Control of Avian Influenza in Poultry with Antivirals and Molecular Manipulation

43 Pages·2015·0.65 MB·English

Control of Avian Influenza in Poultry with
Antivirals and Molecular Manipulation

El-Sayed M. Abdelwhab and Hafez M. Hafez

1 Introduction

Influenza A virus, the only orthomyxovirus known to infect birds, are negative-sense,
single-stranded, enveloped viruses contain genomes composed of eight separate ribonucleic
acid (RNA) segments encode for at least 10 viral proteins. Two surface glycoproteins; hemag-
glutinin (HA) and neuraminidase (NA) are playing a vital role in attachment and release of the
virus, respectively (Palese & Shaw, 2007). To date, 18 HA and 11 NA subtypes of avian influ-
enza viruses (AIV) have been detected. All AIV subtypes except H17N10 (Tong et al., 2012)
and H18N11 (Tong et al., 2013) - which have recently been identified in bats - are known to
infect birds. According to their pathogenicity for poultry, AIV are divided into low pathogenic
(LPAIV) resulting in mild or asymptomatic infections and highly pathogenic (HPAIV) causing
up to 100% morbidity and mortality (Swayne, 2009). Hitherto, only few strains of H5 or H7
subtypes fulfilled the defined criteria of high pathogenicity which potentially evolve from low
virulent precursors (Lupiani & Reddy, 2009). Constant genetic and antigenic variation of AIV
is an intriguing feature for continuous evolution of the virus in nature (Brown, 2000). Gradual
antigenic changes due to acquisition of point mutations known as “antigenic drift” are com-
monly regarded to be the driving mechanism for influenza virus epidemics from one year to
the next. However, possible “antigenic shift or reassortment” of influenza virus occurs by ex-
change genes from different subtypes is relatively infrequent, however it results in severe
pandemics (Ferguson et al., 2003).
HPAIV H5N1 is responsible for magnificent economic losses in poultry industry and
poses a serious threat to public health (Webster et al., 1992; Peiris et al., 2007). Measures to con-
trol the virus in domestic poultry are the first step to decrease risks of human infections
(Mumford et al., 2007). Enhanced biosecurity measures, surveillance, stamping out and
movement restriction are the basic principles for control of HPAIV epidemics in poultry (Yee
et al., 2009). However, mass depopulation of poultry in the face of an outbreak led to high eco-
nomic losses for governments, stakeholders and consumers (Capua & Marangon, 2003; Capua
& Alexander, 2006; Swayne et al., 2011).

2 Vaccines

The use of vaccines as an option for the control of AI in poultry was not applied in the field
until 1995. During the outbreak of HPAI H5N2 in 1994-1995 Mexico applied large-scale vac-
cination campaign using inactivated homologous H5N2 vaccines (Garcia et al., 1998; Lee et al.,
2004). Also, Pakistan used inactivated H7N1 vaccines to control HPAI H7N1 outbreaks in 1995
(Naeem & Hussain, 1995; Naeem et al., 1999; Naeem & Siddique, 2006). Thereafter the use of
vaccines as emergency, prophylactic or routine strategy was frequently reported to control H5,
H7 and H9 viruses. The inactivated H7N3 and H7N1 vaccines as a part of the intervention
plan were used in Italy against H7N1 and H7N3 in 2000-2002, respectively (Capua &
Marangon, 2007), in Pakistan against H7N1 in 2003-2004 (Naeem & Siddique, 2006), in USA
against LPAIV H7N2 in 2003 (Capua & Alexander, 2004) and in North Korea against H7N7 in
2005 (Swayne, 2012a). Recently, inactivated H7N3 vaccines were used in Mexico to control the
ongoing outbreaks of HPAI H7N3 since 2012 (Kapczynski et al., 2013). After the re-emergence
of the Asian H5N1 in 2003, vaccines were used in many countries to mitigate the economic
and social impact of the disease. Currently, four countries use different H5N1 vaccines in
poultry: China since 2004, Indonesia since 2004, Viet Nam since 2005 and Egypt since 2006
(Swayne, 2012a). Occasionally, vaccines for HPAI H5N1 have been used for short periods in
Cote d’Ivoire, France, Kazakhstan, Mongolia, Netherlands, Pakistan, Russia and Sudan
(Swayne, 2012a). Furthermore, 10 countries used inactivated H9N2 vaccines in poultry. Cana-
da and USA used vaccines to control H1 and H3 swine influenza viruses in turkeys. Germany,
South Africa and USA used vaccines to control H6 outbreaks and also USA used H2 and H4
vaccines (Swayne, 2012a). The use of bivalent H5-H7 and H7-H9 inactivated vaccines were
used in Italy (Capua & Alexander, 2004) and Pakistan (Capua & Marangon, 2007), respective-
ly.
The conventional inactivated whole virus vaccines are the currently the most used vac-
cines in poultry and it was expected to continue for the next 10 years (Swayne, 2012a;
Spackman & Swayne, 2013). However, using recent molecular techniques a considerable num-
ber of vaccines with high efficiency to protect poultry against different AIV infections have
been developed. Recombinant viral-vectored vaccines containing the HA and rarely NA of
AIV expressed in fowl pox virus (FPV), Newcastle disease virus (NDV), herpes virus of tur-
keys (HVT), infectious laryngotracheitis virus (ILT), adenovirus or baculovirus have been fre-
quently described (Capua & Marangon, 2007; Abdelwhab et al., 2014). So far, only H5-
expressing viral vectored vaccines have been used in the field to control HPAI H5N1 and
H5N2 outbreaks in poultry (i.e.: in China, Egypt and Mexico) (Bublot et al., 2007; Swayne,
2012a).
The major advantages of the vaccine to control AIV in poultry are to reduce shedding of
the virus, morbidity, mortality, bird-to-bird transmission and to limit decrease in egg produc-
tion. Moreover, viral-vectored vaccines, can be applied by mass vaccination (e.g. spray, drink-
ing water, etc.) to protect birds simultaneously against several poultry viral pathogens. Also,
as a form of live vaccines, the recombinant vaccines elicit not only humoral but also mucosal
and cellular immune responses. The generation of recombinant or genetically-modified vac-
cines can overcome the availability of antigenic match between circulating and vaccine strains
as well as providing a tool to differentiate between infected and vaccinated animals "DIVA"
(for more information the readers are referred to (Suarez, 2005; Swayne, 2012a; 2012b;
Spackman & Swayne, 2013; Abdelwhab et al., 2014).
Nevertheless, several challenges facing the efficiency of the vaccine to control the
HPAIV H5N1 outbreaks have been reported: (1) Vaccine is HA subtype specific and in some
regions where multiple subtypes are co-circulating (i.e., H5, H7 and H9), vaccination against
multiple HA subtypes is required (Suarez & Schultz-Cherry, 2000). (2) Vaccine-induced anti-
bodies hinder routine serological surveillance and differentiation of infected birds from vac-
cinated ones requires more advanced diagnostic strategies (Suarez, 2005). (3) Vaccination may
prevent the clinical disease but can’t prevent the infection of vaccinated birds, thus continuous
“silent” circulation of the virus in vaccinated birds poses a potential risk of virus spread
among poultry flocks and spillover to humans (Savill et al., 2006; Naeem et al., 2007; Capua &
Alexander, 2008; Hafez et al., 2010). (4) Immune pressure induced by vaccination on the circu-
lating virus increases the evolution rate of the virus and accelerates the viral antigenic drift to
evade the host-immune response (Lee et al., 2004; Boni, 2008; Escorcia et al., 2008; Cattoli et al.,
2011a; Cattoli et al., 2011b; Park et al., 2011; Lee et al., 2012a; Lee & Song, 2013). (5) After emer-
gence of antigenic variants, the vaccine becomes useless and/or inefficient to protect the birds
and periodical update of the vaccine is required (Lee et al., 2004; Abdelwhab et al., 2011; Grund
et al., 2011; Kilany et al., 2011; Rauw et al., 2011). (6) Vaccine-induced immunity usually peaks
three to four weeks after vaccination and duration of protection following immunization re-
mains to be elucidated (Swayne & Kapczynski, 2008). (7) Maternally acquired immunity in-
duced by vaccination of breeder flocks could interfere with vaccination of young birds (De
Vriese et al., 2010; Kim et al., 2010; Sarfati-Mizrahi et al., 2010; Maas et al., 2011; Abdelwhab et
al., 2012). (8) Other domestic poultry (i.e., ducks, geese, turkeys), zoo and/or exotic birds even
within the same species (i.e., Muscovy vs. Pekin ducks) respond differently to vaccination
which have not yet been fully investigated compared to chickens (Oh et al., 2005; Philippa et
al., 2005; Tian et al., 2005; Bertelsen et al., 2007; Kapczynski & Swayne, 2009; Koch et al., 2009;
Lecu et al., 2009; Cagle et al., 2011). (9) Concomitant or prior infection with immunosuppres-
sive pathogens or ingestion of mycotoxins can inhibit the immune response of AIV-vaccinated
birds (Robinson & Easterday, 1979; Hao et al., 2008; Sun et al., 2009; Hegazy et al., 2011). (10)
For the recombinant vaccines, keeping cold-chain is pivotal, it can cause or aggravate respira-
tory tract infections and reassortment with wild type viruses can not be totally excluded. (11)
And last but not least, factors related to vaccine manufacturing, quality, identity of vaccine
strain, improper handling and/or administration can be decisive for efficiency of any AIV
vaccine (Swayne & Kapczynski, 2008; Swayne, 2009).
Therefore, presence of new alternative and complementary strategies target different AIV
serotypes/subtypes/drift-variants should be encouraged. Insights into possible alternative ap-
proaches for control of AIV in poultry particularly against the HPAI (H5N1) subtypes are de-
scribed below.

3 Antivirals

3.1 Chemotherapy

The use of chemotherapeutic agents for control of AIV in poultry was concurrently studied
just after discovering their anti-microbial effects (Moses et al., 1948; Tolba & Eskarous, 1959). In
the last four decades attention was paid to the M2 blockers and neuraminidase inhibitors
(NAIs), the commonly used antivirals in control of influenza viruses in human, to be used in
eradication of AIV in poultry (Table 1).
On one hand, many antivirals had a potent activity against all subtypes of AIV as
prophylaxis or therapeutic treatment in a wide range of animals including birds. The protec-
tion starts relatively rapidly but varies according to the stage of infection. Some of these anti-
influenza drugs are cheap and can be given by mass administration (e.g. feed, water, etc.). On
the other hand, the emergence of resistant mutants and subsequently hazards of kicking out
cornerstone antivirals in case of pandemic are the most disadvantages. As described below,
some antivirals require a long application period to be effective (e.g. Amantadine HCL) or are
very expensive in a flock level (e.g. oseltamivir). Moreover, the majority of the novel antivirals
were tested only in cell culture and rarely in birds (Table 1). In addition, residues in meat and
eggs and compliance with other medical agents are not fully addressed (Table 2).

M2 Blockers (Adamantanes)
Amantadine hydrochloride and rimantadine are two M2 blockers which interrupt virus life
cycle by blocking the influx of hydrogen ions through the M2 ion-channel protein and prevent
uncoating of the virus in infected host-cells (Kato & Eggers, 1969; Kamps & Hoffman, 2006;
Sugrue et al., 2008).

3.1.1 Amantadine

Amantadine is one of the cheapest anti-influenza drugs. The prophylactic activity of aman-
tadine in poultry was firstly studied by Lang et al. (1970) in experimentally infected turkeys
with an HPAIV H5N9 isolated in 1966 from Ontario, Canada. Optimum prophylaxis was ob-
tained only when amantadine was administered in an adequate, uninterrupted and sustained
amount from at least 2 days pre-infection to 23 days post-infection. During H5N2 outbreaks in
Pennsylvania, USA in early 1980s, one of control proposals was the use of amantadine as a
therapeutic and/or prophylactic approach. Under experimental condition, amantadine given
in drinking water was efficacious to decrease morbidity, mortality, transmissibility and limit
decrease in egg production (Webster et al., 1986; Beard et al., 1987). Nonetheless, all recovered
birds were susceptible to reinfection (Lang et al., 1970; Webster et al., 1986; Bean et al., 1989)
and subclinical infection was reported in most of treated birds (Lang et al., 1970). Importantly,
amantadine lost its effectiveness as amantadine-resistant mutants emerged within 2–3 days of
treatment and killed all in-contact chickens. Amantadine-resistant strains were irreversible,
stable and transmissible with pathogenic potential comparable to the wild-type virus. Even
more, the resistant mutants replaced the wild-type virus and became dominant (Scholtissek &
Faulkner, 1979; Bean & Webster, 1988; Bean et al., 1989). It is worth pointing out that several
subtypes of AIV including the HPAIV H5N1 that currently circulate in both humans and birds
around the world are mostly resistant to amantadine (Bright et al., 2005; Ilyushina et al., 2005;
Bright et al., 2006; Cheung et al., 2006; Hurt et al., 2007; He et al., 2008; Lan et al., 2010; Tosh et
al., 2011). A recent study indicated that the frequency of H5N1 amantadine-resistant variants
in humans from 2002 to 2012 was approximately double (62.2%) compared with the number of
resistant strains of avian origin (31.6%) (Govorkova et al., 2013), which has been also con-
firmed in-vitro (Nguyen et al., 2013; Wang et al., 2013). Since the late 1990s, positive selection of
amantadine-resistant HPAI H5N1 viruses in poultry in China has been proven to be increased
due to extensive illegal application of the relatively inexpensive amantadine by some farmers
to control HPAIV H5N1 (and LPAIV H9N2) infections in chickens (Cyranoski, 2005; Parry,
2005; Sipress, 2005; He et al., 2008; Huang et al., 2009). Hence, rapid selection of amantadine-
resistant variants threatens the effective use of the drug for control of human influenza epi-
demics and/or pandemics (Wainright et al., 1991), therefore the extra-label use of amantadine
in poultry was banned by all concerned international organizations (WHO, 2005; CDC, 2006).
References (Lang et al., 1970; Scholtissek & Faulkner, 1979; Webster et al., 1986; Beard et al., 1987; Bean & Webster, 1988; Bean et al., 1989; Wainright et al., 1991; Bright et al., 2005; Ilyushina et al., 2005; Bright et al., 2006; Cheung et al., 2006; Hurt et al., 2007; He et al., 2008; Lan et al., 2010; Tosh et al., 2011; Nguyen et al., 2013; Wang et al., 2013) (Webster et al., 1985; Cao et al., 2013; Hai et al., 2013) (Leneva et al., 2000; Meijer et al., 2004; de Jong et al., 2005; Ward et al., 2005; Kamps & Hoffman, 2006; Kaleta et al., 2007; McKimm-Breschkin et al., 2007; Yen et al., 2007; Earhart et al., 2009; Hill et al., 2009; Moscona, 2009; Smith, 2010; Kayali et al., 2011; Lee et al., 2011; Orozovic et al., 2011; Brojer et al., 2013; Gillman et al., 2013; Govorkova et al., 2013; Leang et al., 2013; Younan et al., 2013) (Meijer et al., 2004; Kamps & Hoffman, 2006) (Sun, 2007; Waldmann et al., 2014) (Li et al., 2011) (Rashad et al., 2010a; Rashad et al., 2010b; Flefel et al., 2012) (Bodian et al., 1993; Hoffman et al., 1997; Russell et al., 2008; Bliu et al., 2012; Antanasijevic et al., 2013; Shen et al., 2013) (Bliu et al., 2012) (Luo et al., 1996) (Basu et al., 2014) (Liu et al., 2011; Li et al., 2012)
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Antiviral M2 Blockers (Adamantanes) Amantadine Rimantadine Neuraminidase Inhibitors (NAIs) Oseltamivir Zanamivir Inhibitors targeting the HA protei SA analogs Neo6 compound Synthetic derivatives of pyrazolopyrimidine nucleoside, pyrazole, pyridazinone, oxadiazole, triazole, thiazolidine and thioxopyrimidine TBHQ FEB BMY-27709 MBX2329 & MBX2546 CL-385319
(O'Keefe et al., 2003; Smee et al., 2007; Smee et al., 2008) (Kiso et al., 2010a; Kubo et al., 2010; Ikematsu & Kawai, 2011; Shobugawa et al., 2012; Ison, 2013; Samson et al., 2013) (Beigel & Bray, 2008; Udommaneethanakit et al., 2009; Sorbello et al., 2012; Cao et al., 2013; Hai et al., 2013; Hu et al., 2013; Ison et al., 2013; Kamali & Holodniy, 2013; Nguyen et al., 2013; Yen et al., 2013) (Furuta et al., 2002; Takahashi et al., 2003; Sidwell et al., 2007; Smee et al., 2009; Boltz et al., 2010; Kiso et al., 2010b; Sleeman et al., 2010; Smee et al., 2010; Furuta et al., 2013) (Barnard et al., 2007; De Clercq & Neyts, 2007; Beigel & Bray, 2008; Gilbert & McLeay, 2008; Smee et al., 2008; Boltz et al., 2010; Smee et al., 2010; Samson et al., 2013) (Sidwell et al., 2005; Boltz et al., 2010) (Jablonski et al., 2012) (Jablonski et al., 2012) (Zhirnov et al., 1982) (Becker et al., 2012) (Belser et al., 2007; Chan et al., 2009; Triana-Baltzer et al., 2009; Zhang, 2009; Triana-Baltzer et al., 2010; Larson et al., 2011; Moss et al., 2012; Nguyen et al., 2013) complex) (Sood et al., 2012) (Gangopadhyay et al., 2011) (Shang et al., 2010) (Barbour et al., 2006; Barbour et al., 2011)
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Cyanovirin Cell culture, mice, ferrets Inhibitors targeting the HA protein Laninamivir Cell culture, humans, mice Peramivir Cell culture, humans, mice Inhibitors targeting the polymerase protein Favipiravir Cell culture, humans, mice Ribavirin Cell culture, humans, mice Viramidine Cell culture, humans, mice Inhibitors targeting the NS1 protein HENC Cell culture NSC125044 Cell culture Inhibitors targeting host furin proteases Aprotinin Cell culture, chickens Inhibitor 15 Cell culture Inhibitors targeting host sialic acid DAS181 Cell culture, humans, mice, ferrets Herbs (Direct effect, targeting the HA protein; RNA synthesis, R Eugenia jambolana Cell culture, embryonated chicken eggs Menthol, eucalyptol and Computational analysis ormosinine NAS preparation Chickens Eucalyptus, peppermint Chickens
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Green tea (Catechins) Statin/caffeine Stachyflin Ribes nigrum folium Capparis sinaica Veill Aloe hijazensis Red Sea grass Thallasode ciliatum Phellinus igniarius Isatis indigotica Andrographis paniculata Lycoris radiata Table 1: !
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Limitations HA subtype specific hinder routine serological surveillance (specially homologous vaccines) individual application (e.g.: by injection) “silent” circulation of the virus in vaccinated birds can’t be totally prevente immunity peaks three to four weeks after vaccination duration of protection is variable maternal immunity interferes with vaccination of young birds variable response among domestic poultry species or types elicit humoral immunity only affected by immunosuppression affected by vaccine manufacturing, handling and/or administration increas the antigenic drift of the virus due to immune pressure ineffective against antigenic-drift variants periodical update of the vaccine is required HA subtype specific “silent” circulation of the virus in vaccinated birds can’t be totally prevente duration of protection is short immunity (due to maternal, prior vaccination or infection) against the vecto virus interferes with vaccination of young birds not suitable for all types of birds (e.g.: ILT only for chickens) variable response among domestic poultry species or types affected by immunosuppression keeping cold-chain is critical implication in respiratory illness is not uncommon reassortment with wild type virus can not be totally excluded increases the antigenic drift of the virus due to immune pressure ineffective against antigenic-drift variants periodical update of the vaccine is required
Advantages decrease shedding of the virus decrease morbidity and mortality decrease bird-to-bird transmission increase bird resistance to disease reduce virus replication limit drop in egg production mass administration (e.g. spray, drinking water, etc.) protect birds simultaneously against several poultry viral pathogens immunity peaks quickly after vaccination elicit humoral, mucosal and cellular immune responses overcome the availability of antigenic match between circulating and vaccine strains provide a tool for "DIVA"
me es) nt A on s
Inactivated vaccines: Homologous (carrying the sa HA and NA gen or heterologous (carrying differe NA genes) Recombinant vaccines: Expression of H (and NA) genes FPV, NDV, ILT, HVT, adenoviru or baculovirus
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Hazards of kicking out cornerstone antivirals in case of pandemic Emergence of resistant mutants Require long application period to be effective Expensive in flock level (Oseltamivir) Residues in meat and eggs was not fully addressed Compliance with other medical agents need to be considered Extraction is very expensive Affection with antigenic changes, herb-drug interactions, cytotoxicity and biochemical traits were not fully investigated Extraction methods, preparation, purity of the crude extracts greatly influence the efficacy. Batch-to-batch variations are high due to variable plantations conditions. Animal models of infection are limited Efficacy against AIV particularly HPAIV is still questionable Instability High production costs No mass production Field application limitations Specificity to the viral genome without interference with the host genome and non-specifically inhibition of cellular gene activity is critical. Delivery to the host, costs, mass production, storage and handling of the fin products consider questionable aspects. Possibility for arise of mutants with the ability to evade the siRNA activity should not be fully guaranteed Quickly degraded in-vivo
Rapid protection Mass administration (feed, water) Cost-effective for individual birds (amantadine HCL) Suitable for all types of birds against all types of AIV Direct antiviral activity Immunoadjuvant effect Additional effects as antioxidants, anti-inflammatory, etc. No adverse effects on body weight, egg production Direct and indirect antiviral activity Immunoadjuvant effect Dual use as a vaccine-vector and immunomodulator Not affected by antigenic changes Broad spectrum antiviral activities Inhibition of any influenza subtype/serotype/variant High specificity to particular strain/subtype/variant Do not require intact immune system Use as a prophylactic and/or
Chemotherapy M2 Blockers (Amantadine and Rimantadine) and Neuraminidase inhibitors (Oseltamivir and Zanamivir) Natural Antivirals Herbs Probiotics Avian Cytokines RNA interference
Antivirals Molecular approaches
y
or n
Induce a transient & short-term protection and multiple-dose is required In-vivo research studies still missing Results on the contribution of the Mx gene to AIV resistant are contradict Resistant breeds are mostly low producer native breeds. Interrelation of disease-resistance and production should be weighed Studies have been conducted only on a limited number of native breeds i some countries Replacement of backyard flocks Consumer preferences Food safety Regulatory approval Costs of production Mutations of AIV pproaches for control of avian influenza viruses in poultry.
a
therapeutic Few breeds of chickens and ducks can survive challenge with HPAIV in nature Although all infected transgenic birds succumbed to the infection however the virus did not spread to the in-contact transgenic and non-transgenic cagemates ntages and limitations of different
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Naturally resistant birds (Myxovirus Mx resistant gene and other candidate genes) Transgenic birds Table 2: A
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