Download L3 The current situations and control strategies of avian influenza

L3 The current situations and control strategies of avian influenza,Newcastle
disease and infectious bronchitis in poultry in China
Xiufan Liu
Animal Infectious Disease Laboratory, College of Veterinary Medicine,Yangzhou University, China
E-mail：[email protected]
The rapid development and growth in poultry industry in China in the past two decades have brought
about several big challenges, one of which is the poultry disease problem. The inherited structural features of the poultry industry greatly affect the disease management. In this review we will discuss three
most important diseases for poultry industry in China: the Asian H5N1 highly pathogenic avian influenza (HPAI), Newcastle disease (ND) and infectious bronchitis (IB). The epidemiology features and the
pathogen evolution, the control strategies and vaccine development for each of these diseases will be addressed.
H5N1 HPAI
Although a number of subtypes of avian influenza viruses (AIVs) including H1, H3, H4, H5, H6, H7,
H9, H10, and H11 have been isolated from poultry flocks in China in the past two decades, the H5N1
highly pathogenic avian influenza (HPAI) has the most important economic impact to poultry industry
and imposes great threat to public health (3, 6, 9). This Asian lineage H5N1 HPAI virus has spread to more
than 63 countries in Asia, Europe and Africa since its first emergence in 1996 in Guangdong province,
China (1, 3, 22, 24, 31) while its most recent descendants of H5N8 viruses have transmitted to more than 10 countries in Asia, Europe and North America since 2014 and generated novel reassortant H5N2 viruses in
North America (3, 13, 21). The Asian lineage H5 HPAI has become enzootic and persists more than ten years in
poultry flocks in several countries including China (9, 23, 24).
Epidemiology features and virus evolution
The Asian lineage H5N1 HPAI virus was first detected from diseased geese in Guangdong Province in
1996 (31), and has been repeatedly detected in poultry in Southern China since then (3). Up to Jan. 2016, nearly 200 outbreaks have been reported in more than 20 provinces covering most major poultry raising areas
of the country and the H5N1 virus has become enzootic in poultry and wild birds since 2004 (http://www.
oie.int/animal-health-in-the-world/update-on-avian-influenza/2016/). Vaccination has been an important
component in the control strategy against H5N1 HPAI in poultry in China since 2004 (3, 9, 23, 24). The H5N1
HPAI in China shares the following epidemiology features associated with the inherited structural and
trading characteristics of the poultry industry. Firstly, outbreaks mainly occur in small-scale farms and
backyard level raisings which are very popular and in huge number, because their vaccination coverage
and biosecurity measures are relatively poor when compared with the medium to large scale operations
(3)
. Secondly, the domestic waterfowl which are in huge quantity (3.8 to 4.0 billion) and largely in free
range, play a very important role in the transmission and maintenance of H5N1 HPAI in poultry since
both ducks and geese usually demonstrate much lower immune response to vaccination and are less protected when compared with chickens (3). In addition, almost all strains of Asian lineage H5N1 HPAI virus
are highly pathogenic to chickens, while they vary greatly in virulence to ducks and geese, from avirulent to very virulent (3, 5, 8, 33). So, domestic waterfowl can be asymptomatic carriers for some H5N1 viruses which are nonpathogenic for waterfowl but highly pathogenic for chickens. They can also be a good
reservoir for AIVs to generate novel viruses by reassortment (5, 33). Thirdly, mass trading in live poultry
markets (LPMs), either wholesales or retails, which are very popular and scattered all over the major
production areas contribute greatly to the persistence of H5 HPAI in poultry as evidenced by the fact
that the virus detection rate in LPMs is much higher than on farms(3, 33). Fourthly, outbreaks in vaccinated
poultry flocks are mostly associated with the antigenic drift of the circulating field viruses from vaccine
strains which become less protective as the former are constantly evolving (3, 5, 9, 23, 26, 29).
The HA gene of Asian lineage H5N1 virus changes much more rapidly in endemic area with selective
pressures than that of any other subtypes of AIV in poultry (3, 24). This genetic change is correlated with an14
tigenic drift (23). To address all the genetic changes of the H5 gene, a revised nomenclature system, the
clade system was proposed (26-29). Each clade or subclade is at least 2% different in nucleotide sequence.
The H5 virus has evolved into 10 clades (0- 9) in China since 1996. As the time passed, some of the
clades wan out while others persist and continue to evolve into subclades of different order (26- 29). The
prevalent clades or subclades are dynamic scenarios that vary from year to year and from area to area. In
the past five years, H5 viruses of fourth order subclades 2.3.2.1 and 2.3.4.4 and second order subclade
7.2 circulated concomitantly in poultry flocks in China while the prevailing one varied with time (29). On
the other hand, the H5N1 virus has reassorted with other subtypes of AIV to have generated a number of
novel AIVs which bear the Asian lineage H5 HA gene but have different NA subtypes and internal gene
constellation since 2008 (5, 9, 33). Therefore, H5N2, H5N5, H5N6 and H5N8 subtypes HPAIVs bearing different subclades of Asian lineage H5 gene in addition to original H5N1 virus were frequently isolated
from poultry in China in the past five years (10). Thus, the H5 HPAI outbreaks in China are very complicated: not only induced by H5N1 viruses of different subclades but also induced by H5 viruses bearing
different subtypes of NA gene.
The control strategies and vaccine development
Because of the inherited structure features of the poultry production and the trading chain together
with the insufficient veterinary service resources in China, the initial efforts targeted for the immediate
eradication of H5N1 HPAI by culling infected and contact birds and an emergency vaccination program
in buffer zones of the outbreak areas in 2004 proved to be unsuccessful (3, 23, 24). Soon after, the control
strategy was replaced by a compulsory routine (mass) vaccination program for all poultry in the country
combined with biosecurity, surveillance and culling of infected birds and movement restriction, which
has been lasted more than ten years ever since (http://www.oie.int/animal-health-in-the-world/update-onavian-influenza/2004/).
A number of vaccines against H5N1 HPAI, either inactivated or live vectored, have been developed
and used in China since 2004 (3, 23, 24). For the inactivated vaccines, we have A/turkey/England/N- 28/73
based H5N2 vaccine and recombinant Asian H5N1 vaccine of clade 0 (Re-1) and its updated versions
for matching the prevailing clades with time from clade 7 (Re-4), clade 2.3.4 (Re-5), clade 2.3.2.1 (Re6), clade 7.2 (Re-7) to clade 2.3.4.4 (Re-8) (www.ivdc.org.cn). For live virus vector vaccines, fowlpox
virus vectored and NDV vectored vaccines have been in use since 2005 and 2006 respectively and the
DEV (duck enteritis virus) vectored vaccine is in the process of licensing. A DNA vaccine (pCAGGoptiHA) was also licensed. These vaccines played a role in reducing the morbidity and mortality of the clinical disease and virus shedding of the infected animals but do not eliminate the virus while vaccination
failure occurs frequently in different conditions. According to Swayne (23, 24), China accounted for 90.9%
of the total vaccine used in the world for HPAI, in hundreds billions doses during 2002 to 2010. Experience in China emphasizes that vaccination alone is not enough to control the H5N1 HPAI, neither to
eliminate the virus nor to reduce its evolutionary rate.
Perspectives
The final goal of the H5 HPAI control program in China is the eradication of the disease nationwide.
The vaccination of poultry in the present control strategy against the disease is a double-bladed sword
because of its negative aspects such as the potential for silent infections and subclinical shedding of the
virus, difficulty in identifying infections in a vaccinated population, the high cost of vaccines and their
labor-intensive administration, the delay in protection for at least seven to 14 days after administration
and trade restrictions imposed by importing countries (23). It is time for China to develop practicable vaccine exit strategies based on risk analysis of the present production system in poultry after more than ten
years implementation of the compulsory vaccination program. We have a long way to go to reach the final goal of H5 HPAI eradication in China.
ND
ND is a devastating disease in poultry caused by the virulent Newcastle disease virus (NDV) as defined
by OIE (http://www.oie.int/en/international-standard-setting/terrestrial-code/). The first report suspected
of ND outbreak in China can be traced to late 1920s while the first ND cases in village chickens con15
firmed by virus isolation and identification occurred in 1946 (15). ND has become one of the most important poultry diseases since the development and commercialization of poultry industry in 1970s. Intensive
vaccination programs have been implemented to all commercial poultry sector since 1980 (17, 18).
Epidemiology features and virus evolution
ND is enzootic in most major poultry raising areas of the country. ND in China has the following epidemiology features. 1) Most outbreaks in vaccinated flocks are so-called atypical form of ND with low
mortality and milder symptoms such as egg-drop, dilute droppings, and some respiratory signs while outbreaks in non-vaccinated backyard and village flocks are classic form with high mortality and morbidity
(17, 18)
. 2) Along with the emergence of genotype VII virus, ND has expanded its host range, not only
pathogenic to chickens but also to domestic waterfowl, especially to geese since late 1990s (17, 30). Just as
for avian influenza viruses, domestic waterfowl are also a good reservoir for avian paramyxoviruses including NDV and play important role in their evolution. NDV, especially genotype VII can be transmitted mutually between chicken flocks and waterfowl flocks which are mostly in free range, so that the
ND epidemiology in China is very complicated (17, 18, 25, 30). 3) The phylogenetic and antigenic differences
between vaccine strains and epidemic field viruses contribute greatly to the persistence of the field virus
in intensively immunized poultry flocks as evidenced by the vaccination-challenge test (10).
The genotype VII NDV which induces more severe lesions in lymphoid organs than early virulent viruses has become dominant in poultry in China since late 1990s (12, 17, 18, 28). According to the surveillance
data in recent years in China, over 95% of the virulent NDVs isolated from both chickens and domestic
waterfowl are genotype VIId while most strains isolated from pigeons and doves are genotype VIb (17, 18,
28)
. Genotype VIId NDVs both from geese or chickens sharing high sequence homology, characteristic
amino acid substitutions and very similar pathobiological features can infect both species and cause disease equally and no host- associated genetic phenotypic characteristics are found between them (25). On
the other hand, the most extensively used vaccine strain for both inactivated and live ND vaccines is La
Sota which belongs to genotype II virus isolated in the US in the mid 1940s. The differences in sequence
identity of F and HN genes between genotype VIId and La Sota are 84.1%～84.4% and 84.1%～84.4%
respectively (10). The antigenic differences in F and HN epitopes are correlated to the corresponding genetic differences in sequence identity (10). Laboratory researchers and field practitioners argue that the
La Sota vaccine does not provide full protection against the challenge of epidemic field strains, especially in terms of reducing virus shedding although NDV has only single serotype (10, 18, 19, 20).
The control strategies and vaccine development
Vaccination is an important component for the control of ND in China for both small scale production
units with poor biosecurity and medium- to large- scale operations with high level of biosecurity (17). There
are indications that ND outbreaks still occur despite the fact that most of the commercial farms in poultry
industry in China implement an intensive vaccination program with high frequency and high antibody titers against ND (17, 18, 30). These situations suggest that it is the antigenic variation between vaccine strain
and prevalent strain rather than poor flock immunity due to inadequate vaccination practices that may be
responsible for outbreaks and spreading of virulent NDV field strains. Indeed, it has been shown that the
extent of homology between vaccine and challenge strains is a critical factor in reducing the shedding of
virulent virus (10, 18, 19, 20).
To improve the antigenic match between vaccine and currently circulating virulent strains in China, a
genotype VII-matched vaccine (A-VII strain) based on reverse genetics has been developed and licensed
in use since 2014 (10, 11). Laboratory studies and field trials showed that this vaccine not only induces significantly higher (2-3 log2 HI titer) and quicker (one week) immune response but also significantly reduces the virus shedding (by 10-100 folds) after circulating genotype VIId virus challenge when compared with the mismatched conventional La Sota vaccine (10, 11). The application of this novel matched
vaccine proved to be useful in optimizing the ND vaccination schedule and reducing the vaccination frequency in commercial poultry flocks in China.
Perspectives
As for the H5 HPAI control, the final goal for ND control in China is also its eradication nationwide.
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The present strategy for ND control in China mainly relies on the vaccination program which only reduces the clinical disease but by no means eliminates the virus. ND and H5 HPAI are the two most important poultry diseases which share similar epidemiology features and control strategies in China. It is time
for China to develop a combined eradication program of both H5 HPAI and ND and work out the practicable strategies step by step from disease free with vaccination to disease free without vaccination.
IB
The first outbreaks of IB in poultry in China confirmed by virus isolation and identification were in
late 1970s and early 1980s although suspected diagnostic reports were much earlier (32). As in most other
countries, IB is also one of the major diseases causing heavy economic losses in either vaccinated or unvaccinated poultry flocks in China (4, 7).
Epidemiology features and virus evolution
In China, IB always induced heavy losses when it accompanies with secondary bacterial infection or
co- infection with other viral pathogens, especially H9N2 low pathogenicity avian influenza virus and
some immunosuppressive viruses（7，16）. IB itself manifests diversified clinicopathological patterns involving the respiratory system (inflammation of the trachea, bronchi, lungs and air sacs), renal systems (kidney damage) and/or the female reproductive tract (egg production drops and false layers) (4). On the other
hand, the IB virus (IBV) evolves continuously to generate new variants by random mutation and genetic
recombination. Therefore, IB frequently occurs in some intensively vaccinated flocks. More than 15 genotypes/serotypes of IBVs isolated in China have been identified in the last two decades while the variant
QX-like (LX4-type) maintains the dominant state (7). According to Han et al. (7) and Zhang et al. (Zhang et
al, personal communication), 54.1% (119/220) of the isolates during 1995-2009 and 74.5% (105/141) of
the isolates during 2010-2015 are genotype/serotype QX-like whereas the average nucleotide and amino
acid sequence identities of S1 between QX-like strains and the most extensively used Mass-type vaccine
strains are less than 77% and 78% respectively. The minor genotypes/serotypes circulating in recent
years include LSC/99I, LDT3/03, TW-1, TW-2, HN-08, Mass and 4/91 each of which accounts for only
a small percentage less than 10. It is worth mentioning that China had never 4/91 type IBV strains before the unauthorized introductions of the 4/91 vaccine which contributed to the emergence of this type
variant in the field (7).
The control strategies and vaccine development
Effective control of IB is not possible without vaccination although improved biosecurity and high
standard management are essential. Currently we have three types of IB vaccines in use: licensed Mass
type (H120, H52, Ma5, 28/86 and W93) and LDT3/03 type (strain LDT3- A) and unauthorized 4/91
type. Single Mass type or 4/91 type vaccine is less protective to the dominant QX-like field virus since
the S1 gene sequence similarity between them is less than 78% . LDT3/03 type vaccine which was licensed recently is better than the Mass or 4/91 type vaccine while there is still room for improvement
since the S1 gene sequence similarity between LDT3-A and QX-like is only 86%. More recently, a QX
type vaccine with promising features in safety and efficacy is in the process of licensing (34). Laboratory experiments and field trials showed that this vaccine is very efficacious against the challenge of QXlike field viruses.
Perspectives
Licensing new vaccines matching serotypically and genotypically with the dominant variant types in
addition to enhancing biosecurity and reducing co-infection and secondary infection will be conducive
to the control of IB in China. The use of unauthorized vaccines should be banned to reduce the risks of
generating new variants by recombination from vaccine strain and field viruses.
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