|Henipavirus Vaccine Development
|Jackie Pallister1*, Deborah Middleton1, Christopher C. Broder2 and Lin-Fa Wang1
|1CSIRO Livestock Industries, Australian Animal Health Laboratory, 5 Portarlington Road, Geelong, VIC, 3220, Australia
|2Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA
||Dr. Jackie Pallister
CSIRO Livestock Industries
Australian Animal Health
5 Portarlington Road, Geelong
VIC, 3220, Australia
Tel: 61 3 5227
Fax: 61 3 52275555
|Received July 16, 2010; Accepted September 07, 2011; Published September
|Citation: Pallister J, Middleton D, Broder CC, Wang LF (2011) Henipavirus
Vaccine Development. J Bioterr Biodef S1:005. doi:10.4172/2157-2526.S1-005
|Copyright: © 2011 Pallister J, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
|The henipaviruses, Hendra virus and Nipah virus, belong to the family Paramyxoviridae which has long been
a source of highly contagious pathogens for both humans and animals. Some notable paramyxoviruses such as
measles virus have spilled over from animals into humans to cause significant morbidity and mortality. Since 1994
the henipaviruses have periodically emerged from their animal reservoir in flying foxes to cause disease in human
and animal populations. The recent emergence of these viruses coupled with the high mortality rate associated with
henipavirus infections and the lack of any licensed prophylactic or therapeutic treatments, makes them agents of
particular concern in the area of both human and agricultural biodefense. Advances in our understanding of henipavirus
infection and pathogenesis has led to the development of several promising vaccine candidates making it likely that
vaccines for henipavirus infections may be available in the near future.
|Henipavirus; Vaccine; Hendra virus; Nipah virus
|The history of the interaction of man and animals is one involving
a constant exchange of microorganisms; according to one survey an
estimated 61% of human infections are caused by zoonotic organisms
that have transferred from animals to humans . The vast majority
of new pathogens recognised in humans since 2001 are zoonotic 
including those causing very high impact infections such as acquired
immunodeficiency syndrome (AIDS), a result of infection with
human immunodeficiency virus type-1 (HIV-1) , and severe acute
respiratory syndrome (SARS) [4-6]. Plague is perhaps one of the best
known and most terrifying of the zoonoses. The causative agent, the
bacterium Yersinia pestis, is carried by rodents. The first recorded
outbreaks were in the 6th and 7th centuries, and later the most notable
one in the 14th century when, by some estimates, half the population of
Europe died. The devastation caused by the natural spread of zoonotic
agents such as these into human populations provides an insight
into the destructive potential of deliberately introduced pathogens,
particularly those to which humans have had little or no previous
exposure, and for which there are no therapeutic treatments.
|The use of biological agents as weapons is a time honoured tradition
in the field of human conflict. Perhaps the earliest recorded instance is
the catapulting of plague-ridden bodies into cities in the 14th century
. In World War I horses and mules were deliberately infected with
glanders and anthrax , both agents capable of infecting humans as
well as horses. More recently, in 2001, anthrax spores were posted in
the United States mail and infected 22 people, of whom 11 contracted
pulmonary anthrax and 5 died .
|The virus family Paramyxoviridae, consisting of viruses possessing
non-segmented, single stranded negative sense RNA genomes, is also
the source of several highly contagious pathogens such as measles virus
and mumps virus in humans and canine distemper virus in dogs .
Measles virus is most closely related to the etiologic agent of "cattle
plague", rinderpest virus, and is thought to have been acquired from
this species at the time of domestication of cattle, possibly around
the 11th to 12th century . On contact with naïve populations in
the Americas in the 16th century the measles virus is reported to have
killed 50% of certain human populations as well as two thirds of the
population of Cuba in 1529. Some hundreds of years after measles
virus is thought to have crossed into man, the paramyxoviruses as a group have continued to be a source of emerging zoonotic infections:
two new additions to the paramyxovirus family, Nipah virus (NiV)
and Hendra virus (HeV) emerged to cause infections among humans
at the end of the last century. HeV and NiV were assigned to a new
genus, the henipaviruses [12-14], based in part on both their broad host
range and ability to cause mortalities in both humans and animals and
their unique and distinctly large genomes size - 18,234 nucleotides for
HeV , and 18,246 or 18,252 nucleotides for NiV Malaysia and NiV
Bangladesh respectively [15,16] - which are approximately 15% larger
than other paramyxovirus genomes.
|Epidemiology of henipavirus infections
|The source of these new henipavirus infections was not
immediately apparent. In the first outbreak in 1994, HeV infected and
caused mortalities in horses and humans . In an effort to determine
the reservoir species for HeV, a serological survey was carried out in
eastern Queensland with sera collected from 46 species including 34
species of wildlife. No antibody was detected in this initial survey, but
in a second survey targeting flying foxes and birds, antibodies capable
of neutralizing HeV were detected in the 4 mainland species of pteropid
bats found in eastern Australia  and virus was subsequently isolated
from the reproductive tract and urine of wild-caught bats . NiV
appeared some 4 years later in an outbreak that primarily affected pigs
and humans in peninsular Malaysia and Singapore , and was later
shown to be closely related to HeV by immunological and molecular
analyses [21,22]. Pteropid bats were the suspected reservoir host based
on the similarities between HeV and NiV. Again surveillance of animal
species identified neutralizing antibody to NiV mainly in flying foxes
(Pteropus sp). Virus was isolated from urine of these animals and from
partially eaten fruit  under trees in which bats foraged.
|For both HeV and NiV a major mechanism of spillover infection
is thought to be contamination of food sources by bats; such as pasture
underneath fruit trees for horses in Queensland or contaminated date
palm sap or fruits consumed by humans in Asia. Since 1994 there have
been 31 outbreaks of HeV, unusually 17 of these have occurred in 2011
(Table 1). On each occasion, horses have been infected and, in 5 of
these, transmission to humans has occurred. Although the number
of known human infections is small, the mortality rate is high with 4
deaths recorded among 7 cases. In all instances the infection of humans
has been through horses infected with HeV and no known cases of
direct transmission from bats to humans have been reported .
In nature, HeV has so far only been isolated from bats, humans and
horses, although other mammals replicate virus following exposure
under laboratory conditions.
|Since 1998 NiV has re-emerged more than a dozen times in
Bangladesh and neighbouring parts of India (Table 2) and these
outbreaks differed from the initial emergence of NiV in Malaysia. In
the Malaysian outbreak the disease appeared to be largely encephalitic
with respiratory signs recorded in only a small percentage of patients
. While there was no clinical evidence of human-to-human
transmission, abnormal cerebral magnetic resonance imaging was seen
in a nurse with asymptomatic NiV infection, indicating that human-tohuman
spread may occur . The mortality rate was approximately
40% . By comparison the later episodes of human NiV infection in Bangladesh and India were characterized by a higher mortality rate
and clear evidence of human-to-human spread [28-33]. Respiratory
symptoms were more severe and the fatality rate approached 70%
. In the Faridpur outbreak in Bangladesh in 2004, 75% of patients
developed respiratory difficulty and the associated fatality rate was
73% . In addition, patients with respiratory symptoms were more
likely to transmit the virus , and the case for the role of respiratory
secretions in the human-to-human spread was further strengthened
by the identification of NiV RNA in the respiratory secretions of
infected patients [16,37]. In the most recent emergence of NiV in
Bangladesh in early 2011, the mortality rate has exceeded 75% .
NiV infects humans, bats, pigs and dogs  in nature, and like HeV,
other mammals replicate virus following exposure under laboratory
||Table 1: Hendra virus outbreaks in Australia, August 1994-August 2011.
||Table 2: Nipah virus outbreaks in Bangladesh, India, Malaysia and Singapore, September 1998 to May 2011.
|One of the distinguishing characteristics of the henipaviruses in
comparison to all other paramyxoviruses is the ability to induce severe
disease across a broad range of vertebrate hosts. Some of the reasons for
this became clear with the identification of ephrin-B2 and ephrin-B3 as
the host cell receptors for these viruses [40-43]. Ephrins act as a ligand
for their receptors, Eph molecules, and both are members a large family
of tyrosine kinase receptors. Both the ephrin ligands and their Eph
receptor partners are highly conserved and evolutionarily ancient bi-directional signalling cell surface molecules [44,45]. Sequencing of the
ephrin-B2 and ephrin-B3 genes of the human, pig, horse, cat, dog and
bats showed over 95% identity at the amino acid level . Binding of
ephrins to the Eph receptor facilitates communication between cells
by triggering cellular signalling pathways that regulate cell movement,
positioning and adhesion (reviewed in ). They are expressed on
most human tissues , but are most highly expressed on neurons,
arterial endothelial cells and smooth muscle reflecting their role
in development of the nervous and cardiovascular systems and in
erythropoiesis [49-52]. Ephrins also play a role in many adult organ
systems through regulation of cell migration and tissue assembly .
Ephrins have been found in all mammalian species examined and in a
number of lower order species such as C. elegans . However, ephrin
expression alone is not sufficient to confer susceptibility to henipavirus
infection. Mice have so far proved to be refractory to systemic infection
despite expressing ephrin B2 , suggesting that other factors such as
the ability of the host cell to replicate the virus or co-receptors may be
|Similar to other paramyxoviruses, henipavirus infection of the host
cell is mediated by two membrane anchored surface glycoproteins- and
HeV and NiV possess an attachment (G) and fusion (F) glycoprotein
(Figure 1) [10,56]. The G glycoprotein is present as tetramer anchored
in the lipid membrane of the virus  which appears to be associated
with the trimeric F glycoprotein prior to receptor binding . The
F glycoprotein is a typical class I viral fusion glycoprotein and its
activity is dependent on the cleavage of the inactive F0 glycoprotein
into two subunits, F1 and F2 by the proteolytic enzyme Cathepsin L
. Following binding of G to its ephrin receptors, conformational
changes are speculated to occur within the G glycoprotein oligomer
(reviewed in ). The receptor engagement of the G glycoprotein in
turn triggers a conformational change in the F glycoprotein, the exact
details of which remain ill-defined, leading to the exposure of the
fusion peptide which inserts into the juxtaposed-host cell membrane
to form a physical link between the viral and cellular membranes. This
is followed by a dramatic refolding of the F glycoprotein structure and
association of its two α-helical heptad repeat domains referred to as the
6-helix bundle formation which is believed to facilitate the merger of the viral and cellular membranes [59-61] (reviewed in Dutch 2010 ). The
end result of the fusion process is entry of the nucleocapsid into the
cytoplasm of the cell and the onset of viral replication.
||Figure 1: Henipavirus structure. A diagrammatic representation of the
henipavirus particle indicating the six structural proteins associated with the
virion and highlighting the two membrane glycoproteins, F and G that serve as
vaccine target antigens.
|The utilisation of ephrin-B2 and ephrin-B3 as the receptor on the
host cell leads to fundamental similarities in the disease processes
caused by HeV and NiV regardless of the species infected. Principally,
tropism for the vascular endothelium is responsible for the widespread
vasculitis seen in humans, monkeys, horses, hamsters, cats and
ferrets infected with HeV [62-65]; and in humans, pigs, guinea pigs,
cats, hamsters, ferrets and monkeys infected with NiV [66-70]. Viral
tropism for neurons is reflected in the common finding of central
nervous system (CNS) neuronal infection which may or may not result
in encephalitis. Autopsy of fatally infected NiV patients, and isolation of virus from nasopharyngeal secretions of human patients infected
with NiV  suggested that respiratory and lymphoid tissues could
be the primary site of virus replication, followed by a viraemic phase
. Outcomes of virus infection studies in ferrets are consistent with
this. Recently, ferrets were treated with a cross reactive and henipavirus
neutralizing human monoclonal antibody (mAb) specific for the HeV
G glycoprotein [72,73] to evaluate the therapeutic benefit of passively
administered antiviral mAb on an otherwise lethal HeV infection
scenario. Passive immunotherapy with mAb m102.4 reduced viral
replication sufficiently to prevent lethal disease. However, viral RNA
was detected in the nasal washes and oral swabs and at post mortem
viral genome was detected in the retropharyngeal lymph nodes that
drain the nasal cavity even where genome was not detected in any other
tissues. These results suggested that the primary site of HeV replication
could well be in respiratory and lymphoid tissue, in accordance
with observations made for NiV  and the well characterized
paramyxovirus, measles .
|In the viraemic phase, viral antigen was found in the endothelial
cells of small blood vessels and in arteriolar smooth muscle, with viral
infection leading to systemic vasculitis including in the CNS (reviewed in
[65,70]). Multinucleated syncytial endothelial cells were also seen both
in HeV infections [17,75] and in the initial NiV outbreak in Malaysia,
and are considered by some authors to be diagnostic of henipavirus
infection . The route of viral infection to the brain is thought to be
via infection of endothelium, with local extension to neurons following
infarction and resulting injury to nervous tissue . In pigs exposed
to NiV, anterograde infection of the brain has also been proposed 
and data derived from experimentally infected ferrets also supports the
possibility of this scenario under certain conditions (J. Pallister and D.
Middleton, unpublished results).
|Persistent infection with virus is thought to be responsible for
henipavirus disease recurring sometime after an apparent recovery
from a previous infection. In the initial NiV outbreak in Malaysia, 7.5%
of those who survived acute encephalitis suffered recurrent neurological
disease known as relapsed encephalitis and 3.4% suffered late-onset
encephalitis where neurological manifestations were first seen some
time after recovery from an acute non encephalitic or asymptomatic
infection [25,77]. Both outcomes were reportedly due to recrudescence
and rapid replication of virus that persisted following the initial
infection [14,77] although NiV was not isolated from the neurological
tissues of these patients . A similar disease pattern occurred in a
Mackay farmer who initially contracted HeV from infected horses. He
recovered from the initial infection but developed encephalitis and died
13 months later. Again no virus was isolated from the brain although
PCR, immunohistochemistry and electron microscopy indicated the
presence of HeV .
|In a small number of cases, an acute measles virus infection
can also lead to a persistent infection which in turn leads to the
development of subacute sclerosing pan-encephalitis (SSPE). SSPE is a
progressive neurological disorder of children and young adults [78,79])
characterized by severe demyelination and infection of neurons
leading to death. The disease appears on average 7-10 years post an
acute infection with measles , but is now rare in western countries
where it has largely been eliminated by vaccination . The hallmark
of viruses that persist to cause SSPE is the accumulation of mutations,
particularly in the M protein and the cytoplasmic tail of the F protein;
both proteins that play an integral role in viral budding [10,82]. In all
SSPE measles strains the F glycoprotein loses the carboxy-terminal pentadecapeptide that is highly conserved in morbilliviruses and
thought to be involved in budding . In addition, the M protein
is severely reduced or lacking in these viruses [83,84] and rapid posttranslational
degradation of the M protein was shown to lead to defects
in virus budding . Together these observations have led to the
suggestion that defective viral budding is a mechanism of persistence.
|Threat to biosecurity
|Henipaviruses have been classified as category C priority pathogens
and Biosafety Level-4 (BSL-4) agents by the Centers for Disease Control
and Prevention (CDC), and the National Institute of Allergy and
Infectious Diseases (NIAID). The NIAID Strategic Plan for Biodefense
Research (NIAID Biodefense Research Agenda) encompasses emerging
animal pathogens considered as potential biothreats - like NiV which
is designated as the example pathogen defining category C agents
. Some of the reasons for inclusion of henipaviruses are (i) the
high mortality rate associated with henipavirus infection (greater than
50%) (ii) the absence of vaccines and post-exposure treatments - one
of the reasons that these agents have been designated as Biosafety Level
4 (BSL-4) organisms (iii) there has been no co-evolution of humans
and henipaviruses that might reduce the virulence of the infection in
humans (iv) carriage of these viruses by wildlife and their relative ease
of propagation means that the agent is theoretically accessible from
nature (v) their very broad host range amongst mammalian species and
(vi) possible confusion with other more common ailments leading to
|The recent emergence of these viruses and the sporadic nature of
disease outbreaks have made the development and testing of vaccines
and therapeutics for henipavirus infections a low commercial priority.
However, the development of such countermeasures is a crucial
component of any preparedness plan against an outbreak or emergence
whether deliberate or natural. Vaccines have been used very successfully
to control other well known and debilitating paramyxovirus infections
including measles and mumps infection of humans and rinderpest
virus infection of cattle. Vaccination with an attenuated live measles
virus vaccine began in 1963 and was highly successful in reducing the
infection rate with measles virus. In the United States alone, the first 20
years of vaccination is estimated to have prevented 52 million cases of
the disease, 17,400 cases of mental retardation and 5200 deaths .
As a result of vaccination the United States has been declared free of
endemic measles . Importantly, an historic announcement in May
2011 declared rinderpest as the first animal disease ever to be eradicated
by humankind . Vaccination was a central plank of the campaign
to eradicate the virus.
|Successful resistance to paramyxovirus infection that is conferred
by vaccination is commonly mediated by an adaptive immune
response to viral surface proteins/glycoproteins  particularly for
infections associated with a viraemic phase such as those caused by
the measles virus and the mumps virus [91,92]. Consequently, vaccine
development for the henipaviruses has focused on the viral F and G
envelope glycoproteins either expressed in a recombinant virus or as a
recombinant subunit immunogen.
|Hamsters vaccinated with recombinant vaccinia viruses encoding
NiV G or F were protected against a lethal challenge with NiV.
However a strong anamnestic response to the challenge virus suggested
that vaccination did not prevent virus replication . Similarly, pigs
vaccinated with canarypox viruses encoding either NIV G or F were protected against a lethal NiV infection and although virus was not
reisolated from any tissues low levels of viral RNA were detected in
several samples .
|Several studies have also been carried out with a HeV recombinant
soluble G glycoprotein (sG)-based subunit immunogen (HeVsG). In
one experimental study, cats survived a lethal NiV challenge with no
clinical signs  and the data supported the development of sterilizing
immunity in this animal model. In a second study carried out in cats,
virus was reisolated from one vaccinated animal and viral RNA was
detected in the brains of several animals receiving the two highest doses
of vaccine . The authors speculated that the detection of genome in
the brain in the face of significant levels of neutralizing antibody prior
to challenge indicated that 'a persistent infection might occur despite
pre-existing immunity'. In a vaccine antigen dose sparing study, ferrets
immunized with HeVsG survived an otherwise lethal HeV challenge.
Here, all vaccine antigen doses prevented clinical disease and there was
no anamnestic antibody response detected following challenge, nor
could any challenge virus be reisolated from any animal . While
all three of these studies utilized HeVsG as the vaccine immunogen,
variations in adjuvant used, immunogen dose and challenge virus
dose make it difficult to directly compare the experimental outcomes.
However, the results of two of three studies indicate that it is possible to
prevent establishment of a HeV infection by vaccination, and indeed all
three studies indicated that vaccination could prevent clinical illness.
|Development of an effective vaccine ideally requires an
understanding of how the agent in question interacts with the host to
cause disease. Anterograde infection of the brain has been proposed
in henipavirus infection, as well as infection via the systemic route. In
addition to preventing systemic disease, an ideal vaccine would prevent
infection of the CNS by either route and thus eliminate the possibility
of recrudescent CNS disease - vaccination against measles virus
did reduce the incidence of persistent infection manifested as SSPE.
Clinical trials of a potential vaccine against a BSL-4 agent could not be
carried out in humans; instead there is a requirement by the U.S. FDA
that candidate vaccines be tested in at least two different animal models
. Relevant animal models that reproduce the nervous and systemic
aspects of henipavirus infection and a thorough understanding of
henipavirus pathogenesis in these animal models will be essential to
this activity. To this end, the development of a model for henipavirus
infection in a non-human primate (African green monkey) was an
important step, and indeed disease progression mediated by either
HeV or NiV in these animals essentially mirrors that seen in humans
[64,69]. Other species that may be suitable include golden hamsters,
ferrets and cats .
|The strategy for the deployment of successful therapeutics is
relatively straightforward but a successful vaccine may be deployed
differently in different circumstances. While the outbreaks caused by
henipaviruses remain sporadic in nature and involve relatively small
numbers of people and animals (except in the NiV outbreak in Malaysia
where over one million pigs were culled), mass vaccination is unlikely
to be a viable approach. Vaccination of select human populations at risk
may be warranted in some circumstances; one such population might
be, for example, horse veterinarians and horse owners in north eastern
Australia. However, the primary strategy for containing HeV outbreaks
in Australia is to vaccinate horses in at-risk areas. Human infection
with HeV is so far only known to have occurred via close contact with
infected horses and so vaccination of horses would hopefully prevent
the chain of transmission to humans. The same principle may apply if for instance, pigs (or any other animal) became a significant source
of human infection, as seen in the initial NiV outbreak in Malaysia
and Singapore. Should the nature of henipavirus outbreaks change
or bioterrorism involving these agents become a reality then mass
vaccination may become a viable option.
|Experience with paramyxoviruses indicates that the opportunity
for significant reduction in transmission risk by vaccination is great.
There is potential for recrudescence of the virus but the potential for
sterilizing immunity seen with some HeVsG candidate vaccines may
circumvent this risk - as measles vaccine reduced the incidence of the
persistent infection manifested as SSPE. The challenges in developing
a vaccine against a BSL-4 agent are significant but not insurmountable.
The requirement to carry out challenge experiments at BSL-4 imposes
constraints on the speed with which the preliminary vaccine work can
be conducted, and the process is further complicated by the rigorous
testing required prior to release of a vaccine for human use. However,
vaccine development is progressing and, in conclusion, it would seem
that vaccines for henipavirus infections are likely to be available in the
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