A VLP-based vaccine provides complete protection against Nipah virus challenge following multiple-dose or single-dose vaccination schedules in a hamster model

Walpita, Pramila; Yu, Cong; Jahrling, Peter B.; Rojas, Oscar; Postnikova, Elena; Yú, Shuǐqìng; Johns, Lisa M; Holbrook, Michael R.

doi:10.1038/s41541-017-0023-7

Cited by 59 publications

(47 citation statements)

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“…Finally, the results in this study may have implications for improving henipavirus vaccine development. VLP-based henipaviral vaccines using the matrix (M) and the F and G glycoproteins recently have been shown to protect against NiV disease in a hamster model (3). Vaccine formulations composed of chimeric G or F glycoproteins or glycoproteins from two different henipaviruses may improve cross-protection against both HeV and NiV.…”

Section: Discussionmentioning

confidence: 99%

Nipah and Hendra Virus Glycoproteins Induce Comparable Homologous but Distinct Heterologous Fusion Phenotypes

Bradel-Tretheway

Zamora

Stone

et al. 2019

J Virol

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Nipah and Hendra viruses (NiV and HeV) exhibit high lethality in humans and are biosafety level 4 (BSL-4) paramyxoviruses in the growing genus Henipavirus. The attachment (G) and fusion (F) envelope glycoproteins are both required for viral entry into cells and for cell-cell fusion, which is pathognomonic of henipaviral infections. Here, we compared the fusogenic capacities between homologous and heterologous pairs of NiV and HeV glycoproteins. Importantly, to accurately measure their fusogenic capacities, as these depend on glycoprotein cell surface expression (CSE) levels, we inserted identical extracellular tags to both fusion (FLAG tags) or both attachment (hemagglutinin [HA] tags) glycoproteins. Importantly, these tags were placed in extracellular sites where they did not affect glycoprotein expression or function. NiV and HeV glycoproteins induced comparable levels of homologous HEK293T cell-cell fusion. Surprisingly, however, while the heterologous NiV F/HeV G (NF/HG) combination yielded a hypofusogenic phenotype, the heterologous HeV F/NiV G (HF/NG) combination yielded a hyperfusogenic phenotype. Pseudotyped viral entry levels primarily corroborated the fusogenic phenotypes of the glycoprotein pairs analyzed. Furthermore, we constructed G and F chimeras that allowed us to map the overall regions in G and F that contributed to these hyperfusogenic or hypofusogenic phenotypes. Importantly, the fusogenic phenotypes of the glycoprotein combinations negatively correlated with the avidities of F-G interactions, supporting the F/G dissociation model of henipavirus-induced membrane fusion, even in the context of heterologous glycoprotein pairs. IMPORTANCE The NiV and HeV henipaviruses are BSL-4 pathogens transmitted from bats. NiV and HeV often lead to human death and animal diseases. The formation of multinucleated cells (syncytia) is a hallmark of henipaviral infections and is caused by fusion of cells coordinated by interactions of the viral attachment (G) and fusion (F) glycoproteins. We found via various assays that viral entry and syncytium formation depend on the viral origin of the glycoproteins, with HeV F and NiV G promoting higher membrane fusion levels than their counterparts. This is important knowledge, since both viruses use the same bat vector species and potential coinfections of these or subsequent hosts may alter the outcome of disease.

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Section: Discussionmentioning

confidence: 99%

Nipah and Hendra Virus Glycoproteins Induce Comparable Homologous but Distinct Heterologous Fusion Phenotypes

Bradel-Tretheway

Zamora

Stone

et al. 2019

J Virol

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“…[39][40][41] To evaluate the capacity of antibodies elicited by the NIPARAB vaccine to neutralize NiV, we employed an in vitro fluorescence reduction neutralization assay 50 (FRNA50). 15 FRNA50 was performed as described in Materials and Methods. (Fig.…”

Section: Vaccine-induced Niv G Neutralizing Antibody Titersmentioning

confidence: 99%

“…In fact, this has been demonstrated experimentally: ferrets vaccinated with a live attenuated vesicular stomatitis virus (VSV) vaccine expressing NiV G from the Bangladesh strain were 100% protected against heterologous challenge with a Malaysian isolate of NiV. 45 Studies have also successfully utilized the F protein of NiV to develop protective vaccines against both strains and HeV, 15,19 but we decided to target the glycoprotein to block virion-receptor binding, an entry step that occurs before membrane fusion.…”

Section: Nipah Virus Is One Of Eight Viruses Designated By the World mentioning

confidence: 99%

“…Moreover, incomplete lethality in the model allowed for survival in control groups not receiving vaccination, thereby complicating the vaccine-specific effect on survival. 15 Further testing in preclinical models is warranted. A single administration of liveattenuated replication-competent recombinant vesicular stomatitis virus (VSV) lacking its native glycoprotein but expressing both Ebola GP and NiV G (rVSV-ZEBOV-GP-NiVG) was shown to prevent virus shedding, replication, and Nipah disease in AGMs.…”

Section: Introductionmentioning

confidence: 99%

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Rabies-based vaccine induces potent immune responses against Nipah virus

et al. 2019

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Nipah Virus (NiV) is a re-emerging zoonotic pathogen in the genus Henipavirus of the Paramyxoviridae family of viruses. NiV is endemic to Bangladesh and Malaysia and is highly fatal to both livestock and humans (human case fatality rate = 74.5%). Currently, there is no approved vaccine against NiV on the market. The goal of this study was to use a recombinant RABV vector expressing NiV glycoprotein (NiV G) to develop a bivalent candidate vaccine against NiV disease and rabies virus (RABV) disease, which is also a significant health burden in the regions where NiV is endemic. The rabies vector is a well-established vaccine strain that lacks neurovirulence and can stably expresses foreign antigens that are immunogenic in various animal models. Mice inoculated intranasally with the live recombinant RABV/NiV vaccine (NIPARAB) showed no signs of disease. To test the immunogenicity of the vaccine candidate, groups of C57BL/6 mice were immunized intramuscularly with a single dose of live vaccine particles or two doses of chemically inactivated viral particles. Both vaccination groups showed NiV G-specific seroconversion, and the inactivated (INAC) vaccine group yielded higher titers of NiV G-specific antibodies. Furthermore, cross-reactivity of NiV G-specific immune sera against Hendra virus (HeV), was confirmed by immunofluorescence (IF) and indirect ELISA against soluble recombinant HeV glycoprotein (HeV G). Both live and killed vaccines induced neutralizing antibodies. These results indicate that NIPARAB may be used as a killed virus vaccine to protect humans against NiV and RABV, and possibly as a preventative measure against HeV as well.

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“…The major focus of these approaches was to evaluate the immunogenicity and efficacy in the context of NiV challenge infection. In those studies, efficacy has been mostly associated with the generation of NiV-specific antibodies, and immune monitoring is mainly relying on the detection of virus-neutralizing antibodies [31,60,61]. However, there is relatively little known about the induction and the relevance of NiV-specific cellular immune responses.…”

Section: Discussionmentioning

confidence: 99%

A Soluble Version of Nipah Virus Glycoprotein G Delivered by Vaccinia Virus MVA Activates Specific CD8 and CD4 T Cells in Mice

Kalodimou

Veit²,

Jany³

et al. 2019

Viruses

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Nipah virus (NiV) is an emerging zoonotic virus that is transmitted by bats to humans and to pigs, causing severe respiratory disease and often fatal encephalitis. Antibodies directed against the NiV-glycoprotein (G) protein are known to play a major role in clearing NiV infection and in providing vaccine-induced protective immunity. More recently, T cells have been also shown to be involved in recovery from NiV infection. So far, relatively little is known about the role of T cell responses and the antigenic targets of NiV-G that are recognized by CD8 T cells. In this study, NiV-G protein served as the target immunogen to activate NiV-specific cellular immune responses. Modified Vaccinia virus Ankara (MVA), a safety-tested strain of vaccinia virus for preclinical and clinical vaccine research, was used for the generation of MVA-NiV-G candidate vaccines expressing different versions of recombinant NiV-G. Overlapping peptides covering the entire NiV-G protein were used to identify major histocompatibility complex class I/II-restricted T cell responses in type I interferon receptor-deficient (IFNAR−/−) mice after vaccination with the MVA-NiV-G candidate vaccines. We have identified an H2-b-restricted nonamer peptide epitope with CD8 T cell antigenicity and a H2-b 15mer with CD4 T cell antigenicity in the NiV-G protein. The identification of this epitope and the availability of the MVA-NiV-G candidate vaccines will help to evaluate NiV-G-specific immune responses and the potential immune correlates of vaccine-mediated protection in the appropriate murine models of NiV-G infection. Of note, a soluble version of NiV-G was advantageous in activating NiV-G-specific cellular immune responses using these peptides. the first time NiV emerged in southern India [2]. Two strains of NiV have been identified, Malaysia and Bangladesh strains, which share 91.8% sequence homology [3]. NiV causes severe respiratory disease and encephalitis [4][5][6], with average case fatality rates (CFR) of 40-75% [7]. Moreover, long-term neurological sequelae and even relapse of encephalitis are observed in many survivors of infections with both strains of NiV [8][9][10].The natural reservoir of NiV and Hendra virus (HeV) are the fruit bats of the genus Pteropus, which are widely distributed in Asia, Australasia, and parts of Africa [11,12]. Moreover, NiV has a broad species tropism and can cause disease in a many animal species [13][14][15]. NiV can infect humans via several routes, which include the consumption of food contaminated with bat secretions [16], transmission from amplification hosts such as pigs [4], and direct human-to-human transmission between very close contacts [17]. Currently there are no licensed treatments or preventative vaccines available for use in humans, which make the development of effective prophylactic measures imperative.Evidence to date indicates that the Henipavirus glycoprotein G is a highly promising target of virus-neutralizing antibodies to counteract infections with highly pathogenic henipaviruses. The G gly...

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A VLP-based vaccine provides complete protection against Nipah virus challenge following multiple-dose or single-dose vaccination schedules in a hamster model

Cited by 59 publications

References 50 publications

Nipah and Hendra Virus Glycoproteins Induce Comparable Homologous but Distinct Heterologous Fusion Phenotypes

Nipah and Hendra Virus Glycoproteins Induce Comparable Homologous but Distinct Heterologous Fusion Phenotypes

Rabies-based vaccine induces potent immune responses against Nipah virus

A Soluble Version of Nipah Virus Glycoprotein G Delivered by Vaccinia Virus MVA Activates Specific CD8 and CD4 T Cells in Mice

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