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3rd Periodic Report (06/2020 - 11/2021)

Summary of the context and overall objectives of the project

Avian influenza is a major impediment to healthy and profitable poultry production in Europe and other parts of the world. The dynamics of avian influenza virus (AIV) infection in poultry populations have changed dramatically in recent years, resulting in major mortality of birds and significant economic losses. 
In addition to the risk for poultry holdings worldwide, the potential for animal influenza viruses to become pandemic in humans is of great concern to public health and underlined by reports on human infections with HPAIV H5N6 in China and HPAIV H5N8 in Russia. In addition, poultry-origin viruses in pigs are of concern for public health, e.g.  the emergence of a reassortant H1N1 influenza virus with gene segments from human, pig, and avian viruses in 2009 which caused the first influenza pandemic of the 21st century.
The overall objective of DELTA-FLU is to determine the key viral, host-related, and environmental factors that determine the dynamics of avian influenza in poultry and other host species, with the goal of improving prevention and control strategies against this important disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our research continued to be focused on the key questions of DELTA-FLU yielding new achievements important for influenza science. Using GSM-GPS loggers the movement of wild ducks was followed. By receiving tracks from Eurasia and North America gaps could be filled regarding the overlap of migratory birds in Siberian breeding grounds. These studies showed that jointly used Northern breeding areas of wild bird populations may lead to HPAIV transmission and spread to different wintering places of these birds in Eurasia. Moreover, studies with wild birds have been performed to investigate levels of virulence, patterns of excretion and effects of prior exposure to HPAIV. Ducks infected with a less virulent HPAIV were shown to develop immunity that was protective against a subsequent infection with a more virulent HPAIV later. Additional studies were performed to determine the interaction between raptors and HPAI H5 virus during field outbreaks.
It was shown that domestic duck populations are an important intermediate host population for HPAI viruses switching from wild waterbirds to terrestrial poultry. Ecological and environmental factors associated with AIV incursion from wild birds to poultry were investigated. Visual and audio census methods in addition to camera traps were used to generate a database which provides input for models to enable prediction of species distribution close to poultry farms in specific environments. Positive sediment and environmental samples have been collected from sheds of an H6N5 AIV infected poultry farm in the UK. A database with more than 2,000 entries could be generated and is already applied in a current outbreak in British Columbia to characterize AIV on site. Personal hygiene measures seem to have a huge impact on prevention of virus incursion.
The impact of host genetics and immunity on the outcome of an AIV infection, the potential differences of the immune response in response to genetically highly related LPAIV and HPAIV pairs and the importance of host-related factors especially of the host immune response that drive evolution of virus pathogenicity was studied. Comparative infection studies were performed to reveal the early stages of transcriptional responses. The molecular basis of LPAIV to HPAIV transition was investigated identifying virulence determinants other than the HA segment were found to be relevant for expression of a highly virulent phenotype.  These additional virulence determinants differ dependent on virus strain and host species. Furthermore, different models for in vitro virus characterisation have been established that contribute to minimize in vivo trials. It was also studied whether co-infections of circulating LPAI H7N9 and endemic H9N2 viruses facilitated the emergence of HPAI H7N9 virus in China in 2017. The results suggest that although genetic reassortment may occur frequently between different avian influenza viruses upon co-infection events, not all novel reassortant viruses possess sufficient fitness for onward transmission to co-housed contact chickens. Virulence studies have been carried out to investigate the pathogenicity of poultry-origin viruses in pigs. The results revealed that H9N2 and H3N1 viruses were not efficient in replication in pig nasal mucosa informing risk assessment of potential adaptation of bird viruses to mammals.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The collection and analysis of migration data will contribute to an improved understanding of connectivity between Asia and Europe via migratory birds as a potential portal of AIV incursion, which has a high impact on all future risk analyses and will allow new insights into AIV ecology. The results will form a basis for more targeted temporal and geographical surveillance of AIV in migratory waterfowl and identification and strengthening of weak spots in biosecurity around poultry holdings. 
The database on notifiable AIV outbreak data since 2005, the collection of data about the ecology of the wild bird-poultry interface, and the experimental modelling of the biosecurity barriers around poultry holdings elucidating possibly unrecognized routes by which AIV can cross the biosecurity barriers around poultry holdings, as well as variations among AIV strains in stability on fomites and ability to switch from anseriform to galliform hosts. 
Understanding the underlying innate immune characteristics of poultry and the results obtained in AIV infection experiments will elucidate the relative importance of different components of the innate immune system against AIV infections, and the impact of the pre-infection adaptive immune status of poultry on the early detection and evolution of AIV. This will provide the necessary knowledge for future risk assessments and control strategies. This is of high importance since both the number of AIV introductions into Europe and the number of connected outbreaks in wild birds and poultry are as high as never before. The socio-economic impact of our data is therefore much higher as also the impact of AIV has so much increased within the last few years. Besides the commercial poultry farming it has also a considerable influence on the private breed of poultry and also the wild bird area, especially as far as protected species are concerned. It is therefore directly influencing and helping the commercial and the private sector and people who are engaged in those areas. The knowledge can then also be used by international organizations and the measures that have now been developed can also be taken into consideration in national and EU legislation. Finally, private industry working in the poultry field might implement measures developed here within the consortium to improve the biosecurity measures and lower the introduction rates.
Our studies will also help to assess the zoonotic risk and to improve the understanding of human spill over infections or the development of influenza virus strains with pandemic potential.
The establishment of ex vivo explants from chicken and ducks and of the porcine respiratory tract explant system is an effective way of representing the in vivo conditions and of reducing the number of animals used in experiments. This is of high impact for animal welfare ethics and is very much in compliance with the 3R principles.