of H5N1 cases, may be the first suggestion of a viral or epidemiologic change, they are being thoroughly investigated in order to determine any direct human-tohuman transmission of the virus (35). Such clusters involving highly probable human-to-human transmission have been documented in Egypt, China, Thailand, Vietnam, Indonesia and Pakistan (6,12). Furthermore, it was recently observed that undetected H5N1 cases might be occurring in Egypt, given the unusual agespecific and sex-specific case incidence and fatality rates, which can be partly attributed to the existence of undetected fatal or non-fatal atypical or asymptomatic human H5N1 infections (12). Asymptomatic human infections with H5N1 have been also reported from China, Vietnam, Japan, Thailand, and Korea (22).
Tumpey et al., who reconstructed the H1N1 virus of 1918, have identified a number of common points between Spanish H1N1 and recent H5N1 subtype of AIVs. It was concluded that it is especially the polymerase (PA, PB1 &PB2), the hem agglutinin (HA) and neuraminidase (NA) genes that caused the extreme virulence and that the sequences of the polymerase proteins of the 1918 virus differ by only 10 amino acids from the AIVs (20). Human forms of seven out of the 10 amino acids have already been identified in currently circulating H5N1 viruses. It is likely that the other mutations will eventually emerge and make the H5N1 virus better suited for human-to-human transmission.
Another important factor is the change of the HA protein to a binding preference for alpha 2,6 sialic acid, which is the major form in the human respiratory tract. In AIVs, the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, it seems that only a few mutations are needed to make the H5N1 subtype of AIV, as a pandemic virus, with possible mortality rates resembling the rates of the Spanish flu, which killed over 40 million people worldwide. The H1N1 Spanish virus, was initially an AIV, like the H5N1 (19). 
Genetic characterization of circulating H9N2 viruses
During the last two decades, antigenic and genetic analyses of H9N2 isolates showed their gradual and complex evolution. Several distinct sub lineages from the Eurasian lineage have become established in domestic birds. Phylogenetic and genotypical analysis revealed that H9N2 viruses have undergone extensive reassortments to generate multiple novel genotypes with gene segments from different lineages. Notably, previous studies of the phylogenetic diversity of H9N2 viruses have focused on limited periods, regions, hosts or viral lineages, and detailed characteristics of H9N2 viruses have not been well defined. Moreover, H9N2 viruses have evolved into many different lineages and sublineages, but how many genotypes actually exist within H9N2 viruses is still unclear. Some lineages and sublineages have been recognized, such as the Ck/Bei-like lineage and G1 sublineag (14).
Dong et al., (2011), performed a large-scale sequence analysis of 571 viral genomes from the NCBI Influenza Virus Resource Database, representing the spectrum of H9N2 influenza viruses isolated from 1966 to 2009. They demonstrated a panoramic framework for better understanding the genesis and evolution of H9N2 influenza viruses, and for describing the history of H9N2 viruses circulating in diverse hosts. Panorama phylogenetic analysis of the eight viral gene segments revealed the complexity and diversity of H9N2 influenza viruses. The 571 H9N2 viral genomes were classified into 74 separate lineages, which had marked host and geographical differences in phylogeny. Panorama genotypical analysis also revealed that H9N2 viruses include at least 98 genotypes, which were further divided according to their HA lineages into seven series (A–G). Phylogenetic analysis of the internal genes showed that H9N2 viruses are closely related to H3, H4, H5, H7, H10, and H14 subtypes of AIVs. Their results indicated that H9N2 viruses have undergone extensive reassortments to generate multiple reassortants and genotypes, suggesting that the continued circulation of multiple genotypical H9N2 viruses throughout the world in diverse hosts has the potential to cause future influenza outbreaks in poultry and epidemics in humans (5). 
Genetic characterization of circulating H9N2 viruses in Iran
Several researchers in Iran, Karimi et al., Pourbakhsh et al., Ghalyanchi et al., Noroozian et al., Moosakhani et al., Pazani et al., Ghadi et al., Toroghi et al., Kianizadet et al., Shooshtari et al., Dadras et al., Bozrgmehrifard et al., Nili et al., Seyfiabad et al., Vatandour et al., Ebrahimi et al., analyzed different external and internal genes of H9N2 viruses related to different provinces of Iran (2,13,14,15,16,17,24,25,28). The H9N2 viruses used in their studies, belonged to different years. In a few investigation, they are analyzed complete sequence of selected gene. Bashashati and Vasfi Marandi, Emadi and Vasfi Marandi and Golami et al., have recently started to sequence all of 8 genes of two H9N2 AIVs strains isolated in 1998 and 2010. They are analyzing the whole genes of given viruses, in order to finds the best H9N2 virus vaccinal strains for future protection of Iranian poultry flocks against the circulating H9N2 viruses.
Emadi et al. , (2012). were investigated the complete sequences of five NS1 and NS2 genes of various H9N2 strains isolated between 1998 and 2010. Whole sequence of NS genes composed of 890 nucleotides with 230 amino acids. In this regard, only two Iranian strains from GenBank, had 217 amino acids in NS1 protein. It revealed that all Iranian H9N2 strains, subdivided into two distinct sublinages including I & II. Comparative analysis of NS genes of Iranian strains showed that since 2003, it might be originated from Pakistan H7N3 strains; whereas, from 2008, these genes could be originated from Pakistan H9N2 strains. In overall, although the low-pathogenic H9N2 subtype, are permanently circulating from 1998 to date in Iran. However, focusing on NS gene phylogenetic tree of H9N2 strains revealed that in recent years, sublinage II is more circulating in poultry industry of Iran. This epidemiologically variations could be related to vaccination pressure due to of massive vaccination or NS gene reassortment in rural and backyard chickens (9). 
Antiviral susceptibility of AIVs in the world
Until the production of vaccines for prophylaxis against influenza H5N1 virus infection is completed, antiviral drugs are the first line of defense. For the treatment of seasonal influenza, two drug categories are currently commercially available, the neuraminidase (NA) inhibitors: Oseltamivir and Zanamivir, and the matrix protein 2 (M2) inhibitors: Amantadine and Rimantadine. Early administration of these drugs can reduce the severity and duration of humain illness from seasonal influenza viruses (30).
Though clinical data related to H5N1 infections are limited, it has been shown that early administration of NA inhibitors can decrease the severity of the disease and increase the prospects of survival. In case of a pandemic, the H5N1 virus is expected to be susceptible to the NA inhibitors. M2 inhibitors could also be administered against pandemic influenza, however, resistance to these drugs may occur rapidly thus reducing their efficacy against the virus. In addition, a high percentage of currently circulating avian influenza H5N1 strains is already fully resistant to those drugs (31).
WHO has reserved a certain amount of Oseltamivir for use in the first areas affected by an emerging pandemic virus. Based on mathematical modeling studies, the drugs could be utilized for protection purposes at the beginning of a pandemic in order to delay its international spread and gain time to complete the vaccine supply. Influenza surveillance in the affected areas needs improvement, especially regarding the detection of clusters of cases which are closely related in time and place, in order to increase the chances that WHO's rapid intervention will be successful (3,11). Resistance to antiviral drugs in influenza viruses can emerge following medication or may result from natural variation. 
Antiviral drugs production in Iran.
Despite of activity of the numerous pharmaceutical companies in Iran, no one has not been tried to produce antiviral drugs neither for NA inhibitors nor for M2 blocking. However, regardless of strict surveillance of veterinary organization of Iran in illegal application of amatadine, some minority broiler farmers was used this drug to control H9N2 outbreaks. Besides, there are some reports about resistance of various H9N2 strains against amantadine (24). 
Avian influenza vaccine development in the world
One of the major priorities of WHO is to develop candidate vaccines with representative H5N1 viruses from all currently circulating clades. As of February 2009, a number of H5N1 reassortants have completed the regulatory approval. These reassortants belong to clades 1, 2.1, 2.2, 2.3.4 and 4 and have been developed by National Institute for Biological Standards and Control (NIBSC), in United Kingdom; Centre for Disease Control and Prevention (CDC), in USA; Food and Drug Administration (FDA), in USA; and a consortium of St Jude Children's Research Hospital US, University of Hong Kong, in China and National Institute of Allergy and Infectious Disease, in USA. A number of reassortant viruses that belong to clades 2.2, 2.3.2 and 7 are prepared and awaiting regulatory approval and there are two vaccinal viruses including clade 2.3.4 (A/chicken/Hong Kong/AP156/2008) and clade 7 (A/chicken/Viet Nam/ NCDV-03/2008) that have been proposed by WHO for candidate vaccine preparation (32).
To date, there are four licensed pre-pandemic and pandemic vaccines in the European Union (EU). The first approved pre-pandemic vaccine is Prepandrix; it is an H5N1 adjuvant vaccine manufactured by GlaxoSmithKline (GSK) that could potentially protect against a range of different emerging H5N1 strains. The second is Daronrix vaccine, also developed by GSK, which contains inactivated H5N1 virus of the A/Viet Nam/1194/2004 (H5N1) strain. When the WHO declares a pandemic, Novartis is approved by EMEA to adapt Focetria vaccine to contain the pandemic strain. In addition, Baxter's H5N1 vaccine, Celvapan, is the first approved pandemic vaccine that is cell-cultured based. A number of other countries, including US, Australia, Japan and China, also have licensed products (7). 
Avian influenza control In Iran
Vasfi Marandi et al., (27) was formulated an experimental oil-emulsion vaccine was with a ratio of 4 parts oil adjuvant ISA-70 and 1 part formalin inactivated A/Chicken/Iran/ZMT-101(101)/98(H9N2) antigen. Thirty 2-week-old Aryan broilers and thirty two-week-old white Hy-line pullets were vaccinated subcutaneously. The latter was delivered a booster 10 weeks after primary vaccination. All vaccinated and control birds were bled for HI test, at least one week intervals. Half of the birds were challenged via intranasal and intravenous routes with a H9N2 strain at 8 and 27 weeks of age in broiler and layer birds, respectively. A high HI titers were observed in both vaccinated and unvaccinated birds, when examined at 2 weeks post challenge (PC). Viral isolation or shedding from tracheal and cloacal swaps of both vaccinated broiler and layer was decreased at 2 weeks PC, as compared with unvaccinated control birds. All control birds became morbid, and egg production decreased on day 3 PC. The results suggested that the inactivated oil-emulsion H9N2 AI vaccine may be protects both chickens against viral shedding and egg drop in field conditions.
Zamani et al., (29) compared the efficacy of different local and imported killed H9N2 vaccines in expermentall infection in broiler chicken. At present, the all grant parent and breeder flocks of Iran follow a vaccination schedule, programmed by veterinary organ izayion of Iran. Unfortunately, despite of massive vaccination of breeder flocks, the H9N2 strains continues to circulate about in all province of Iran.
Prevention, control and/or eradication are three different goals dealing with both avian influenza (AI) due to H5 and H7 subtypes or velogenic Newcastle disease (vND) outbreaks in commercial poultry of Iran. These goals are achieved through various strategies developed using components of education, biosecurity measures, surveillance and diagnostic activities. The preferred outcome for highly pathogenic avian influenza (HPAI) and velogenic Newcastle disease has been stamping out polices, for which the veterinary organization of Iran, as regulatory authority, has responsibility to declare an emergency and performs the immediate elimination and/or eradication of poultry farms with high mortality suspected by each of velogenic NDV or eventual HPAI pathotype of AIVs including H5 and H7 subtypes. Whereas, the preferred strategy to control low pathogenic avian influenza (LPAI) pathotype of AIV like H9N2 and NDVs are vaccination strategy by inactivated and/or attenuated vaccines. The vaccines used for H9N2 infections in poultry industry of Iran are produced by locally or imported from international vaccine companies. There is not any special regulation for application, production and/or importation of inactivated or recombinant live vaccines of H5 or H7 subtypes in Iran. 

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