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24  |  Perez et al.

          death in challenge studies; however, further studies are needed   and Halvorson, 2003). Estimates of the global impact from the
          to evaluate vaccine effectiveness in viral shedding and transmis-  massive HPAI epizootic of H5N1 in Asia since 2003 run into bil-
          sion and, most importantly the generation of mucosal immunity.   lions (FAO, 2005). More than 100 million birds have either died
          Influenza virus reverse genetics has provided an alternative for   or been killed to contain the outbreak. For East and Southeast
          making live attenuated or inactivated vaccines (Subbarao et al.,   Asian countries, where the outbreak began, the economic impli-
          1995, 2003; Parkin et al., 1997; Takada et al., 1999). One such   cations were tremendous. In 2014–2015, H5 HPAIV caused the
          reverse genetics-generated oil-emulsion inactivated vaccine was   largest poultry outbreak in US history, resulting in the death or
          used against H5N1 viruses circulating in Hong Kong, China   destruction of more than 50 million birds (USDA APHIS, 2016).
          showing excellent results for protection against challenge (Liu et   The outbreak led to losses of 8% and 12% of turkey and egg-laying
          al., 2003b). It also reduced transmission of the challenge virus.   chicken inventories, severely impacting egg and turkey produc-
          The reverse genetics Hong Kong vaccine carried the H5 HA   tions in the country (Ramos et al., 2017). The US government
          gene of currently circulating viruses and an N3 subtype NA, to   allocated almost $1 billion for response/preparedness activities
          differentiate vaccinated from infected birds (DIVA). The DIVA   and indemnity payments, and total cost to the US economy is
          approach was successfully implemented following the 1999 HPAI   thought to be closer to $3.3 billion (USDA APHIS, 2016).
          Italian outbreak (Capua et al., 2003b) in combination with a strict   Countries that are large importers of poultry products may
          territorial control program. A live attenuated influenza vaccine   implement severe import restrictions as a result of outbreaks (or
          (LAIV) containing an HA tag at the C-terminus of the PB1 gene   suspected outbreaks) that ultimately disrupt the market share of
          as a DIVA marker in addition to temperature-sensitive mutations   big poultry exporters. The USA is the second largest exporter of
          in PB1 and PB2 showed to be safe and protective against low- and   poultry in the world, only behind Brazil, exporting approximately
          high-pathogenic influenza strains in chickens (Song et al., 2007).   3 million tons of broiler meat and generating around $3 billion
          The application of a DIVA vaccination policy enables veterinary   dollars revenue per year. The 2014–2015 outbreak resulted in a
          public health organizations to establish that infection is not cir-  ban to US poultry by China, and Brazil emerged as China’s main
          culating any longer and allows the possibility of marketing meat   supplier (Foreign Agricultural Service, 2017).
          obtained from animals vaccinated against an OIE List A disease.

          Economic importance                                   Public health significance
          The economic and social impacts of AI, particularly HPAI,   Although influenza viruses show restricted host range, in the
          depends on the magnitude of the outbreak, the efficiency of the   past decades IAVs of avian origin have caused zoonoses by direct
          measures taken to eradicate the virus, and the relative economic   transmission from birds to humans. Some poultry-adapted
          importance of the poultry sector to the affected country. Epizoot-  strains, such as HPAIV H5N1 and LPAIV and HPAIV H7N9,
          ics of HPAI in commercial farms or large live bird market systems   have shown remarkable ability to cause zoonotic outbreaks. These
          have resulted in the greatest economic impact, a result of direct   zoonotic transmissions pose a significant threat to public health
          deaths caused by infection and disease, deaths due to stamping   because of their inherent disease severity and mortality and the
          out measures and all costs involved with controlling the outbreak.   concern that they could trigger a pandemic if a novel virus shows
          Losses associated with outbreaks of HPAI go beyond the direct   efficient human-to-human transmission. All influenza pandemics
          costs involved with containing the spread of the virus; the poultry   in the last 100 years were caused by viruses with gene segments
          industry can also be affected by temporary loss of consumer confi-  originating from  animals, mostly from  avian species (Tauben-
          dence, decreases in demand, drops in domestic and export prices,   berger and  Morens, 2009).  Land-based birds (quail, chickens,
          and loss of global trade. Economic impact estimates of avian influ-  turkeys, among others), have been proposed as potential ‘ampli-
          enza are usually focused on outbreaks rather than the prolonged   fiers’ of avian/human reassortant influenza viruses (Makarova et
          effects of endemic circulation. These could be substantial and   al., 2003; Perez et al., 2003b, 2005; Pillai et al., 2010; Perez and de
          include costs with continuous biosecurity measures, prolonged   Wit, 2016).
          use of vaccination, and sustained trade restrictions. The breadth   In 1997, 18 people became infected with an H5N1 virus during
          of economic disruption can be even more devastating to smaller   an outbreak of HPAI in Hong Kong. Patients developed symp-
          economies and small or backyard producers.            toms of fever, sore throat, and cough and, in several of the six fatal
            The impact associated with HPAI outbreaks has been tremen-  cases, severe respiratory distress secondary to viral pneumonia.
          dous and is reviewed in Table 1.1. For instance, the 1983–1984   Depopulation of more than 1 million birds in poultry markets and
          H5N2 outbreak in Pennsylvania cost the US government more   chicken farms in December 1997 is thought to have eliminated
          than $60 million to eradicate the disease, with estimated indirect   the virus and prevented new cases (Sims et al., 2003a). However,
          costs of $250 million. Although $40 million were spent in indem-  other H5N1 outbreaks in poultry repeated in Hong Kong in 2001
          nities, producers still had to absorb an additional $15 million in   and 2002 and spread to other countries in Asia, with new human
          non-indemnified losses (Swayne and Halvorson, 2003; Lupiani   cases documented. Countries such as Cambodia, China, Egypt,
          and  Reddy, 2009).  Another  example,  the  cost to  eradicate  the   Indonesia and Viet Nam, where H5N1 HPAIV remains endemic,
          H7N1 virus that caused an HPAI outbreak in Italy in 1999–2000   continue to report occasional human infections (Malik Peiris,
          was approximately $100 million in compensations, and total indi-  2009; Yuan et al., 2014). Since the re-emergence as an epizootic
          rect losses have been calculated in excess of $500 million (Swayne   in poultry in 2003, 860 human cases of H5N1 have been reported
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