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Avian influenza H5N1 clade 2.2.1 and H5N8 clade 2.3.4.4 viruses were introduced into Egypt by wild birds in February 2006 and November 2017, respectively. The H5N1 virus has evolved into several genetic and antigenic distinct clades/subclades: 2.2.1.1 clade dominated viruses in the commercial sector of poultry, while 2.2.1.2 was prevalent in humans and backyards. Likewise, similar diversity was seen among the newly emerging H5N8 viruses. These viruses caused significant losses in the poultry industry and posed a public health threat. In this dissertation, some aspects of the epidemiology of H5N1 and H5N8 viruses in poultry in Egypt are described. In chapter two, a novel H5N1 was isolated from commercial turkey flock vaccinated with inactivated H5 vaccines. The virus was genetically distinct from the parent 2.2.1.2 viruses and therefore was allocated in a new phylogroup designated 2.2.1.2A along with viruses from poultry in Israel and Gaza. Viruses in this group carried mutations in the receptor binding domain resembling those 2.2.1.2 viruses isolated from humans in Egypt. In addition to other mutations in the immunogenic epitopes correlated with antigenic drift of 2.2.1.1 viruses in vaccinated birds. The spread of such viruses in poultry in Egypt and neighboring countries emphasized the need to revise the current control measures (i.e. massive vaccination) to mitigate the socioeconomic losses in both poultry and humans. In chapter three, the effect of climatic and biological factors on the endemicity of H5N1 in Egypt were investigated. The ambient temperature and increased thermostability of the involved strains are probably two important factors for persistence and/or spread of the virus in poultry in Egypt. In addition, while Muscovy ducks were severely affected and exhibited high mortality after infection with 2.2.1.1 and 2.2.1.2a H5N1 viruses, Pekin ducks were apparently healthy and excreted viruses for up to 14 days post inoculation suggesting an important role as a reservoir. In chapter four, the first record for isolation of the panzootic H5N8 viruses of clade 2.3.4.4b from four commercial poultry farms in early 2018 was described. Strikingly, the four viruses possessed different gene constellations giving evidence for multiple and independent introductions of H5N8 viruses into Egypt. Interestingly, viruses isolated from commercial poultry were different from the H5N8 viruses isolated from captive birds in Egypt in late 2017. The Egyptian H5N8 viruses were closely related to divergent avian influenza viruses isolated from wild birds and commercial poultry in Europe, Asia and Russia. Findings described in this dissertation are important to better understand the epidemiology of the endemic and emerging avian influenza viruses in Egypt, spillovers to poultry in neighboring countries and multiple introductions from Europe and Asia into Africa. Continuous monitoring and surveillance is needed. Effective biosecurity measures should be applied to prevent the infection of poultry with AIV and /or to reduce the spread of infection.