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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