A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available

Ishikawa, Takahiro; Yamanaka, Akira; Konishi, Eiji

doi:10.1016/j.vaccine.2014.01.040

Cited by 157 publications

(154 citation statements)

References 106 publications

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“…Replicon RNAs of one flavivirus can be packaged by structural genes derived from another flavivirus (34,(54)(55)(56). Additionally, several flavivirus vaccine candidates are chimeric viruses in which the structural proteins of one virus are inserted into the genomic background of a heterologous virus type (reviewed by Ishikawa et al [57]). To study mechanisms of flavivirus neutralization, our laboratory has produced RVPs by complementation of a WNV replicon (WNVrep) with structural genes derived from WNV, DENV, and the tick-borne flavivirus Langat (34,35,44).…”

Section: Resultsmentioning

confidence: 99%

Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly

VanBlargan

Davis

Dowd

et al. 2015

J Virol

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The molecular mechanisms that define the specificity of flavivirus RNA encapsulation are poorly understood. Virions composed of the structural proteins of one flavivirus and the genomic RNA of a heterologous strain can be assembled and have been developed as live attenuated vaccine candidates for several flaviviruses. In this study, we discovered that not all combinations of flavivirus components are possible. While a West Nile virus (WNV) subgenomic RNA could readily be packaged by structural proteins of the DENV2 strain 16681, production of infectious virions with DENV2 strain New Guinea C (NGC) structural proteins was not possible, despite the very high amino acid identity between these viruses. Mutagenesis studies identified a single residue (position 101) of the DENV capsid (C) protein as the determinant for heterologous virus production. C101 is located at the P1= position of the NS2B/3 protease cleavage site at the carboxy terminus of the C protein. WNV NS2B/3 cleavage of the DENV structural polyprotein was possible when a threonine (Thr101 in strain 16681) but not a serine (Ser101 in strain NGC) occupied the P1= position, a finding not predicted by in vitro protease specificity studies. Critically, both serine and threonine were tolerated at the P1= position of WNV capsid. More extensive mutagenesis revealed the importance of flanking residues within the polyprotein in defining the cleavage specificity of the WNV protease. A more detailed understanding of the context dependence of viral protease specificity may aid the development of new protease inhibitors and provide insight into associated patterns of drug resistance. West Nile virus (WNV) and the four serotypes of dengue virus (DENV1 to -4) are mosquito-borne viruses of the Flavivirus genus that significantly impact public health (1, 2). Despite a clear need, neither vaccines nor therapeutics for WNV or DENV have been licensed for use in humans. The flavivirus genome is an ϳ11-kb, single-stranded, positive-sense RNA that encodes a single open reading frame flanked by 5= and 3= untranslated regions. The viral genome is translated on endoplasmic reticulum (ER)-derived membranes into a single polyprotein that undergoes co-and posttranslational cleavage by the viral protease NS2B/3 and host proteases into 10 functionally distinct proteins, including the structural proteins capsid (C), premembrane (prM), and envelope (E) that form the virus particle. During assembly, membrane-anchored prM and E glycoproteins are incorporated into virions as they bud into the ER lumen. The C protein associates with the viral genome in the cytoplasm to form an unstructured nucleocapsid that is incorporated into the budding particle via unknown mechanisms (3). The carboxy terminus (C terminus) of the C protein includes a signal sequence, flanked by protease cleavage sites, that directs the translocation of prM into the ER lumen and tethers C to the cytosolic face of the ER membrane.Cleavage at both sites is essential for virion morphogenesis and occurs in a sequenti...

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Section: Resultsmentioning

confidence: 99%

Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly

VanBlargan

Davis

Dowd

et al. 2015

J Virol

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“…There is an immediate requirement for ZIKV vaccine. Some practical approaches are: attenuated chimeric vaccine (dengue vaccine employing the yellow fever vaccine backbone, presently in Phase III clinical trial), killed or live attenuated vaccine from human cell lines (as that of yellow fever and Japanese encephalitis vaccines) and DNA and recombinant protein vaccine [103].…”

Section: Preventionmentioning

confidence: 99%

Zika virus disease: a current review of the literature

et al. 2016

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“…The success of the YFV-17D vaccine has led to multiple attempts at producing live attenuated vaccines against other flaviviruses (78). In the case of JEV, a live attenuated JEV vaccine, SA 14 -14-2, was developed in China and has been successfully used for decades in China and now in other Asian countries (79,80), although it is not recommended for global use due to a theoretical risk for reversion to neurovirulence.…”

Section: Discussionmentioning

confidence: 99%

A Single Amino Acid Substitution in the M Protein Attenuates Japanese Encephalitis Virus in Mammalian Hosts

Wispelaere

Khou

Frenkiel

et al. 2016

J Virol

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Japanese encephalitis virus (JEV) membrane (M) protein plays important structural roles in the processes of fusion and maturation of progeny virus during cellular infection. The M protein is anchored in the viral membrane, and its ectodomain is composed of a flexible N-terminal loop and a perimembrane helix. In this study, we performed site-directed mutagenesis on residue 36 of JEV M protein and showed that the resulting mutation had little or no effect on the entry process but greatly affected virus assembly in mammalian cells. Interestingly, this mutant virus had a host-dependent phenotype and could develop a wild-type infection in insect cells. Experiments performed on infectious virus as well as in a virus-like particle (VLP) system indicate that the JEV mutant expresses structural proteins but fails to form infectious particles in mammalian cells. Using a mouse model for JEV pathogenesis, we showed that the mutation conferred complete attenuation in vivo. The production of JEV neutralizing antibodies in challenged mice was indicative of the immunogenicity of the mutant virus in vivo. Together, our results indicate that the introduction of a single mutation in the M protein, while being tolerated in insect cells, strongly impacts JEV infection in mammalian hosts. IMPORTANCEJEV is a mosquito-transmitted flavivirus and is a medically important pathogen in Asia. The M protein is thought to be important for accommodating the structural rearrangements undergone by the virion during viral assembly and may play additional roles in the JEV infectious cycle. In the present study, we show that a sole mutation in the M protein impairs the JEV infection cycle in mammalian hosts but not in mosquito cells. This finding highlights differences in flavivirus assembly pathways among hosts. Moreover, infection of mice indicated that the mutant was completely attenuated and triggered a strong immune response to JEV, thus providing new insights for further development of JEV vaccines. F laviviruses such as Japanese encephalitis virus (JEV) are arthropod-borne pathogens (arboviruses) that are transmitted through the bite of an infected mosquito and cause serious human diseases worldwide (1). JEV is the causative agent for Japanese encephalitis, one of the most important viral encephalitis diseases of medical interest in Asia, with an incidence of approximately 67,900 human cases per year (2). Up to 30% of the symptomatic cases are fatal, while 30 to 50% of survivors can develop long-term neurologic sequelae (3).JEV has a positive-sense RNA genome encoding a single polyprotein. This polyprotein is processed by host-and JEV-encoded proteases into 10 proteins: three structural proteins (core [C], premembrane [prM], and envelope [E]) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Like other flaviviruses, JEV enters cells via receptor-mediated endocytosis (4, 5). The acidic environment in the host endosome serves as the physiological trigger for a major conformational change in the E protein...

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A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available

Cited by 157 publications

References 106 publications

Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly

Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly

Zika virus disease: a current review of the literature

A Single Amino Acid Substitution in the M Protein Attenuates Japanese Encephalitis Virus in Mammalian Hosts

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