Vaccine 35 (2017) 5974–5980

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

The role of vaccination in risk mitigation and control of Newcastle

disease in poultry
Jo Mayers a,⇑, Karen L. Mansfield a,b, Ian H. Brown a
a
Virology Department, Animal and Plant Health Agency (APHA), Woodham Lane, New Haw, Surrey KT15 3NB, United Kingdom
b
Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Newcastle disease is regarded as one of the most important avian diseases throughout the world and con-
Available online 23 September 2017 tinues to be a threat and economic burden to the poultry industry. With no effective treatment, poultry
producers rely primarily on stringent biosecurity and vaccination regimens to control the spread of this
Keywords: devastating disease. This concise review provides an historical perspective of Newcastle disease vaccina-
Newcastle disease tion and how fundamental research has paved the way for the development of instrumental techniques
APMV-1 which are still in use today. Although vaccination programmes have reduced the impact of clinical dis-
AAvV-1
ease, they have historically been ineffective in controlling the spread of virulent viruses and therefore
Vaccine
Biosecurity
do not always offer an adequate solution to the world’s food security problems. However, the continued
development of novel vaccine technology and improved biosecurity measures through education may
offer a solution to help reduce the global threat of Newcastle disease on the poultry industry.
Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.

1. Introduction
Newcastle disease (ND), caused by virulent strains of avian
paramyxovirus type 1 (APMV-1), which has recently been reclassi-
fied as avian avulavirus 1 (AAvV-1) [1,2] is regarded as one of the
most important avian diseases throughout the world. ND remains
endemic in many countries with frequent epizootics occurring
throughout Africa, Asia and the America’s [3]. All strains of
AAvV-1 belong to the Avulavirus genus of the family Paramyxoviri-
dae and are regarded as a single serotype [4], however, antigenic
variation between strains are frequently detected [5]. Although
the majority of bird species are considered susceptible to ND, the
clinical signs observed may vary and are dependent on a number
of factors [6]. These include the strain of virus, host species, health
and immune status as well as environmental factors. The intensive
production systems employed by some poultry producers are often
considered stressful and along with other associated environmen-
tal conditions e.g. high and low temperatures, or stocking densities,
can increase the susceptibility of birds to disease.
The clinical signs and pathology of ND in poultry encompass a
wide spectrum of disease, ranging from inapparent infections to
those associated with high mortality varying with both virus strain
⇑ Corresponding author at: Virology Department, Animal and Plant Health
Agency (APHA)-Weybridge, Addlestone, Surrey, KT15 3NB, United Kingdom.
E-mail address: jo.mayers@apha.gsi.gov.uk (J. Mayers).
and host. Clinical signs may include depression, inappetance, respi-
ratory signs, torticollis, circling, reduced egg production and paral-
ysis (Fig. 1.) Strains of AAvV-1 are classified according to their
mean death time (MDT), and are generally grouped into three
pathotypes on the basis of the clinical signs observed in infected
chickens [7,8]. Lentogenic isolates of low pathogenicity cause mild
respiratory or enteric infections, viruses of intermediate virulence
that cause respiratory disease are termed mesogenic, while viruses
that are highly pathogenic are known as velogenic, as defined by
[9]. The virulence of NDV is dependent on a number of factors, with
the F protein cleavage site sequence (amino acid residues 113–
117) being the principle determinant of virus virulence [10]. The
presence of multi basic amino acids at the cleavage site of virulent
viruses means they can be cleaved by proteases present within
hosts tissues and organs allowing the virus to spread systemically
usually causing high mortality [11]. In contrast, lentogenic viruses
of low pathogenicity are restricted in their ability to infect and
replicate e.g. cleaved only by trypsin-like enzymes located within
the respiratory and intestinal tract. However, it has been demon-
strated that other regions of the Newcastle disease virus (NDV)
genome contribute to the virulence and pathogenicity of the virus.
The V protein has been shown to play a role in virulence through
the antagonism of IFN-1 responses and may also be involved in
host restriction for NDV [12]. The pathogenicity of NDV strains
has been determined on the basis of various properties such as
mean death time (MDT) in embryonated fowls eggs or intravenous

https://doi.org/10.1016/j.vaccine.2017.09.008
0264-410X/Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.
 J. Mayers et al. / Vaccine 35 (2017) 5974–5980
Fig. 1. Chicken with torticollis and green diarrhoea characteristic of ND clinical signs. Photographs courtesy of Dr. Dennis Alexander.
pathogenicity index in six-week-old chickens. However, based on
international agreement, a definitive assessment of virus virulence
is based on the intracerebral pathogenicity index (ICPI) in day-old
chicks (Gallus gallus). The variation in pathogenicity of different
AAvV-1 isolates is reflected in the index range, from 0.0 (avirulent)
to 2.0 (highly virulent). Strains are defined as virulent if they meet
one of the following criteria, (i) the virus has an ICPI score in day-
old chicks of 0.7 or greater, or (ii) the virus has multi basic amino
acids at the C-terminus of the F2 protein and phenylalanine at resi-
due 117 [3]. ND is an OIE (World Organisation for Animal Health)
designated disease and detection of virulent strains of the virus
requires reporting to the OIE [3] for the purposes of trade. How-
ever, due to the variability in disease presentation and the wide-
spread use of live vaccines, differential diagnosis of AAvV-1/NDV
is required before ND can be confirmed e.g. presence of a virulent
cleavage site or ICPI > 0.7. This highlights the need for careful diag-
nosis, which is necessary for the purposes of international trade,
control measures and policies.
Newcastle disease continues to be a threat and cause an eco-
nomic burden to the commercial poultry industry and backyard
flocks throughout the world. Since there is no effective treatment
for ND, the poultry industry relies primarily on stringent biosecu-
rity regimens and vaccination procedures for the control of this
devastating disease. Since the 1930s, live vaccines have been
developed to help protect flocks from the disease [13,14]. These
vaccines are licensed in many parts of the world and are even obli-
gatory in many countries. Although live vaccines have been useful
in the control of clinical ND, concerns have been raised about their
Fig. 2. Schematic summarising the timeline of ND vaccine development.
5975
role in permitting the transmission of the virus and their ability to
provide adequate protection against contemporary circulating
strains [15,16], especially in cases where avirulent strains have
mutated to a virulent form resulting in disease outbreaks [17]. This
review offers a concise evaluation of the role of biosecurity and
vaccination measures to protect against ND along with the consid-
eration of advances in new vaccine development technology which
may offer improved strategies to help eliminate the burden of this
disease.
2. History of Newcastle disease vaccination
Vaccination for ND in domestic poultry was first proposed in
the early 1930s shortly after its identification [18,19] and has been
used extensively ever since, making it one of the most widely used
veterinary vaccine in the world. A timeline for the development of
ND vaccination since the 1930s is summarized in Fig. 2. The iden-
tification of less virulent strains such as Hitchner B1 and LaSota
[13,14] has been instrumental in the development of these vacci-
nes and these strains are still in use today. Much of the NDV vac-
cine development work that was carried out during the 1970s
has been fully described in the handbook entitled ‘’Newcastle dis-
ease vaccines: their production and use’’ by Allan et al. [20], with
many of the protocols still practiced today. ND vaccines have been
propagated in embryonated fowls’ eggs for decades; however,
developments in vaccine technology have led to genetic engineer-
ing techniques where partial antigenic components are used to
5976 J. Mayers et al. / Vaccine 35 (2017) 5974–5980

stimulate an immune response [20–22]. Research undertaken on
NDV has enabled the understanding of its genome structure and
replication [10,23,24]. This, together with advances in the develop-
ment of molecular techniques especially in the form of genetic
sequencing and phylogenetics, has allowed the distinction
between different field strains and their virulence [25]. Further-
more, they have shown that AAvV-1 strains continue to evolve
and have been associated with vaccine failure and escape mutants
[16,26,27]. Numerous vaccination studies have been undertaken
over the decades with varying success, and it is often difficult to
compare the experimental results due to the variety of protocols
and ND strains used. However, vaccination continues to play an
important role in the control and eradication of ND throughout
the world, and remains in debt to the fundamental scientists
who conducted its early research and development. On this basis
the most widely used vaccine strains are La Sota and Hitchner B1
(lentogenic strains) and remains the basis of many of the commer-
cially available vaccines produced today [3].
3. Current Newcastle disease vaccines and practices
Since ND was first identified, there have been a number of
review articles published summarising the current status of ND
and the different control strategies available, however, ND still
remains a threat to the poultry industry and backyard producers
today [28–34]. A number of NDV strains have been cultivated
which form the basis of many commercial vaccine seed stocks,
and these include a range of avirulent, lentogenic and mesogenic
strains (Table 1). ND vaccines are available in the form of live, inac-
tivated or attenuated and are licensed for use in many countries
around the world. However, there are many factors that influence
the design of a vaccination programme for the control of ND, with
the aim of any vaccine control programme to ultimately protect
the birds from infection and avoid any adverse reactions that
may affect the production of the flock. Although current vaccines
do not provide sterilising immunity, the use of vaccination pro-
vides birds with an increased resistance to natural virus challenge,
therefore a higher virus dose would be needed to establish infec-
tion. The main areas of consideration involve the age and breed
of the birds, other endemic infections such as Infectious Bursal Dis-
ease (IBD) which can weaken the birds immune system, and the
type of production system e.g. broilers, breeders, layers, turkeys,
back yard or pet birds – racing pigeons, parrots [34]. A variety of
vaccination regimes are employed in poultry flocks and vary
depending on the local circumstances, level of protection required,
current immune status and the type of strains circulating in the
area. However, the main strategies used are to either vaccinate
the birds with a live lentogenic strain at 2–4 weeks when they
are fully susceptible, or when they are a day old. The latter is then
followed by a revaccination at 2–4 weeks and again at 10 weeks
with an inactivated lentogenic or mesogenic strain [3]. Mass vacci-
nation techniques are favoured by large scale poultry producers
using aerosol equipment or via the drinking water as it is a cost
Table 1
Table summarising the main AAvV-1 strains utilised in current ND vaccine
production.
Virus strain Pathotype Vaccine type Origin
F Lentogenic Live or inactivated India
Hitchner B1 Lentogenic Live or inactivated USA
LaSota Lentogenic Live or inactivated USA
V4 Avirulent Live or inactivated Australia
V4-HR Avirulent Live (Thermostable) Australia
I-2 Avirulent Live (Thermostable) Australia
Mukteswar Mesogenic Live (Booster) India
Komarov Mesogenic Live (Booster) Israel
effective and convenient delivery method. Unfortunately, field con-
ditions are often sub optimal due to stocking densities and varying
uptake rate with vaccine success rates reduced to 53% in flocks
through aerosol dissemination and 60% when delivered through
water drinkers [35]. However, labour in some developing countries
is often inexpensive which means that individual vaccine adminis-
tration can be economically feasible, although due to the nature of
these mass application systems, flock immunity can vary [36,37].
However, it was not until the 1990s that a technique to vaccinate
via the in ovo route was developed, as previous attempts had either
killed or weakened the embryo. Techniques have since been devel-
oped, which involve treating the virus with ethyl methanesul-
fonate [38], or through the preparation of virus/neutralizing
antibody complexes which attenuate the virus and make it suitable
for in ovo application [39]. Such in ovo regimens in the hatchery
offer an additional benefit to poultry producers and are currently
practiced for Mareks disease, fowl pox and infectious bursal dis-
ease by administration at day 18/19 of incubation [40]. In addition,
the use of live vaccines may mask clinical signs when infections
with NDV occur in vaccinated populations, or on occasion cause
disease, but in contrast they are inexpensive to produce and can
be administered on a large scale to induce mucosal immunity.
Inactivated vaccines are usually administered to layers and breed-
ing flocks as these types of vaccines are known to produce high
antibodies titres, with longer duration and have the added benefit
that since they induce very high antibody titres they can pass the
immunity to their offspring for a limited period through mater-
nally derived antibodies (MDA).
The decision to vaccinate does not always lie with the farmer,
but may arise from national or international policies that are in
place to focus primarily on trade legislation and compliance with
the OIE regulations. The different vaccination programmes
employed throughout the world for the control of ND are depen-
dent on a number of factors such as regional infrastructure, current
disease status, state veterinary structure and climate, all of which
pose an economical and logistical burden on the poultry producer.
The use of prophylactic and emergency vaccination is permitted
within the European Union (EU) according to community measures
for the control of Newcastle disease directive [41] and also widely
around the world. Vaccination policies can also vary at country
level. For example currently the Netherlands enforces a compul-
sory vaccination policy on their poultry producers whereas other
European countries such as Ireland, Sweden and Norway prohibit
the use of vaccine for routine preventative use. However, in the
event of an outbreak of ND in these countries a ‘ring vaccination’
policy followed by stamping out may be employed to prevent
the spread of this disease [42]. In developing countries such as
many parts of Africa, where the disease is endemic and ND poses
a huge economic burden on poultry producers, the use of vaccina-
tion regimens are routinely practiced [43]. Booster vaccinations
using live mesogenic strains such as Roakin, Mukteswar and
Komarov are administered to increase immunity, however, they
have since become prohibited in many countries where ND is con-
sidered exotic due to concerns about the spreading of virulent
virus and causing disease outbreaks since by definition many of
these strains have ICPI values >0.7. However, in countries such as
Egypt, India and Pakistan where ND is considered endemic, live
mesogenic vaccines are licensed for use in poultry [44].
4. Immune response to infection and vaccination
The main aim of any vaccination programme is to generate ster-
ilising immunity where all individual birds are protected from a
specific disease or at least protect flock health. However, due in
 J. Mayers et al. / Vaccine 35 (2017) 5974–5980
part to the nature and the large scale production of the poultry
industry, this has yet to be achieved by ND vaccines.
NDV targets the epithelial cells of the respiratory system and
depending on the pathogenicity of the virus can spread systemi-
cally to other essential tissues within the bird causing high levels
of mortality. The incubation period and onset of clinical disease
ranges from three to six days, subsequently inducing active immu-
nity (cell-mediated, humoral and mucosal) [8]. However, innate
immunity, including the interferon system, is considered one of
the first lines of the host response against viral infections through
the inhibition of viral replication to limit the spread of virus within
the host before the induction of specific immunity [45,46]. A num-
ber of in vitro studies have shown that NDV induces expression of a
number of innate immunity genes, including IFN-a, IFN-b, IFN-c
and the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-1
[47]. These genes were also shown to be among those up-
regulated during in vivo studies, along with a number of chemokine
genes suggestive of immune cell recruitment [48]. However, in vitro
studies have shown that NDV also has the ability to antagonize IFN
responses as well as possessing host tropism qualities. Further-
more, it has been demonstrated that avirulent strains are unable
to overcome the host’s immune response whilst virulent strains
demonstrate the ability to antagonize the IFN pathways (Mayers,
Unpublished data). Although there has been considerable progress
on the development and understanding of avian immunology, there
are still many areas that have not yet been explored especially the
precise role of cellular immunity against NDV.
With regard to the humoral response following infection with
NDV (or vaccination with a live vaccine), antibodies have been
shown to be detectable from approximately six days after infection
or vaccination [49]. Protection through the use of vaccination to
generate neutralising antibodies is considered an essential compo-
nent for the protection against NDV, inhibiting the virus from
attaching to the host cells and preventing viral spread. Humoral
immunity is usually generated after 6–10 days post vaccination,
with studies demonstrating that some of the highest antibody
titres are achieved via ocular and nasal routes or through the use
of inactivated vaccines or mesogenic strains [50]. However, vacci-
nation in day-old chicks is largely ineffective due to MDA and
should be considered a preliminary measure rather than a fully
protective procedure. The vaccination of young birds with live vac-
cines whilst their MDA levels are still high can lead to inhibition of
the vaccine virus and interfere or delay the immune response to
vaccination, resulting in up to 55% of unprotected birds post-
vaccination [51–53]. Therefore, in flocks with high MDA titres, vac-
cination at three weeks is undertaken to provide a better protec-
tion [20]. Applications with live vaccines have the added
advantage of triggering cellular and humoral immunity and reduc-
ing virus replication at the mucosal sites as mucosal immunity
plays an important role in the protection against ND infections
[54–57].
In order to monitor the host immune response produced by vac-
cination, the most frequently used method for the detection of
antibodies is the haemagglutination inhibition test (HI), which uti-
lises a panel of appropriate antigens and controls as outlined in the
OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Ani-
mals [3]. Previous studies have been conducted using enzyme
linked immunosorbent assays (ELISA) to monitor the antibody
response against NDV infections, and have demonstrated that
IgM was detectable approximately 4 days after primary inocula-
tion, whereas IgA and IgY were detectable after 7 days [49].
Although these kinds of studies only provide information on anti-
body production they do not necessarily correlate with the level of
transmission of the virus. Therefore, further research is warranted
to improve our understanding of avian immune responses to NDV.
5977
5. Considerations for vaccine development and use
Vaccination of poultry against NDV has been used extensively in
many parts of the world to limit disease and enhance global food
security. However, these vaccines, produced from live or inacti-
vated lentogenic strains such as Hitchner B1 or La Sota, have histor-
ically been ineffective in controlling the spread of virulent viruses
[58,59], nevertheless, they have been effective in preventing clinical
disease. As all NDV strains represent a single serotype, any ND vac-
cine should potentially induce protection from any virulent NDV
viruses. However, small antigenic variations between strains can
induce variation in vaccine efficacy and viral shedding [26,59].
Although ND vaccination has reduced the burden of clinical disease,
both experimental and field observations have shown that, in par-
ticular, sub-optimal vaccinated poultry are not immune to infec-
tion, and on occasion disease, allowing these birds to shed virus,
thus contributing to the establishment of endemic NDV infection
in a poultry population. The inability to prevent virus shedding in
vaccinated poultry when infected with NDV may be intensified by
poor vaccine match with current circulating strains [26,59–61].
Several vaccine variant viruses have been identified in poultry
stocks across the EU following disease investigations, and have
been reported to the EURL on an annual basis, demonstrating a
continued trend of vaccine-like detections in EU member states
that routinely vaccinate their flocks (International Reference Labo-
ratory for ND, Weybridge – Personal communication). This high-
lights the problems live vaccines pose on poultry keepers which
have financial implication as they will remain under restriction
until it has been characterised. Furthermore, wild bird surveillance
studies have been undertaken which have detected ND vaccine-
derived isolates from 17 species across four continents. These
detections of low genetic differences in non-target species have
suggested they are a spillover from live vaccines, and has the
potential to transmit across several avian orders and continents
undetected as there is no evidence of any epidemiological link
between isolates. The most frequently detected vaccine-derived
virus corresponds to the most widely used ND vaccines (LaSota
and Hitchner B1). From these observations, it is apparent that the
recovery of vaccine-derived viruses from both samples submitted
to diagnostic laboratories and wild bird detections have been
negated in the past since they do not meet the international agree-
ment of ND reporting [62]. Lentogenic strains, such as LaSota, may
even induce clinical signs such as mild respiratory disease and
decline in egg production [52], placing premises under restriction
until an ICPI assay and statutory sequencing of the cleavage site
can be performed to differentiate vaccination from infection with
wild type NDV. Additionally, they require stringent administration
regimens and suitable cold chain facilities (often a problem in hot
climatic conditions such as Africa), potentially interfering with
surveillance, and can be compromised by MDA.
Alternatively, inactivated vaccines offer the benefit of easier stor-
age and they do not cause disease, however, application on mass
scale is more challenging. Although inactivated vaccines generally
produce high antibody levels and long lasting protective immunity,
they are generally expensive and labour intensive to produce since
they require relatively large amounts of antigen. They are often
administered to layers and breeding flocks to provide long lasting
immunity antibody levels that can be passed on to their off-spring
[49], although their main disadvantage is that they require individ-
ual administration by subcutaneous or intramuscular injection,
which is extremely expensive and labour-intensive. This would
minimise their usage in certain large commercial poultry units,
and particularly in resource-limited settings. Therefore individual
vaccination is generally limited to small back yard or smaller breed-
ing flocks where vaccines may be easily applied.
5978 J. Mayers et al. / Vaccine 35 (2017) 5974–5980

When designing a vaccination program for a poultry flock, sev-
eral factors need to be taken into consideration such as age, mater-
nal antibody level, breed as well as the presence of other infections
and likelihood of infection. Whilst current vaccines are able to pro-
tect from disease, they do not prevent infection or control the
shedding of the virus with potential consequences for onward
transmission to susceptible birds. Therefore, there is a need for
the continual improvement of control strategies for ND, through
enhanced vaccine design and biosecurity practices to reduce the
burden of ND on the poultry industry and developing countries.
vaccines or trained administrators, enabling mass immunization
without the need to handle individual birds [81]. However, many
of these new applications have not been produced on a large scale
by commercial vaccine companies or fully utilised for backyard
purposes due to the high production costs associated with these
technologies and limitation of cold chain facilities. Additionally,
they appear to offer no perceived financial benefit to vaccine man-
ufactures compared to current live vaccines that are available,
which are cheap to produce and offer good immunity.

7. Biosecurity
6. New developments in vaccine technology
Biosecurity plays a crucial role in preventing the introduction
and spread of NDV and other avian diseases. Although ND is con-
Advances in vaccine technology have allowed the development
sidered the single most significant disease of poultry throughout
and utilisation of novel strategies to help improve vaccine efficacy.
the world, this has been overshadowed recently by the emergence
These have included the mapping of antigenic properties of viruses
of highly pathogenic avian influenza (HPAI) of multiple H5 sub-
that are routinely circulating to develop new seed vaccine viruses.
types including H5N1 [82–85]. Nevertheless, control measures
This employs a computational technique called ‘antigenic cartogra-
adopted by large scale commercial poultry producers remain sim-
phy’ which can play an important part in understanding the effi-
ilar. The development and implementation of procedures that help
cacy and long term use of vaccines. These tools have played a
reduce the risk for introduction and/or transmission of such patho-
crucial role in understanding the antigenic drift in viruses such
gens to susceptible flocks are the major principles for disease con-
as influenza where vaccines are tailored to offer protective immu-
trol. The main components of poultry biosecurity includes the
nity against circulating field strains [63]. Other novel develop-
protection of bird houses, feed and water containers to prevent
ments have included the evolution of DNA vaccines that utilise
access from wild birds, the quarantine of all new stock separated
nanoparticle technology as a delivery system to improve the effi-
from the main production birds, the sourcing and storage of feed
cacy of DNA vaccines [21,64–67], recombinant vaccines utilising
that is free from contamination with wild bird faeces, the cleaning
reverse genetic systems such as baculovirus and expressing a small
and disinfecting of poultry houses (and any equipment used
proportion of the NDV protein (F or HN) that provide immunogenic
therein) prior to re-stocking, and the adherence to stringent onsite
properties have been explored by [68,69], viral vaccine vectors
protocols that prevent personnel introducing or transmitting dis-
such as Modified Ankara Vaccinia (MVA) vector systems which
ease between poultry houses [30]. The use of approved disinfec-
are encoded with immunodominant proteins [22,70,71] that are
tants is a highly important factor, as well as the contact time
designed to stimulate cross-reactive T-cell responses that provide
viruses are exposed to disinfectant, to ensure sufficient inactiva-
cross-protection against different strains. In addition, NDV itself
tion in the disinfection process before the introduction of new
has been a useful virus vector for the development of new vaccines
birds [86], Warren et al.; unpublished data) together with ongoing
and has been successfully applied in the development of vaccines
sanitation of footwear, equipment and clothing. Wild birds pose a
for human and veterinary applications [72].
significant risk to domestic poultry as they have been reported to
The development of multiplexed vaccines that offer protection
carry a number of avian diseases that can have huge economic
against multiple pathogens within a single immunization provides
implications for domestic poultry. Protecting poultry housing from
several advantages to the poultry industry [73–75]. These include
the potential introduction of wild birds or their excretions, espe-
vaccines which protect against ND as well as Mareks disease, Infec-
cially those of the Columbiforme family, is essential for controlling
tious Bursal Disease or avian influenza. During the 1990s, vaccines
spread of this disease, particularly as pigeons are known to be
were developed utilising the herpes virus of turkeys (HVT) as a
infected with a variant of AAvV-1 known as pigeon paramyxovirus
vector to express the NDV F protein offering protection against
(PPMV-1) which has been demonstrated to be the cause of many
NDV and Marek’s Disease [76,77]. The basis of this work has led
NDV outbreaks throughout the world [32,87–90]. Therefore, a
to the development of commercially available bivalent recombi-
multi-faceted approach involving strict management protocols
nant HVT vaccines, which are now licensed in many countries
combining the use of quarantine, stringent hygiene practices and
around the world. Whilst they offer many benefits to poultry pro-
vaccination are adopted to provide a suitable disease prevention
ducers such as in ovo administration, limited affects from MDA,
and control programme. Once an outbreak of ND has been identi-
and the provision of long term immunity, they require strict cold
fied, the infected premise is required to undergo strict control mea-
chain facilities and take four weeks until full protective immunity
sures, which include depopulation, restrictions on the movement
is achieved [78]. DIVA vaccines are required to enable differentia-
of birds and associated products, in addition to stringent cleaning
tion between vaccinated and infected poultry and help eliminate
and disinfection protocols. These restrictions have a significant
problems associated with premises undergoing disease control
economic impact for the farmer, so therefore it is essential that
restrictions due to vaccine detection. DIVA vaccines have been
vaccine-induced clinical signs are differentiated from those
developed by [79], employing recombinant chimeric technology,
induced by active wild type viral infection as quickly as possible.
in addition to [69], which utilised the HN protein of APMV-4 that
However, vaccination of susceptible poultry flocks against ND
does not cause disease in poultry.
may also contribute to the biosecurity measures in place by
To overcome the problems associated with the lack of cold
increasing resistance to infection by requiring exposure to a larger
chain in developing countries where ND continues to be a huge
infectious dose should virus breach the other measures.
economic burden on the poultry industry, thermostable strains
have also been explored, and a range of avirulent Australian strains
have been assessed for their thermostable properties to help elim- 8. Summary
inate the need for cold chain facilities [80]. Additionally, other
novel ideas have been developed with the use of vaccine coated The optimal requirements of a ND vaccination program are to
cereal grains that eliminate the need for temperature controlled induce a lifelong immunity with a single vaccine at the earliest
 J. Mayers et al. / Vaccine 35 (2017) 5974–5980 5979

possible age (in ovo) without side effects such as mortality or [22] Espion D, Henau S De, Letellier C, Wemers C-D, Brasseur R, Young JF, et al.
Expression at the cell surface of native fusion protein of the Newcastle disease
effects upon growth. Additionally, the vaccine must be suitable
virus (NDV) strain Italien from cloned cDNA. Adv Virol 1987;95:79–95.
for mass administration methods, and easy to store, cheap to pro- [23] Hanaguchi M, Yoshida T, Nishikawa K, Naruse H, Nagai Y. Transcriptive
duce with the potential for multivalent applications to minimise a complex of ND virus I. Both L and P proteins are required to constitute an
vaccination regime. Ideally, it would also employ a DIVA strategy active complex. Virology 1983;128:105–17.
[24] Rifkin DB, Quigley JP. Virus-induced modification of cellular membranes
to allow differentiation of infected birds from vaccinated. The relating to viral structure. Ann Rev Micobiol 1974;28:325–52.
development of such a vaccine that fulfils all of these criteria to [25] Alexander DJ, Aldous EW, Fuller CM. The long view: a selective review of 40
meet the needs of large scale poultry production systems and back- years of Newcastle disease research. Avian Pathol 2012;41:329–35.
[26] Borland LJ, Allan WH. Development of the AG68L strain of newcastle disease
yard flocks throughout the world, would be a positive step to help vaccine (1) modification of the existing AG68L vaccine by clone purification
reduce the global burden of Newcastle disease on the poultry and its subsequent testing. Avian Pathol 1980;9:261–9.
industry especially in developing countries. [27] Animal and Plant Health Inspection Services (APHIS). Vaccination-a-two edge
sword. Eradication of exotic Newcastle disease in Southern California 1971-74.
United States Department of Agriculture; 1978. p. 36–41.
Acknowledgements [28] Awan MA, Otte MJ, James AD. The epidemiology of Newcastle disease in rural
poultry: a review. Avian Pathol 1994;23:405–23.
[29] Gallili GE, Ben-Nathan D. Newcastle disease vaccines. Biotechnol Adv
This work was funded by the Department for Environment, 1998;16:343–66.
Food and Rural Affairs, Scottish Government and Welsh Govern- [30] Alexander DJ, Bell JG, Alders RG. Technology review: Newcastle Disease with
ment (grant SE2208). The authors are grateful to Dennis Alexander special emphasis on its effect on village chickens. FAO Animal Production and
Health Paper 2004;161:1–55.
for his invaluable advice and critically reviewing the manuscript. [31] Al-Garib SO, Gielkens ALJ, Gruys E, Koch G. Review of Newcastle disease virus
with particular reference to immunity and vaccination. World’s Poultry Sci J
References 2003;59:185–200.
[32] Alexander DJ. Newcastle disease in the European Union 2000 to 2009. Avian
Pathol 2011;40:547–58.
[1] Amarasinghe GK, Bào Y, Basler CF, Bavari S, Beer M, Bejerman N, et al.
[33] Dimitrov KM, Afonso CL, Yu Q, Miller PJ. Newcastle disease vaccines – A solved
Taxonomy of the order Mononegavirales: update 2017. Adv Virol
problem or a continuous challenge? Vet Microbiol 2017;206:126–36.
2017;162:2493–504.
[34] Senne DA, King DJ, Kapczynski DR. Control of Newcastle disease by
[2] Wajid A, Dimitrov KM, Wasim M, Rehmani SF, Basharat A, Bibi T, et al.
vaccination. Development Biol 2004;119:165–70.
Repeated isolation of virulent Newcastle disease viruses in poultry and captive
[35] Degefa T, Dadi L, Yami A, G/mariam K, Nassir M. Technical and economic
non-poultry avian species in Pakistan from 2011 to 2016. Preventative
evaluation of different methods of Newcastle disease vaccine administration. J
Veterinary Med 2017;142:1–6.
Veterinary Med 2004;51:365–9.
[3] Office International des Epizootics OIE. Manual of diagnostic tests and vaccines
[36] Winterfield RW, Goldman CL, Seadale EH. Newcastle disease immunisation
for terrestrial animals. Chapter 2.3.14; 2015.
studies 4. Vaccination of chickens with B1, F and LaSota strains of NDV
[4] Mayo MA. A summary of taxonomic changes recently approved by ICTV. Adv
administered through drinking water. Poult Sci 1957;36:1076–88.
Virol 2002;147:1655–63.
[37] Corbanie EA, Remon JP, Van Reeth K, Landman WJM, Van Eck JHH,
[5] Alexander DJ, Manvell RJ, Lowings JP, Frost KM, Collins MS, Russell PH, et al.
Vervaet C. Spray drying of an attenuated live Newcastle disease vaccine
Antigenic diversity and similarities detected in avian paramyxovirus type 1
virus intended for respiratory mass vaccination of poultry. Vaccine
(Newcastle disease virus) isolates using monoclonal antibodies. Avian Pathol
2007;25:8306–17.
1997;26:399–418.
[38] Ahmed J, Sharma JM. Evaluation of modified live virus administered in ovo to
[6] Miller PJ, Koch G. Newcastle disease. In: Swayne DE, Glisson JR, McDougald LR,
protect chickens against ND. Am J Vet Res 1992;53:1999–2004.
Nolan LK, Saurez DL, Nair V, editor. Disease of poultry. Hoboken, New Jersey:
[39] Ricks CA, Avakian A, Bryan T, Gildersleeve R, Haddad E, Ilich R, et al. In ovo
Wiley-Blackwell. p. 89–138.
vaccination technology. Adv Veterinary Med 1999;41:495–515.
[7] Hanson RP, Brandly CA. Identification of vaccine strains of Newcastle disease
[40] Williams CJ, Zedek AS. Comparative field evaluations of in ovo applied
virus. Science 1955;122:156–7.
technology. Poult Sci 2010;89:189–93.
[8] Alexander DJ. Newcastle disease pathotypes. Avian Pathol 1974;4:269–78.
[41] CEC. Council directive 92/66/EEC of 14 July 1992 introducing community
[9] Beard CW, Hanson RP. Newcastle disease. In: Hofstad MS, Barnes HJ, Calnek
measures for the control of Newcastle disease. Official J Eur Commun 1992;
BW, Reid WM, Yoder HW, editors. Diseases of poultry. Iowa State University
L260:1–20.
Press; 1984. p. 452–70.
[42] Alexander DJ. Newcastle disease and other paramyxoviruses. Rev Sci Technol
[10] Rott R. Molecular basis of infectivity and pathogenicity of myxoviruses. Adv
2000;19:443–62.
Virol 1979;59:285–98.
[43] Snoeck CJ, Ducatez MF, Owoade AA, Faleke OO, Alkali BR, Tahita MC, et al.
[11] Collins MS, Franklin S, Strong I, Meulemans G, Alexander DJ. Deduced amino
Newcastle disease virus in West Africa: New virulent strains identified in non-
acid sequences at the fusion protein cleavage site of Newcastle disease viruses
commercial farms. Adv Virol 2009;154:47–54.
showing variation in the antigenicity and pathogenicity. Adv Virol
[44] VetVac database 2017. Available at http://www.Vetvac.org [date accessed 21/
1993;128:363–70.
06/17].
[12] Huang Z, Krishnamurthy S, Panda A, Samal SK. Newcastle disease virus V
[45] Fontana JM, Bankamp B, Rota PA. Inhibition of interferon induction and
protein is associated with viral pathogenesis and functions as an alpha
signalling by paramyxoviruses. Immunol Rev 2008;225:46–7.
interferon antagonist. J Virol 2003;77:8676–85.
[46] Goodbourn S, Randall RE. The regulation of type 1 interferon production by
[13] Hitchner SB, Johnson EP. A virus of low virulence for immunizing fowls against
paramyxoviruses. J Interferon Cytokine Res 2009;29:539–47.
Newcastle Disease (avian pneumoencephalitis). Veterinary Med
[47] Kapczynski DR, Alfonso CL, Miller PJ. Immune responses of poultry to
1948;43:525–30.
Newcastle disease. Dev Comp Immunol 2013;41:447–53.
[14] Goldhaft TM. Historical note on the origin of the LaSota strain of Newcastle
[48] Rue CA, Susta L, Cornax I, Brown CC, Kapczynski DR, Suarez DL, et al. Virulent
disease virus. Avian Dis 1980;24:297–301.
Newcastle disease virus elicits a strong innate immune response in chickens. J
[15] Kapczynski DR, King DJ. Protection of chickens against overt clinical disease
Gen Virol 2011;92:931–9.
and determination of viral shedding following vaccination with commercially
[49] Al-Garib SO, Gielkens ALJ, Gruys E, Hartog, Koch G. Immunoglobulin class
available Newcastle disease virus vaccines upon challenge with highly virulent
distribution of system and mucosal antibody response to Newcastle disease in
virus from the California 2002 excotic Newcastle disease outbreak. Vaccine
chickens. Avian Dis 2003;47:32–40.
2005;23:3424–33.
[50] Takada A, Kida H. Protective immune response of chickens against Newcastle
[16] Putri DD, Handharyani E, Soejoedono RD, Setiyono A, Mayasari NLPI, Poetri ON.
disease, induced by the intranasal vaccination with inactivated virus. Vet
Pathotypic characterization of Newcastle disease virus isolated from
Microbiol 1996;50:17–25.
vaccinated chicken in West Java Indonesia. Veterinary World 2017;10:438–44.
[51] Giambrone JJ, Closser J. Effect of breeder vaccination on immunization of
[17] Gould AR, Kattenbelt JA, Selleck P, Hansson E, Della-Porta A, Westbury HA.
progeny against Newcastle Disease. Avian Dis 1990;34:114–9.
Virulent Newcastle disease in Austrailia: Molecular epidemiological analysis of
[52] Westbury HA, Parsons G, Allan WH. Comparison of the immunogenicity of
virus isolated prior to and during the outbreaks of 1998–2000. Virus Res
Newcastle disease virus strains V4, Hitchner B1 and LaSota, in chickens. 2 tests
2001;77:51–60.
in chickens with maternal antibodies to the virus. Aust Vet J 1984;61:10–3.
[18] Kranevald FC. A poultry disease in the Dutch East Indes. Nederlands-Indische
[53] Vrdoljak A, Hallas M, Suli T. Vaccination of broilers against Newcastle Disease
Blanden voor Diergeneesklinde 1926;38:448–51.
in the presence of maternally derived antibodies. Tierarztliche Praxis. Ausgabe
[19] Doyle TM. Newcastle disease of fowls. J Comparative Pathol Therapeutics
G, Grosstiere Nutztiere 2017;45:151–8.
1935;48:1–20.
[54] Jeurissen SHM, Boonstra-Blom AG, Al-Garib SO, Hartog L, Koch G. Defence
[20] Allan WH, Lancaster JE, Toth B. Newcastle disease vaccines-their production
mechanisms against viral infection in poultry. Veterinary Quarterly
and use. FAO: FAO Animal production series; 1978.
2000;22:204–8.
[21] Sakaguchi M, Nakamura H, Sonoda K, Hamada F, Hirai K. Protection of chickens
[55] Reynolds DL, Maraqa AD. Protective immunity against Newcastle disease
from newcastle disease by vaccination with a linear plasmid DNA expressing
virus: The role of cell-mediated immunity. Avian Dis 2000;44:145–54.
the F protein of Newcastle Disease virus. Vaccine 1996;14:747–52.
5980 J. Mayers et al. / Vaccine 35 (2017) 5974–5980
[56] Timms L, Alexander DJ. Cell mediated immune response of chickens to
Newcastle disease vaccines. Avian Pathol 1977;6:51–9.
[57] Zinkernagel RM. Some general aspects of immunity to viruses. Vaccine
1994;12:1493–4.
[58] Miller PJ, Estevez C, Qingzhong Y, Suarez DL, King DJ. Comparison of viral
shedding following vaccination with inactivated and live Newcastle disease
vaccines formulated with wild-type and recombinant viruses. Avian Dis
2008;53:39–49.
[59] Miller PJ, King DJ, Afonso CL, Suarez DL. Antigenic differences among
Newcastle disease virus strains of different genotypes used in vaccine
formulation affect viral shedding after a virulent challenge. Vaccine
2007;25:7238–46.
[60] Miller PJ, Estevez C, Yu Q, Suarez DL, King DJ. Comparison of viral shedding
following vaccination with inactivated and live Newcastle disease vaccines
formulated with wild-type and recombinant viruses. Avian Dis
2009;53:39–49.
[61] Miller PJ, Afonso CL, Attrache JE, Dorsey KM, Courtney SC, Guo Z, et al. Effects
of Newcastle disease virus vaccine antibodies on the shedding and
transmission of challenge viruses. Dev Comp Immunol 2013;41:505–13.
[62] Ayala AJ, Dimitrov KM, Becker CR, Goraichuk IV, Arns CW, Bolotin VI, et al.
Presence of vaccine derived Newcastle disease virus in wild birds. Plos One
2016;11(9):e0162484.
[63] Fouchier RAM, Smith DJ. Use of antigenic cartograpghy in vaccine seed strain
selection. Avian Dis 2010;54:220–3.
[64] Zhao K, Zhang Y, Zang X, Li W, Shi C, Guo C, et al. Preparation and efficacy of
Newcastle disease virus DNA vaccine encapsulated in chitosan nanoparticles.
Int J Nanomed 2014;9:389–402.
[65] Zhao K, Rong G, Guo C, Luo X, Luo X, Kang H, et al. Synthesis, characterisation,
and immune efficacy of layered double hydroxide@SiO2 nanoparticles with
shell-core structure as a delivery carrier for Newcastle disease virus vaccine.
Int J Nanomed 2015;10:2895–911.
[66] Firouzamandi M, Moeini H, Hosseini SD, Bejo MH, Omar AR, Mehrbod P, et al.
Preparation, characterisation, and in ovo vaccination of dextran-spermine
nanoparticle DNA vaccine coexpressing the fusion and hemagglutinin genes
against Newcastle disease. Int J Nanomed 2016;11:259–67.
[67] Mohamed MHA, Abdelaziz AM, Kumar S, Al-Habib MA, Megahed MM. Effect of
phylogenetic diversity of velogenic Newcastle disease virus challenge on virus
shedding post homologous DNA vaccination in chickens. Avian Pathol
2016;45:228–34.
[68] Ge J, Liu Y, Jin L, Gao D, Bai, Ping W. Contruction of recombinant baculovirus
vaccines for Newcastle disease virus and assessment of their immunogenicity.
J Biotechnol 2016;231:201–11.
[69] Mebatsion T, Koolen MJM, de Vaan LTC, de Haas N, Braber M, Romer-
Oberdorfer , van den Elzen P, et al. Newcastle disease virus (NDV) marker
vaccine: an immunodominant epitope on the nucleoprotein gene of NDV can
be deleted or replaced by a foreign epitope. J Virol 2002;76:10138–46.
[70] Meulemans G, Letellier C, Gonze M, Carlier MC, Burny A. Newcastle disease
virus f glycoprotein expressed from a recombinant vaccinia virus vector
protects chickens against live-virus challenge. Avian Pathol 1988;17:821–7.
[71] Nishino Y, Niikura M, Suwa T, Onuma M, Gotoh B, Nagai Y, et al. Analysis of the
protective effect of the haemagglutinin-neuraminidase protein in Newcastle
disease virus infection. J Gen Virol 1991;72:1187–90.
[72] Kim S-H, Samal SK. Newcastle disease virus as a vaccine vector for
development of human and veterinary vaccines. Viruses 2016;8:183.
[73] Lee D-H, Park J-K, Kwon J-H, Yuk S-S, Erdene-Ochir T-O, Jang Y-H, et al. Efficacy
of single dose of a bivalent vaccine containing inactivated Newcastle disease
virus and reassortant highly pathogenic avian influenza H5N1 virus against
lethal HPAI and NDV infections in chickens. Plos One 2013;8:1–5.
[74] Park M-S, Steel J, Garcia-Sastre, Swayne D, Palese P. Engineered viral vaccine
constructs with dual specificity: Avian influenza and Newcastle disease. PNAS
2006;103:8203–8.
[75] Ishihara Y, Esaki M, Saitoh, Yasuda A. Combination of two Marek’s disease
virus vectors shows effective vaccination against Marek’s disease, Infectious
bursal disease and Newcastle disease. Avian Dis 2016;60:473–9.
[76] Morgan RW, Gelb Jr, Schreurs CS, Lutticken D, Rosenberger JK, Sondermeijer PJ.
Protection of chickens from Newcastle and Marek’s diseases with a
recombinant herpes virus of turkeys expressing the Newcastle disease fusion
protein. Avian Dis 2012;36:858–70.
[77] Reynolds D, McMillen J, Cook S, Schwartz R, Sharma J. A recombinant HVT
vaccine expressing Newcastle disease virus antigens protects chicks against a
lethal Newcastle disease challenge. In: Forty-second Western Poultry disease
conference, Sacramento, California, Feb 29 to March 2. p. 40–43.
[78] Palya V, Kiss I, Tatá-Kis T, Mató T, Felföldi B, Gardin Y. Advancement in
vaccination against ND: recombinant HVT NDV provides high clinical
protection and reduces challenge virus shedding with the decrease of
vaccine reactions. 2012; 56: 282–287.
[79] Peeters BPH, de Leeuw OS, Verstegen I, Hoch G, Gielkens ALJ. Generation of
recombinant chimeric Newcastle disease virus vaccine that allows serological
differentiation between vaccinated and infected animals. Vaccine
2001;19:1616–27.
[80] Bensink Z, Spradbrow P. Newcastle disease virus strain I2 – a prospective
thermostable vaccine for use in developing countries. Veterinary Micorbiol
1999;68:131–9.
[81] Abdi RD, Amsalu K, Merera O, Asfaw Y, Gelaye, Yami M, Sori Teshale.
Serological response and protection level evaluation in chickens exposed to
grains coated with I2 Newcastle disease virus for effective oral vaccination of
village chickens. BMC Veterinary Res 2016;12:150.
[82] Chen H, Smith GJD, Li SK, Wang J, Fan XH, Rayner JM, et al. Establishment of
multiple sublineages of H5N1 influenza virus in Asia: implications for
pandemic control. PNAS 2006;103:2845–50.
[83] Kang HM, Lee EK, Song BM, Jeong J, Choi JG, Jeong J, et al. Novel reassortment
influenza A (H5N8) viruses among domestic and wild ducks in South Korea.
Emerg Infect Dis 2015;21:298–304.
[84] Harder T, Maurer-Stroh S, Pohlmann A, Starick E, Horeth-Bontgen D, Albrecht
K, et al. Influenza A (H5N8) virus similar to strain in Korea causing highly
pathogenic avian influenza in Germany. Emerg Infect Dis 2015;21:860–3.
[85] Hall S, Voas S, Glossop C, Huey R. Heightened risk of H5N8 highly pathogenic
avian flu. Veterinary Rec 2016;179:577.
[86] Kinde H, Utterback W, Takeshita K, McFarland M. Survival of exotic Newcastle
Disease Virus in commercial poultry environment following removal of
infected chickens. Avian Dis 2004;48:669–74.
[87] Biancifiori F, Fioroni A. An occurrence of Newcastle Disease in pigeons:
Virological and serological studies on isolates. Comparative Immunol,
Microbiol Infectious Dis 1983;6:247–52.
[88] Alexander DJ. Antigenic and biological characterisation of avian
paramyxovirus type I isolates from pigeons – an international collaborative
study. Avian Pathol 1985;14:365–76.
[89] Alexander DJ, Wilson GW, Russel PH, Lister SA, Parson G. Newcastle disease
outbreaks in fowl in Great Britain during 1984. Veterinary Rec
1985;117:429–34.
[90] Aldous EW, Fuller CM, Mynn JK, Alexander DJ. A molecular epidemiological
investigation of isolates of the variant avian paramyxovirus type 1 virus
(PPMV-1) responsible for the 1978 to present panzootic in pigeons. 2004; 33:
258–269.