Hendra virus and Nipah virus animal vaccines
Introduction
Hendra virus (HeV) and Nipah virus (NiV) are enveloped, single-stranded negative sense RNA viruses and the prototype members of the genus Henipavirus in the family Paramyxoviridae [1]. Recently, a third virus isolate Cedar virus (CedPV) has been added to the Henipavirus genus [2]. Whereas HeV and NiV are bat-borne disease-causing zoonoses, CedPV is not known to be zoonotic nor has it been shown to be pathogenic in any animal, including those susceptible to HeV and NiV, although it does reside in nature in the same bat species as HeV. To date, bats appear to be predominant natural reservoir hosts for henipaviruses [3]. Although nucleic acid based detection studies have identified related Henipavirus species, including complete genomic sequences [4], [5], HeV, NiV, and CedPV are the only virus isolates that have been reported.
In several disease-susceptible animal species, and in people, the major pathological observation of HeV and NiV infection is a severe systemic and often fatal neurologic and/or respiratory disease [6], [7], [8]. However, HeV and particularly NiV can also cause relapsed encephalitis which follows a recovery from an acute infection and appears to result from a recrudescence of virus replication in the central nervous system (CNS) [9], [10]. Outbreaks or spillovers of NiV in Bangladesh and India, since its first emergence in peninsular Malaysia, have continued to occur, as has HeV in Australia, making these henipaviruses important transboundary biological threats [11]. Both HeV and NiV are highly pathogenic in a number of mammalian species and possess several characteristics that distinguish them from all other known paramyxoviruses and are classified as Biosafety Level-4 (BSL-4) agents. Indeed, NiV is considered to have the potential to be a pandemic threat since it can infect humans directly from natural reservoirs (bats) or indirectly following amplification in a susceptible animal species (pig) and has a recognized capacity of, albeit limited, human-to-human transmission [12]. Since their discovery and recognition, a variety of approaches have been taken by multiple research groups to devise countermeasures as a means of addressing the transboundary threat issues brought about by HeV and NiV. Several active and passive immunization approaches have been explored and some have led to successful deployment and human clinical trials. Concurrent with these developments, several animal challenge models of HeV and NiV infection and pathogenesis have been established which have provided insight into the nature of HeV and NiV disease [13], [14] and afforded the possibility of testing vaccine and therapeutic countermeasures [15], [16], [17].
Section snippets
Hendra virus and Nipah virus emergence
In 1994 an outbreak of fatal cases of a severe respiratory disease in horses and humans occurred in the Brisbane suburb of Hendra, Australia. The infectious cause of this event was discovered to be a previously unknown paramyxovirus that was distantly related to certain morbilliviruses [18]. In all, 13 horses and a trainer succumbed to infection together with the non-fatal infection of 7 additional horses and a stable hand. In a separate incident that was retrospectively recognized, this same
The viruses, tropism and entry
HeV and NiV particles are enveloped and pleomorphic with spherical or filamentous forms observed by electron microscopy [70], [71], [72]. The viral envelope carries surface projections composed of the viral transmembrane anchored fusion (F) and attachment (G) glycoproteins which have been the major target of antiviral strategies. HeV and NiV are classified into the Henipavirus genus, Paramyxoviridae family [73] and their genomes are unsegmented, single-stranded, negative-sense RNA [1]. Genomic
Clinical and pathological features of human HeV and NiV infection
Human HeV and NiV infections have an incubation period ranging from a few days to about 3 weeks [101], [102]. All human cases of HeV infection have been the result of exposure and transmission of the virus from infected horses to humans. Following an influenza-like illness (fever, myalgia, headaches, lethargy, vertigo, cough, pharyngitis, and cervical lympadenopathy), the majority of human HeV cases developed severe disease and died; only 3 of 7 patients have survived (∼60% mortality rate) [8],
Clinical and pathological features of HeV and NiV infection in animals
Naturally acquired HeV infections have almost exclusively been observed in horses, and only recently have two dogs been reported HeV antibody positive. Whereas in addition to pigs, naturally acquired NiV infection was noted in dogs, cats and horses in the initial Malaysian outbreak [113]. Since their discovery, however, a large number of different species have been examined under experimental conditions for the purposes of developing infection models and characterizing the viral pathogenic
The pig
Experimental NiV infection of pigs has revealed an incubation period of ∼5–7 days post-infection and the respiratory system serving as a major site of virus replication and pathology, with viral antigen and syncytia formation present in the respiratory epithelium (tracheal, bronchial, bronchiolar, and alveolar) and small blood and lymphatic vessels [113], [121], [123]. Virus was also observed in the kidneys and in endothelial and smooth muscle cells of small blood vessels [121]. CNS involvement
The horse
Naturally acquired HeV infection in horses often results in severe disease, with fever and increased heart rate common, and a rapid deterioration with respiratory and/or neurological clinical signs. The case fatality rate is ∼75%. In some naturally occurring cases HeV infection has presented with more subtle clinical signs including absence of fever. An apparent incubation period in naturally infected horses appears to be 5–16 days based on the events of the two large outbreaks; the first in
Non-human primates
The only nonhuman primate model that has uniformly recapitulated human disease for both NiV and HeV infection was developed using the African green monkey (AGM) [126], [127]. Both NiV and HeV produce a uniformly lethal illness following low dose virus challenge by intratracheal inoculation within 7–10 days post-infection. NiV and HeV spread rapidly to numerous organ systems within the first 3–4 days following challenge, followed by the development of a progressive and severe respiratory disease
Therapeutics and vaccines
There are no approved HeV or NiV antiviral therapeutics or vaccines for human use, however, several countermeasure approaches have been evaluated in animal challenge models and have been recently reviewed in detail elsewhere [16]. Here, the focus will be an up to date summary of the HeV and NiV animal vaccine approaches that have been examined in vivo along with the one therapeutic approach for human use that has reached phase I clinical trial evaluation.
Active immunization strategies
There has been a variety of immunization strategies developed for HeV and NiV infection including live-recombinant virus platforms, protein subunit, virus-like particles and DNA vaccines; many of these approaches have only been examined for their ability to illicit HeV- or NiV-specific neutralizing antibody responses [133], [134], [135], [136]. Some approaches, however, have been examined for both immune response and efficacy using a variety of animal challenge models (Table 1). The first
The passive immunization approach
The first passive immunization studies were conducted in the hamster NiV-challenge model and demonstrated that antibody immunotherapy against NiV infection through the targeting of the viral envelope glycoproteins was possible. Protective passive immunotherapy using either NiV G and F-specific polyclonal antiserums, or mouse monoclonal antibodies (mAbs) specific for the NiV or HeV G or F glycoproteins has been demonstrated [118], [137], [149]. These studies demonstrated the importance of viral
Conclusions and future directions
Because of the potential environmental accessibility of HeV and NiV, their highly pathogenic characteristics and ability to infect a broad range of mammalian hosts including people, the development of effective countermeasures against these biothreats has been a major area of research focus. These efforts have led to the development and testing of potential vaccine candidates and antiviral therapeutics. In 2010, the m102.4 mAb producing cell line was provided to the Queensland Government,
Acknowledgements
C.C.B is supported by NIH grant AI054715-06. The authors thank Dr. Kai Xu for providing Fig. 1.
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