Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3′ untranslated region (3′-UTR) or by exchange of the DENV-3 3′-UTR with that of DENV-4

Blaney, Joseph E.; Sathe, Neeraj S.; Goddard, Laura; Hanson, Christopher T.; Romero, Tammy A.; Hanley, Kathryn A.; Murphy, Brian R.; Whitehead, Stephen S.

doi:10.1016/j.vaccine.2007.11.082

Cited by 95 publications

(80 citation statements)

References 38 publications

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“…But the chances that variance in noninfectious particles among the different viruses contributes to virulence are low, in particular when one considers that the DENV strains that were compared differ only by a single amino acid in NS4B in their whole genomes. Specific mutations altering viral replication efficacy that resulted in virulence attenuation have been identified previously mainly in the 3Ј and 5Ј noncoding regions of the DENV genome and have driven the selection of live attenuated DENV vaccine candidates (6,20,34). It was proposed that mutations in these untranslated regions result in alterations of the secondary structure and folding of the RNA molecule that would impair its stability and/or affect replication efficacy.…”

Section: Discussionmentioning

confidence: 99%

A Single Amino Acid in Nonstructural Protein NS4B Confers Virulence to Dengue Virus in AG129 Mice through Enhancement of Viral RNA Synthesis

Grant

Tan

Qing

et al. 2011

J Virol

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Dengue (DEN) is a mosquito-borne viral disease that has become an increasing economic and health burden for the tropical and subtropical world. The lack of an appropriate animal model of DEN has greatly impeded the study of its pathogenesis and the development of vaccines/antivirals. We recently reported a DEN virus 2 (DENV-2) strain (D2Y98P) that lethally infects immunocompromised AG129 mice, resulting in organ damage or dysfunction and increased vascular permeability, hallmarks of severe DEN in patients (G. K. Tan et al., PLoS Negl. Trop. Dis. 4:e672, 2010). Here we report the identification of one critical virulence determinant of strain D2Y98P. By mutagenesis, we showed that a Phe-to-Leu alteration at amino acid position 52 in nonstructural protein NS4B completely abolished the pathogenicity of the D2Y98P virus, as evidenced by a lack of lethality and the absence of histological signs of disease, which correlated with reduced viral titers and intact vascular permeability. Conversely, a Leu-to-Phe alteration at position 52 of NS4B in nonvirulent DENV-2 strain TSV01 led to 80% lethality and increased viremia. The NS4B(Phe52) viruses displayed enhanced RNA synthesis in mammalian cells but not in mosquito cells. The increased viral RNA synthesis was independent of the ability of NS4B to interfere with the host type I interferon response. Overall, our results demonstrate that Phe at position 52 in NS4B confers virulence in mice on two independent DENV-2 strains through enhancement of viral RNA synthesis. In addition to providing further insights into the functional role of NS4B protein, our findings further support a direct relationship between viral loads and DEN pathogenesis in vivo, consistent with observations in DEN patients.Dengue (DEN) disease, caused by any one of the four serotypes of dengue virus (DENV), is a major global public health and economic burden. DENV affects 2.5 billion people worldwide, mostly in tropical and subtropical countries, leading to 50 to 100 million human infections each year (13). Clinical manifestations of DEN disease range from undifferentiated fever to DEN fever (DF) and DEN hemorrhagic fever (DHF), with plasma leakage that may lead to hypovolemic shock (DEN shock syndrome [DSS]). Therapeutic intervention is limited to fluid management for DEN patients who experience severe vascular leakage (41). Currently, no antiviral therapy or vaccine to fight DEN is available on the market (9, 31).DENV belongs to the genus Flavivirus within the family Flaviviridae. Besides DENV, many other flaviviruses are important human pathogens, including yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV). DENV is a small enveloped virus with a positive single-strand RNA of approximately 10,700 nucleotides (18). The DENV genome encodes 10 proteins, comprising 3 structural proteins (capsid [C], premembrane [PrM], and envelope [E]) and 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The structural proteins fo...

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Section: Discussionmentioning

confidence: 99%

A Single Amino Acid in Nonstructural Protein NS4B Confers Virulence to Dengue Virus in AG129 Mice through Enhancement of Viral RNA Synthesis

Grant

Tan

Qing

et al. 2011

J Virol

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“…Live-attenuated vaccines (LAV) for yellow fever and Japanese encephalitis are in widespread use, and LAV for other flavivirus diseases, including dengue and West Nile encephalitis, are in different stages of development (7,8,16,18,21,29,34,35,40). LAV offer considerable advantage over inactivated viral vaccines or subunit vaccines in terms of efficacy and cost.…”

mentioning

confidence: 99%

Identification of Mutated Cyclization Sequences That Permit Efficient Replication of West Nile Virus Genomes: Use in Safer Propagation of a Novel Vaccine Candidate

Suzuki

Fayzulin²,

Frolov³

et al. 2008

J Virol

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“…In the context of vaccines, cDNA clones have allowed the [37]. Thus far infectious clones have been constructed for most of the major pathogenic flaviviruses: DENV-1 [38,39], DENV-2 [40][41][42][43][44], DENV-3 [45,46], DENV-4 [47], JEV [48,49], WNV [50], Kunjin [51], TBEV [52,53], Langat [54], Murray Valley encephalitis virus [55], wild-type YFV [56], and 17D YFV [57]. Mutagenesis and manipulation of these cDNA clones has led to the development of several new vaccine candidates.…”

Section: Infectious Cdna Clonesmentioning

confidence: 99%

Nucleic Acid-Based Infectious and Pseudo-Infectious Flavivirus Vaccines

Roby

Hall

Khromykh

2010

Replicating Vaccines

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The genus Flavivirus contains a number of important pathogens of humans including yellow fever virus (YFV), dengue virus (DENV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and West Nile virus (WNV). Despite causing significant morbidity and mortality worldwide, commercially available vaccines only exist for YFV (live-attenuated), TBEV, and JEV (inactivated). Flavivirus vaccine research has been driven by the need for cheap, safe, thermally stable, and efficacious preparations amenable to use in developing nations. The creation of infectious cDNA clones of various flaviviruses has led to the development of genetically engineered, nucleic acid-delivered, attenuated live vaccine candidates. These provide effective immunity from a single immunisation, however share the same safety concerns as traditional live-attenuated vaccines. The generation of large internal deletions in the capsid gene of flavivirus genomes creates a vaccine that secretes large amounts of immunogenic prM/E particles from self-replicating RNA but does not form a spreading infection. Packaging of these capsid-deleted RNAs into virus-like particles (VLPs) using a cell line that produces capsid gene from another expression vector creates a pseudoinfectious vaccine that elicits a highly efficient immune response from a single dose and is safer than infectious virus. However, production of these VLPs is cumbersome and the resulting product is heat labile. Providing the capsid gene in trans from another promoter but within the same plasmid DNA as the capsid-deleted viral genome creates a DNA vaccine capable of producing VLPs in vivo. Uptake of this plasmid DNA results in the generation of self-replicating, capsid-deleted RNA and the capsid protein in the same cell, leading to production of secreted single-round infectious particles (SRIPs). These SRIPs then deliver capsid-deleted RNA to adjacent cells where it replicates to produce more prM/E particles. As functional

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Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3′ untranslated region (3′-UTR) or by exchange of the DENV-3 3′-UTR with that of DENV-4

Cited by 95 publications

References 38 publications

A Single Amino Acid in Nonstructural Protein NS4B Confers Virulence to Dengue Virus in AG129 Mice through Enhancement of Viral RNA Synthesis

A Single Amino Acid in Nonstructural Protein NS4B Confers Virulence to Dengue Virus in AG129 Mice through Enhancement of Viral RNA Synthesis

Identification of Mutated Cyclization Sequences That Permit Efficient Replication of West Nile Virus Genomes: Use in Safer Propagation of a Novel Vaccine Candidate

Nucleic Acid-Based Infectious and Pseudo-Infectious Flavivirus Vaccines

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