scholarly journals A Yellow Fever 17D Virus Replicon-Based Vaccine Platform for Emerging Coronaviruses

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1492
Author(s):  
Nadia Oreshkova ◽  
Sebenzile K. Myeni ◽  
Niraj Mishra ◽  
Irina C. Albulescu ◽  
Tim J. Dalebout ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Fast Track ◽  
Yellow Fever Virus ◽  
Neutralizing Antibody ◽  
Surface Proteins ◽  
Emerging Viruses ◽  
Vaccine Platform ◽  
E Proteins ◽  
Infected Cells ◽  
In Trans

The tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective vaccines. Yellow fever virus 17D (YF17D) is a live-attenuated virus vaccine with an impressive efficacy record in humans, and therefore, it is a very attractive platform for the development of novel chimeric vaccines against various pathogens. In the present study, we generated a YF17D-based replicon vaccine platform by replacing the prM and E surface proteins of YF17D with antigenic subdomains from the spike (S) proteins of three different betacoronaviruses: MERS-CoV, SARS-CoV and MHV. The prM and E proteins were provided in trans for the packaging of these RNA replicons into single-round infectious particles capable of expressing coronavirus antigens in infected cells. YF17D replicon particles expressing the S1 regions of the MERS-CoV and SARS-CoV spike proteins were immunogenic in mice and elicited (neutralizing) antibody responses against both the YF17D vector and the coronavirus inserts. Thus, YF17D replicon-based vaccines, and their potential DNA- or mRNA-based derivatives, may constitute a promising and particularly safe vaccine platform for current and future emerging coronaviruses.

scholarly journals Yellow Fever Virus Down-Regulates mRNA Expression of SOCS1 in the Initial Phase of Infection in Human Cell Lines

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 802
Author(s):  
Michael B. Yakass ◽  
David Franco ◽  
Osbourne Quaye
Keyword(s):  
Mrna Expression ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Expression Patterns ◽  
Fever Virus ◽  
Effective Vaccine ◽  
Interferon Β ◽  
Infected Cells ◽  
Insight Into

Flaviviruses are constantly evolving diverse immune evasion strategies, and the exploitation of the functions of suppressors of cytokine signalling (SOCS) and protein inhibitors of activated STATs (PIAS) to favour virus replication has been described for Dengue and Japanese encephalitis viruses but not for yellow fever virus (YFV), which is still of global importance despite the existence of an effective vaccine. Some mechanisms that YFV employs to evade host immune defence has been reported, but the expression patterns of SOCS and PIAS in infected cells is yet to be determined. Here, we show that SOCS1 is down-regulated early in YFV-infected HeLa and HEK 293T cells, while SOCS3 and SOCS5 are not significantly altered, and PIAS mRNA expression appears to follow a rise-dip pattern akin to circadian-controlled genes. We also demonstrate that YFV evades interferon-β application to produce comparable viral titres. This report provides initial insight into the in vitro expression dynamics of SOCS and PIAS upon YFV infection and a basis for further investigation into SOCS/PIAS expression and how these modulate the immune response in animal models.

scholarly journals Yellow Fever Virus/Dengue-2 Virus and Yellow Fever Virus/Dengue-4 Virus Chimeras: Biological Characterization, Immunogenicity, and Protection against Dengue Encephalitis in the Mouse Model

2003 ◽  
Vol 77 (6) ◽  
pp. 3655-3668 ◽  
Author(s):  
Thomas J. Chambers ◽  
Yan Liang ◽  
Deborah A. Droll ◽  
Jacob J. Schlesinger ◽  
Andrew D. Davidson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dengue Virus ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
E Proteins ◽  
Dengue Viruses ◽  
Intracerebral Inoculation ◽  
Intraperitoneal Route ◽  
Chimeric Viruses

ABSTRACT Two yellow fever virus (YFV)/dengue virus chimeras which encode the prM and E proteins of either dengue virus serotype 2 (dengue-2 virus) or dengue-4 virus within the genome of the YFV 17D strain (YF5.2iv infectious clone) were constructed and characterized for their properties in cell culture and as experimental vaccines in mice. The prM and E proteins appeared to be properly processed and glycosylated, and in plaque reduction neutralization tests and other assays of antigenic specificity, the E proteins exhibited profiles which resembled those of the homologous dengue virus serotypes. Both chimeric viruses replicated in cell lines of vertebrate and mosquito origin to levels comparable to those of homologous dengue viruses but less efficiently than the YF5.2iv parent. YFV/dengue-4 virus, but not YFV/dengue-2 virus, was neurovirulent for 3-week-old mice by intracerebral inoculation; however, both viruses were attenuated when administered by the intraperitoneal route in mice of that age. Single-dose inoculation of either chimeric virus at a dose of 105 PFU by the intraperitoneal route induced detectable levels of neutralizing antibodies against the homologous dengue virus strains. Mice which had been immunized in this manner were fully protected from challenge with homologous neurovirulent dengue viruses by intracerebral inoculation compared to unimmunized mice. Protection was associated with significant increases in geometric mean titers of neutralizing antibody compared to those for unimmunized mice. These data indicate that YFV/dengue virus chimeras elicit antibodies which represent protective memory responses in the mouse model of dengue encephalitis. The levels of neurovirulence and immunogenicity of the chimeric viruses in mice correlate with the degree of adaptation of the dengue virus strain to mice. This study supports ongoing investigations concerning the use of this technology for development of a live attenuated viral vaccine against dengue viruses.

scholarly journals Mutations in the Yellow Fever Virus Nonstructural Protein NS2A Selectively Block Production of Infectious Particles

2002 ◽  
Vol 76 (10) ◽  
pp. 4773-4784 ◽  
Author(s):  
Beate M. Kümmerer ◽  
Charles M. Rice
Keyword(s):  
Amino Acids ◽  
Yellow Fever ◽  
Cleavage Site ◽  
Infectious Virus ◽  
Yellow Fever Virus ◽  
Nonstructural Protein ◽  
Virus Production ◽  
Fever Virus ◽  
Helicase Domain ◽  
Infected Cells

ABSTRACT Little is known about the function of flavivirus nonstructural protein NS2A. Two forms of NS2A are found in yellow fever virus-infected cells. Full-length NS2A (224 amino acids) is the product of cleavage at the NS1/2A and NS2A/2B sites. NS2Aα, a C-terminally truncated form of 190 amino acids, results from partial cleavage by the viral NS2B-3 serine protease at the sequence QK↓T within NS2A. Exchange of serine for lysine at this site (QKT→QST) blocks the production of both NS2Aα and infectious virus. The present study reveals that this defect is not at the level of RNA replication. Despite normal structural region processing, infectious particles containing genome RNA and capsid protein were not released from cells transfected with the mutant RNA. Nevertheless, production of subviral prM/M- and E-containing particles was unimpaired. The NS2A defect could be complemented in trans by providing NS1-2A or NS1-2Aα. However, trans complementation was not observed when the C-terminal lysine of NS1-2Aα was replaced with serine. In addition to true reversions, NS2Aα cleavage site mutations could be suppressed by two classes of second-site changes. The first class consisted of insertions at the NS2Aα cleavage site that restored its basic character and cleavability. A second class of suppressors occurred in the NS3 helicase domain, in which NS3 aspartate 343 was replaced with an uncharged residue (either valine, alanine, or glycine). These mutations in NS3 restored infectious-virus production in the absence of cleavage at the mutant NS2Aα site. Taken together, our results reveal an unexpected role for NS2A and NS3 in the assembly and/or release of infectious flavivirus particles.

scholarly journals Wolbachia wStri Blocks Zika Virus Growth at Two Independent Stages of Viral Replication

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
M. J. Schultz ◽  
A. L. Tan ◽  
C. N. Gray ◽  
S. Isern ◽  
S. F. Michael ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Viral Replication ◽  
Yellow Fever ◽  
Virus Replication ◽  
Zika Virus ◽  
Chikungunya Virus ◽  
Yellow Fever Virus ◽  
Rna Viruses ◽  
Content Type ◽  
Infected Cells

ABSTRACTMosquito-transmitted viruses are spread globally and present a great risk to human health. Among the many approaches investigated to limit the diseases caused by these viruses are attempts to make mosquitos resistant to virus infection. Coinfection of mosquitos with the bacteriumWolbachia pipientisfrom supergroup A is a recent strategy employed to reduce the capacity for major vectors in theAedesmosquito genus to transmit viruses, including dengue virus (DENV), Chikungunya virus (CHIKV), and Zika virus (ZIKV). Recently, a supergroup BWolbachia wStri, isolated fromLaodelphax striatellus, was shown to inhibit multiple lineages of ZIKV inAedes albopictuscells. Here, we show thatwStri blocks the growth of positive-sense RNA viruses DENV, CHIKV, ZIKV, and yellow fever virus by greater than 99.9%.wStri presence did not affect the growth of the negative-sense RNA viruses LaCrosse virus or vesicular stomatitis virus. Investigation of the stages of the ZIKV life cycle inhibited bywStri identified two distinct blocks in viral replication. We found a reduction of ZIKV entry intowStri-infected cells. This was partially rescued by the addition of a cholesterol-lipid supplement. Independent of entry, transfected viral genome was unable to replicate inWolbachia-infected cells. RNA transfection and metabolic labeling studies suggested that this replication defect is at the level of RNA translation, where we saw a 66% reduction in mosquito protein synthesis inwStri-infected cells. This study’s findings increase the potential for application ofwStri to block additional arboviruses and also identify specific blocks in viral infection caused byWolbachiacoinfection.IMPORTANCEDengue, Zika, and yellow fever viruses are mosquito-transmitted diseases that have spread throughout the world, causing millions of infections and thousands of deaths each year. Existing programs that seek to contain these diseases through elimination of the mosquito population have so far failed, making it crucial to explore new ways of limiting the spread of these viruses. Here, we show that introduction of an insect symbiont,Wolbachia wStri, into mosquito cells is highly effective at reducing yellow fever virus, dengue virus, Zika virus, and Chikungunya virus production. Reduction of virus replication was attributable to decreases in entry and a strong block of virus gene expression at the translational level. These findings expand the potential use ofWolbachia wStri to block viruses and identify two separate steps for limiting virus replication in mosquitos that could be targeted via microbes or other means as an antiviral strategy.

Recombinant vaccinia virus producing the prM and E proteins of yellow fever virus protects mice from lethal yellow fever encephalitis

Virology ◽  
1992 ◽  
Vol 187 (1) ◽  
pp. 290-297 ◽  
Author(s):  
Steven Pincus ◽  
Peter W. Mason ◽  
Eiji Konishi ◽  
Benedito A.L. Fonseca ◽  
Robert E. Shope ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Recombinant Vaccinia Virus ◽  
Fever Virus ◽  
E Proteins ◽  
Recombinant Vaccinia ◽  
Lethal Yellow

scholarly journals Exchanging the Yellow Fever Virus Envelope Proteins with Modoc Virus prM and E Proteins Results in a Chimeric Virus That Is Neuroinvasive in SCID Mice

2004 ◽  
Vol 78 (14) ◽  
pp. 7418-7426 ◽  
Author(s):  
Nathalie Charlier ◽  
Richard Molenkamp ◽  
Pieter Leyssen ◽  
Jan Paeshuyse ◽  
Christian Drosten ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Vero Cells ◽  
Envelope Proteins ◽  
Scid Mice ◽  
Fever Virus ◽  
Chimeric Virus ◽  
E Proteins ◽  
Virus Envelope

ABSTRACT A chimeric flavivirus infectious cDNA was constructed by exchanging the premembrane (prM) and envelope (E) genes of the yellow fever virus vaccine strain 17D (YF17D) with the corresponding genes of Modoc virus (MOD). This latter virus belongs to the cluster of the “not-known vector” flaviviruses and is, unlike YF17D, neuroinvasive in SCID mice. Replication of in vitro-transcribed RNA from this chimeric flavivirus was shown by [3H]uridine labeling and RNA analysis. Expression of the MOD prM and E proteins was monitored by radioimmunoprecipitation and revealed that the MOD proteins were correctly and efficiently produced from the chimeric precursor protein. The MOD E protein was shown to be N-linked glycosylated, whereas prM, as predicted from the genome sequence, did not contain N-linked carbohydrates. In Vero cells, the chimeric virus replicated with a similar efficiency as the parental viruses, although it formed smaller plaques than YF17D and MOD. In SCID mice that had been infected intraperitoneally with the chimeric virus, the viral load increased steadily until death. The MOD/YF virus, like MOD from which it had acquired the prM and E structural proteins, but unlike YF, proved neuroinvasive in SCID mice. Animals developed neurological symptoms about 15 days after inoculation and died shortly thereafter. The distribution of MOD/YF RNA in the brain of infected mice was similar to that observed in MOD-infected mice. The observations provide compelling evidence that the determinants of neuroinvasiveness of flaviviruses are entirely located in the envelope proteins prM and E.

scholarly journals A chimeric Japanese encephalitis vaccine protects against lethal yellow fever virus infection without inducing neutralizing antibodies

2019 ◽  
Author(s):  
Niraj Mishra ◽  
Robbert Boudewijns ◽  
Michael A. Schmid ◽  
Rafael Elias Marques ◽  
Sapna Sharma ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Japanese Encephalitis ◽  
Neutralizing Antibodies ◽  
Yellow Fever Virus ◽  
Neutralizing Antibody ◽  
Fever Virus ◽  
Off Label Use ◽  
Off Label ◽  
Japanese Encephalitis Vaccine ◽  
Label Use

ABSTRACTRecent massive outbreaks of yellow fever virus (YFV) in West Africa and Brazil resulted in rapid depletion of global vaccine emergency stockpiles and raised concerns about being not prepared against future YFV epidemics. Here we report that a live-attenuated virus similar to the Japanese encephalitis virus (JEV) vaccine JE-CVax/Imojev® that consists of YFV-17D vaccine from which the structural (prM/E) genes have been replaced with those of the JEV SA14-14-2 vaccine strain confers full protection in mice against lethal YFV challenge. In contrast to the YFV-17D mediated protection against YFV, this protection is not mediated by neutralizing antibodies but correlates with YFV-specific non-neutralizing antibodies and T cell responses against cell-associated YFV NS1 and other YFV non-structural (NS) proteins. Our findings reveal the importance of YFV NS proteins to mediate protection and demonstrate that chimeric flavivirus vaccines, such as Imojev® can confer protection against two flaviviruses. This dual protection has implications for the possible off-label use of JE-CVax in case of emergency and vaccine shortage during YFV outbreaks. In addition, populations in Asia that have been vaccinated with Imojev® may already be protected against YFV should outbreaks ever occur on that continent as feared by WHO.IMPORTANCEEfficient and safe vaccines exist against yellow fever (e.g. YFV-17D) that provide long-lasting protection by rapidly inducing neutralizing antibody responses. However, vaccine supply cannot cope with an increasing demand posed by massive urban outbreaks in recent years. Here we report that JE-CVax/Imojev®, a YFV-17D-based chimeric Japanese encephalitis vaccine also efficiently protects against YFV infection in mice. In case of shortage of the YFV vaccine during yellow fever outbreaks, (off-label) use of JE-CVax/Imojev® may be considered. Moreover, wider use of JE-CVax/Imojev® in Asia may lower the risk of the much-feared YFV spill over to the continent. More in general chimeric vaccines that combine surface antigens and replication machineries of two distinct flaviviruses can be considered dual vaccines, for the latter pathogen without induction of surface-specific antibodies. Following this rationale, novel flavivirus vaccines that do not hold a risk for antibody-dependent enhancement (ADE) of infection [inherent to current dengue vaccines and dengue vaccine candidates] could be designed.

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