A Single Amino Acid Substitution in the Envelope Protein of Chimeric Yellow Fever-Dengue 1 Vaccine Virus Reduces Neurovirulence for Suckling Mice and Viremia/Viscerotropism for Monkeys

Guirakhoo, Farshad; Zhang, Z.; Myers, Gene; Johnson, Barbara W.; Пугачев, К. В.; Nichols, Richard A.; Brown, Nathan; Levenbook, Inessa S.; Draper, Ken; Cyrek, S.; Lang, Jean; Fournier, C.; Barrère, B.; Delagrave, Simon; Monath, Thomas P.

doi:10.1128/jvi.78.18.9998-10008.2004

Cited by 40 publications

(22 citation statements)

References 34 publications

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“…That corresponds to 1.64 LD 50 /0.03 ml, well below the established limits. In addition, the range of titers observed here is similar to that observed for rhesus monkeys inoculated with the attenuated 17D/JE SA-14-14-2 virus or with the chimeric 17D-den or 17D-204 virus (7,8,20). In addition, no evidence for hepatic, renal, or myocardial dysfunction or pathology was found, suggesting the absence of any unexpected tissue tropism or altered pathogenesis.…”

Section: Discussionsupporting

confidence: 61%

Attenuation of Recombinant Yellow Fever 17D Viruses Expressing Foreign Protein Epitopes at the Surface

Bonaldo

Garratt

Marchevsky

et al. 2005

J Virol

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The yellow fever (YF) 17D vaccine is a live attenuated virus. Three-dimensional (3D) homology modeling of the E protein structure from YF 17D virus and its comparison with that from tick-borne encephalitis virus revealed that it is possible to accommodate inserts of different sizes and amino acid compositions in the flavivirus E protein fg loop. This is consistent with the 3D structures of both the dimeric and trimeric forms in which the fg loop lies exposed to solvents. We demonstrate here that YF 17D viruses bearing foreign humoral (17D/8) and T-cell (17D/13) epitopes, which vary in sequence and length, displayed growth restriction. It is hypothesized that interference with the dimer-trimer transition and with the formation of a ring of such trimers in order to allow fusion compromises the capability of the E protein to induce fusion of viral and endosomal membranes, and a slower rate of fusion may delay the extent of virus production. This would account for the lower levels of replication in cultured cells and of viremia in monkeys, as well as for the more attenuated phenotype of the recombinant viruses in monkeys. Testing of both recombinant viruses (17D/8 and 17D/13) for monkey neurovirulence also suggests that insertion at the 17D E protein fg loop does not compromise the attenuated phenotype of YF 17D virus, further confirming the potential use of this site for the development of new live attenuated 17D virus-based vaccines.The yellow fever (YF) 17D virus is attenuated and used for human vaccination. Some of the outstanding properties of this vaccine include limited viral replication in the host but with significant expansion and dissemination of the viral mass, yielding a robust and long-lived neutralizing antibody response. The vaccine is cheap and applied as a single dose, and there are well-established production methodology and quality control procedures, which include the monkey neurovirulence test (MNVT). Altogether, the 17D virus has become very attractive as an expression vector for the development of new live attenuated vaccines.The development of infectious-clone technology has allowed the genetic manipulation of the YF 17D virus genome toward the expression of foreign genes. Different technical approaches to constructing recombinant viruses based on the YF 17D virus are possible and will differ according to the antigen to be expressed. One major approach has been the creation of chimeric viruses through the exchange of structural prM/M/E genes (reviewed in reference 10). An alternative approach used in the development of YF 17D virus as a vector for heterologous antigens is the expression of particular epitopes in the E protein. In the mature virus, the E protein forms a symmetrical network of 90 dimers. These dimers are anchored into the viral envelope and lie flat on its surface. Each monomer is composed of three domains. The central and dimerization domains (I and II, respectively) are formed of several noncontiguous stretches of the polypeptide chain, while the C-terminal domain III is a c...

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Section: Discussionsupporting

confidence: 61%

Attenuation of Recombinant Yellow Fever 17D Viruses Expressing Foreign Protein Epitopes at the Surface

Bonaldo

Garratt

Marchevsky

et al. 2005

J Virol

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“…For example, an experimental chimeric vaccine consisting of DENV1 prM and E genes in a yellow fever 17D vaccine strain backbone was reported to have a single change in E (K204R), resulting in decreased replication in cell culture, decreased virulence in mice, and decreased viremia in monkeys (68). Additionally, it was recently reported that a newly derived DENV2 with a cluster of mutations in a single region of E, including K128E, is associated with increased vascular permeability in mice (171a).…”

Section: Dengue Virus Genotype and Proteins In Pathogenesismentioning

confidence: 99%

Recent Advances in Deciphering Viral and Host Determinants of Dengue Virus Replication and Pathogenesis

Clyde

Kyle

Harris

2006

J Virol

328

301

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2Dengue virus (DENV) is a member of the Flavivirus genus of the Flaviviridae family of enveloped, positive-strand RNA viruses. The Flavivirus genus includes viruses transmitted by mosquitoes and ticks, as well as zoonotic agents with no known arthropod vector. In addition to DENV, flaviviruses that are significant threats to human health include yellow fever virus, West Nile virus (WNV), Japanese encephalitis virus, and tickborne encephalitis virus. The dengue viruses are comprised of four distinct serotypes, DENV1 through DENV4, which are transmitted to humans through the bites of two mosquito species: Aedes aegypti and A. albopictus.DENV causes a wide range of diseases in humans, from the acute febrile illness dengue fever (DF) to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). DF is a self-limited though debilitating illness characterized by fever, headache, retro-orbital pain, myalgia, arthralgia, and rash. DHF is marked by increased vascular permeability ("plasma leakage"), thrombocytopenia, and hemorrhagic manifestations; DSS occurs when fluid leakage into the interstitial spaces results in shock, which without appropriate treatment may lead to death. Dengue has spread throughout tropical and subtropical regions worldwide over the past several decades, with an estimated 100 million infections and tens of millions of cases occurring annually. DHF/DSS is one of the leading causes of pediatric hospitalization in Southeast Asia, where the syndrome first emerged 50 years ago, and has become endemic to many Latin American countries over the last 25 years (reviewed in references 64 and 184). DENGUE VIRUS REPLICATIONThe intracellular life cycles of the flaviviruses are very similar (Fig. 1). Infection with one of the arthropod-borne flaviviruses begins when the vector takes a blood meal and the virus is introduced into the host. The virus binds to and enters a permissive host cell via receptor-mediated endocytosis. Upon internalization and acidification of the endosome, fusion of viral and vesicular membranes allows entry of the nucleocapsid into the cytoplasm and genome uncoating. Translation of the input strand takes place; then the virus switches from translation to synthesis of a negative-strand intermediate, which serves as a template for the production of multiple copies of positive-strand viral RNA (vRNA). Successive rounds of translation produce high levels of viral proteins; the structural protein capsid or core (C), premembrane (prM), and envelope (E) proteins, along with vRNA, are assembled into progeny virions, which are transported through the Golgi compartment and secreted (reviewed in reference 56). While much that is assumed about DENV has been characterized for related flaviviruses such as yellow fever virus, WNV, Japanese encephalitis virus, and tick-borne encephalitis virus, for the purposes of this review we will focus on recent research that has concentrated specifically on the four serotypes of DENV. CELLULAR TROPISM, BINDING, AND ENTRYThe replication cycle of DENV ...

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“…The other WRAIR PDK-passaged vaccine candidates also contain one or more mutations in regions that interconnect the E protein domains. The dengue-1 PDK20 strain has an E204K mutation at the domain I/II interface (personal observation), dengue-3 PDK30 has an I195N mutation at the domainI/II interface (unpublished observation, Bangti Zhao) and dengue-4 PDK20 has an N366N/S mutation at the domain I/III interface [31]. An understanding of how mutations at the E domain interfaces affect virulence and growth during vaccine manufacture is highly relevant to the development and safety testing of live-attenuated dengue vaccines.…”

Section: Discussionmentioning

confidence: 94%

“…Four mutations of nucleotides 591 in prM, 987 in E, 6,471 in NS3 and 8,907 in NS5 were silent, and one changed a C to T in the 5 0 NCR ( Table 2). Most of these mutations are unique to the dengue-2 S16803 strain passaged in PDK cells but a few are similar in location to mutations found in other WRAIR PDK cell-adapted dengue strains [31]. Because the degree of attenuation of dengue-2 viruses progressively increased with PDK passage level, complete genomic sequences were derived for intermediate PDK passage-level strains PDK10, PDK30 and PDK40.…”

Section: Discussionmentioning

confidence: 99%

Evolution of attenuating mutations in dengue-2 strain S16803 PDK50 vaccine and comparison of growth kinetics with parent virus

et al. 2011

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A live-attenuated dengue-2 virus strain S16803 vaccine candidate that is immunogenic and safe in humans was derived by 50 passages in primary dog kidney (PDK) cells. To identify mutations associated with attenuation of the dengue-2 PDK50 vaccine strain, we determined the nucleotide changes that arose during PDK passage of the dengue-2 virus. Thirteen mutations distinguished the PDK50 virus from low-passage parent resulting in amino acid substitutions in the premembrane (E89G), envelope (E202K, N203D), nonstructural proteins NS1 (A43T), NS2A (L181F), NS2B (I26V), and NS4B (I/T108T, L112F). In addition, the PDK50 virus contained a C to T change of nucleotide 57 in the 5' non-coding region and four silent mutations of nucleotides 591, 987, 6471, and 8907. An infectious PDK50 cDNA clone virus was produced and characterized for growth kinetics in monkey (LLC-MK(2), Vero) and mosquito (C6/36) cells. Identification of mutations in the vaccine strain and availability of an infectious clone will permit systematic analysis of the importance of individual or collective mutations on attenuation of dengue virus.

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A Single Amino Acid Substitution in the Envelope Protein of Chimeric Yellow Fever-Dengue 1 Vaccine Virus Reduces Neurovirulence for Suckling Mice and Viremia/Viscerotropism for Monkeys

Cited by 40 publications

References 34 publications

Attenuation of Recombinant Yellow Fever 17D Viruses Expressing Foreign Protein Epitopes at the Surface

Attenuation of Recombinant Yellow Fever 17D Viruses Expressing Foreign Protein Epitopes at the Surface

Recent Advances in Deciphering Viral and Host Determinants of Dengue Virus Replication and Pathogenesis

Evolution of attenuating mutations in dengue-2 strain S16803 PDK50 vaccine and comparison of growth kinetics with parent virus

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