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Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 TCID(50) within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody.

Nipah virus (NiV) is an enigmatic emerging pathogen that causes severe and often fatal neurologic and/or respiratory disease in both animals and humans. Amongst people, case fatality rates range between 40 and 75 percent and there are no vaccines or treatments approved for human use. Guinea pigs, hamsters, cats, ferrets, pigs and most recently squirrel monkeys (New World monkey) have been evaluated as animal models of human NiV infection, and with the exception of the ferret, no model recapitulates all aspects of NiV-mediated disease seen in humans. To identify a more viable nonhuman primate (NHP) model, we examined the pathogenesis of NiV in African green monkeys (AGM). Exposure of eight monkeys to NiV produced a severe systemic infection in all eight animals with seven of the animals succumbing to infection. Viral RNA was detected in the plasma of challenged animals and occurred in two of three subjects as a peak between days 7 and 21, providing the first clear demonstration of plasma-associated viremia in NiV experimentally infected animals and suggested a progressive infection that seeded multiple organs simultaneously from the initial site of virus replication. Unlike the cat, hamster and squirrel monkey models of NiV infection, severe respiratory pathology, neurological disease and generalized vasculitis all manifested in NiV-infected AGMs, providing an accurate reflection of what is observed in NiV-infected humans. Our findings demonstrate the first consistent and highly pathogenic NHP model of NiV infection, providing a new and critical platform in the evaluation and licensure of either passive and active immunization or therapeutic strategies for human use.

Nipah virus (NiV) (Genus Henipavirus) is a recently emerged zoonotic virus that causes severe disease in humans and has been found in bats of the genus Pteropus. Whilst NiV has not been detected in Australia, evidence for NiV-infection has been found in pteropid bats in some of Australia's closest neighbours. The aim of this study was to determine the occurrence of henipaviruses in fruit bat (Family Pteropodidae) populations to the north of Australia. In particular we tested the hypothesis that Nipah virus is restricted to west of Wallace's Line. Fruit bats from Australia, Papua New Guinea, East Timor and Indonesia were tested for the presence of antibodies to Hendra virus (HeV) and Nipah virus, and tested for the presence of HeV, NiV or henipavirus RNA by PCR. Evidence was found for the presence of Nipah virus in both Pteropus vampyrus and Rousettus amplexicaudatus populations from East Timor. Serology and PCR also suggested the presence of a henipavirus that was neither HeV nor NiV in Pteropus alecto and Acerodon celebensis. The results demonstrate the presence of NiV in the fruit bat populations on the eastern side of Wallace's Line and within 500 km of Australia. They indicate the presence of non-NiV, non-HeV henipaviruses in fruit bat populations of Sulawesi and Sumba and possibly in Papua New Guinea. It appears that NiV is present where P. vampyrus occurs, such as in the fruit bat populations of Timor, but where this bat species is absent other henipaviruses may be present, as on Sulawesi and Sumba. Evidence was obtained for the presence henipaviruses in the non-Pteropid species R. amplexicaudatus and in A. celebensis. The findings of this work fill some gaps in knowledge in geographical and species distribution of henipaviruses in Australasia which will contribute to planning of risk management and surveillance activities.

Hendra virus (HeV) and Nipah virus (NiV) belong to the genus Henipavirus of the family Paramyxoviridae and are unique in that they exhibit a broad species tropism and cause fatal disease in both animals and humans. They infect cells through a pH-independent membrane fusion process mediated by their fusion and attachment glycoproteins. Previously, we demonstrated identical cell fusion tropisms for HeV and NiV and the protease-sensitive nature of their unknown cell receptor and identified a human cell line (HeLa-USU) that was nonpermissive for fusion and virus infection. Here, a microarray analysis was performed on the HeLa-USU cells, permissive HeLa-CCL2 cells, and two other permissive human cell lines. From this analysis, we identified a list of genes encoding known and predicted plasma membrane surface-expressed proteins that were highly expressed in all permissive cells and absent from the HeLa-USU cells and rank-ordered them based on their relative levels. Available expression vectors containing the first 10 genes were obtained and individually transfected into HeLa-USU cells. One clone, encoding human ephrin-B2 (EFNB2), was found capable of rendering HeLa-USU cells permissive for HeV- and NiV-mediated cell fusion as well as infection by live virus. A soluble recombinant EFNB2 could potently block fusion and infection and bind soluble recombinant HeV and NiV attachment glycoproteins with high affinity. Together, these data indicate that EFNB2 serves as a functional receptor for both HeV and NiV. The highly conserved nature of EFNB2 in humans and animals is consistent with the broad tropism exhibited by these emerging zoonotic viruses.

We have previously identified neutralizing human monoclonal antibodies against Nipah virus (NiV) and Hendra virus (HeV) by panning a large nonimmune antibody library against a soluble form of the HeV attachment-envelope glycoprotein G (sGHeV). One of these antibodies, m102, which exhibited the highest level of cross-reactive neutralization of both NiV and HeV G, was affinity maturated by light-chain shuffling combined with random mutagenesis of its heavy-chain variable domain and panning against sGHeV. One of the selected antibody Fab clones, m102.4, had affinity of binding to sGHeV that was equal to or higher than that of the other Fabs; it was converted to IgG1 and tested against infectious NiV and HeV. It exhibited exceptionally potent and cross-reactive inhibitory activity with 50% inhibitory concentrations below 0.04 and 0.6 μg/mL, respectively. The virus-neutralizing activity correlated with the binding affinity of the antibody to sGHeV and sGNiV. m102.4 bound a soluble form of NiV G (sGNiV) better than it bound sGHeV, and it neutralized NiV better than HeV, despite being originally selected against sGHeV. These results suggest that m102.4 has potential as a therapeutic agent for the treatment of diseases caused by henipaviruses. It could be also used for prophylaxis and diagnosis, and as a research reagent

•A novel bicistronic EV-A71 P1 and 3CD expression cassette has been developed.•Highly native EV-A71 virus-like particles were made using the bicistronic cassette.•Purified EV-A71 virus-like particles were highly immunogenic in nonhuman primates.•Vaccination with EV-A71 virus-like-particles protected animals from EV-A71 challenge.•This is the first EV-A71 virus-like-particle efficacy study done in nonhuman primates. A vaccine against human enterovirus 71 (EV-A71) is urgently needed to combat outbreaks of EV-A71 and in particular, the serious neurological complications that manifest during these outbreaks. In this study, an EV-A71 virus-like-particle (VLP) based on a B5 subgenogroup (EV-A71-B5 VLP) was generated using an insect cell/baculovirus platform. Biochemical analysis demonstrated that the purified VLP had a highly native procapsid structure and initial studies in vivo demonstrated that the VLPs were immunogenic in mice. The impact of VLP immunization on infection was examined in non-human primates using a VLP prime-boost strategy prior to EV-A71 challenge. Rhesus macaques were immunized on day 0 and day 21 with VLPs (100μg/dose) containing adjuvant or with adjuvant alone (controls), and were challenged with EV-A71 on day 42. Complete blood counts, serum chemistry, magnetic resonance imaging (MRI) scans, and histopathology results were mostly normal in vaccinated and control animals after virus challenge demonstrating that the fatal EV-A71-B3 clinical isolate used in this study was not highly virulent in rhesus macaques. Viral genome and/or infectious virus were detected in blood, spleen or brain of two of three control animals, but not in any specimens from the vaccinated animals, indicating that VLP immunization prevented systemic spread of EV-A71 in rhesus macaques. High levels of IgM and IgG were detected in VLP-vaccinated animals and these responses were highly specific for EV-A71 particles and capsid proteins. Serum from vaccinated animals also exhibited similar neutralizing activity against different subgenogroups of EV-A71 demonstrating that the VLPs induced cross-neutralizing antibodies. In conclusion, our EV-A71-B5 VLP is safe, highly immunogenic, and prevents systemic EV-A71-B3 infection in nonhuman primates making it a viable attractive vaccine candidate for EV-A71.

Nipah virus (NiV) and Hendra virus (HeV) are closely related deadly zoonotic paramyxoviruses that have emerged and re-emerged over the last 10 years. In this study, a subunit vaccine formulation containing only recombinant, soluble, attachment glycoprotein from HeV (sG HeV) and CpG adjuvant was evaluated as a potential NiV vaccine in the cat model. Different amounts of sG HeV were employed and sG-induced immunity was examined. Vaccinated animals demonstrated varying levels of NiV-specific Ig systemically and importantly, all vaccinated cats possessed antigen-specific IgA on the mucosa. Upon oronasal challenge with NiV (50,000 TCID 50), all vaccinated animals were protected from disease although virus was detected on day 21 post-challenge in one animal. The ability to elicit protective systemic and mucosal immunity in this animal model provides significant progress towards the development of a human subunit vaccine against henipaviruses.

Hendra and Nipah virus are closely related emerging viruses comprising the Henipavirus genus of the subfamily Paramyxovirinae and are distinguished by their ability to cause fatal disease in both animal and human hosts. In particular, the high mortality and person-to-person transmission associated with the most recent Nipah virus outbreaks, as well as the very recent re-emergence of Hendra virus, has confirmed the importance and necessity of developing effective therapeutic interventions. Much research conducted on the henipaviruses over the past several years has focused on virus entry, including the attachment of virus to the host cell, the identification of the virus receptor and the membrane fusion process between the viral and host cell membranes. These findings have led to the development of possible vaccine candidates, as well as potential antiviral therapeutics. The common link among all of the possible antiviral agents discussed here, which have also been developed and tested, is that they target very early stages of the infection process. The establishment and validation of suitable animal models of Henipavirus infection and pathogenesis are also discussed as they will be crucial in the assessment of the effectiveness of any treatments for Hendra and Nipah virus infection.

The productive infection of human monocyte-derived macrophages (Mφ ) by HIV was suppressed by primary CD8+cells from asymptomatic HIV-infected individuals. This anti-HIV response was noncytotoxic; removal of the CD8+cells from the infected Mφ leads to virus production. CD8+cells inhibited HIV replication when separated from the infected Mφ by a transwell filter insert, indicating a diffusible factor made by the CD8+cells suppressed productive infection of Mφ . Three β -chemokines, which can be secreted by activated CD8+cells, RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1α and MIP-1β prevented HIV replication in the Mφ cultures. In addition, incubation of acutely infected Mφ with a mixture of neutralizing antibodies to RANTES, MIP-1α , and MIP-1β enhanced virus replication. Nevertheless, neutralization of β -chemokines with specific antibodies did not abolish the suppression by CD8+cells of HIV replication in Mφ . Thus, even though β -chemokines decrease HIV replication in Mφ , these cytokines are not responsible for the ability of CD8+cells to inhibit HIV production in these cells.

Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 [TCID.sub.50] within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody.