An alphavirus replicon-derived candidate vaccine against Rift Valley fever virus

Heise, Mark T.; Whitmore, Alan C.; Thompson, Jeff. E.; Parsons, M.; Grobbelaar, Antoinette A.; Kemp, Alan C.; Pawęska, Janusz T.; Madric, Kenya; White, Laura; Swanepoel, Robert; Burt, Felicity J.

doi:10.1017/s0950268808001696

Cited by 46 publications

(41 citation statements)

References 31 publications

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“…The replicon RNA genomes used in this study carried the green fluorescent protein (GFP) gene in place of the viral structural genes and were thus capable of GFP expression from the subgenomic 26S RNA promoter but were propagation defective. Construction of the AR86-based pREP89 (26) and Girdwood-based pRgird (29) replicon clones was described previously, and the GFP gene was inserted 3Ј of the 26S promoter 5Ј-untranslated region (5Ј-UTR) by use of the ClaI site, as described previously for insertion of other foreign genes (29). Helper transcripts for the capsid helper construct pCAP86 (26) and the glycoprotein helper pGIRDGLY (29) were generated as previously described.…”

Section: Methodsmentioning

confidence: 99%

A Determinant of Sindbis Virus Neurovirulence Enables Efficient Disruption of Jak/STAT Signaling

Simmons

Wollish

Heise

2010

J Virol

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Previous studies with Venezuelan equine encephalitis virus and Sindbis virus (SINV) indicate that alphaviruses are capable of suppressing the cellular response to type I and type II interferons (IFNs) by disrupting Jak/STAT signaling; however, the relevance of this signaling inhibition toward pathogenesis has not been investigated. The relative abilities of neurovirulent and nonneurovirulent SINV strains to downregulate Jak/STAT signaling were compared to determine whether the ability to inhibit IFN signaling correlates with virulence potential. The adult mouse neurovirulent strain AR86 was found to rapidly and robustly inhibit tyrosine phosphorylation of STAT1 and STAT2 in response to IFN-␥ and/or IFN-␤. In contrast, the closely related SINV strains Girdwood and TR339, which do not cause detectable disease in adult mice, were relatively inefficient inhibitors of STAT1/2 activation. Decreased STAT activation in AR86-infected cells was associated with decreased activation of the IFN receptor-associated tyrosine kinases Tyk2, Jak1, and Jak2. To identify the viral factor(s) involved, we infected cells with several panels of AR86/Girdwood chimeric viruses. Surprisingly, we found that a single amino acid determinant, threonine at nsP1 position 538, which is required for AR86 virulence, was also required for efficient disruption of STAT1 activation, and this determinant fully restored STAT1 inhibition when it was introduced into the avirulent Girdwood background. These data indicate that a key virulence determinant plays a critical role in downregulating the response to type I and type II IFNs, which suggests that the ability of alphaviruses to inhibit Jak/STAT signaling relates to their in vivo virulence potential.

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Section: Methodsmentioning

confidence: 99%

A Determinant of Sindbis Virus Neurovirulence Enables Efficient Disruption of Jak/STAT Signaling

Simmons

Wollish

Heise

2010

J Virol

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“…Strategies to develop RVFV vaccines include subunit (Schmaljohn et al 1989, Mandell et al 2010a, DNA (Spik et al 2006), viruslike particles (VLPs) , de Boer et al 2010, Kortekaas et al 2012, virus replicon particles (Kortekaas et al 2011, Dodd et al 2012, Oreshkova et al 2013), virus-vectored (Wallace et al 2006, Heise et al 2009) modified live vaccines, developed from recombinant viruses engineered using reverse genetics (Ikegami et al 2006, Bird et al 2008, Billecocq et al 2008, Habjan et al 2008, Bird et al 2011, live attenuated (Smithburn 1949, Caplen et al 1985, Muller et al 1995, Dungu et al 2010, Pittman 2012, Morrill et al 2013, and inactivated whole virus vaccines (Pittman et al 2000). Although subunit vaccines for RVFV are generally considered safe, and recently some progress has been made in their development, evaluation of immunogenicity and/or efficacy in a target species, sheep, has been performed for a few candidates (Kortekaas et al 2012, Oreshkova et al 2013).…”

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confidence: 99%

A Glycoprotein Subunit Vaccine Elicits a Strong Rift Valley Fever Virus Neutralizing Antibody Response in Sheep

Faburay

Lebedev²,

McVey³

et al. 2014

Vector-Borne and Zoonotic Diseases

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Rift Valley fever virus (RVFV), a member of the Bunyaviridae family, is a mosquito-borne zoonotic pathogen that causes serious morbidity and mortality in livestock and humans. The recent spread of the virus beyond its traditional endemic boundaries in Africa to the Arabian Peninsula coupled with the presence of susceptible vectors in nonendemic countries has created increased interest in RVF vaccines. Subunit vaccines composed of specific virus proteins expressed in eukaryotic or prokaryotic expression systems are shown to elicit neutralizing antibodies in susceptible hosts. RVFV structural proteins, amino-terminus glycoprotein (Gn), and carboxylterminus glycoprotein (Gc), were expressed using a recombinant baculovirus expression system. The recombinant proteins were reconstituted as a GnGc subunit vaccine formulation and evaluated for immunogenicity in a target species, sheep. Six sheep were each immunized with a primary dose of 50 lg of each vaccine immunogen with the adjuvant montanide ISA25; at day 21, postvaccination, each animal received a second dose of the same vaccine. The vaccine induced a strong antibody response in all animals as determined by indirect enzyme-linked immunosorbent assay (ELISA). A plaque reduction neutralization test (PRNT 80 ) showed the primary dose of the vaccine was sufficient to elicit potentially protective virus neutralizing antibody titers ranging from 40 to 160, and the second vaccine dose boosted the titer to more than 1280. Furthermore, all animals tested positive for neutralizing antibodies at day 328 postvaccination. ELISA analysis using the recombinant nucleocapsid protein as a negative marker antigen indicated that the vaccine candidate is DIVA (differentiating infected from vaccinated animals) compatible and represents a promising vaccine platform for RVFV infection in susceptible species.

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“…Placement of an alternative gene(s) encoding an immunogen at the site of the deleted structural proteins results in its expression in lieu of the viral structural proteins (25,27). Alphavirus replicons have been used successfully to express immunogens for a number of pathogens (28)(29)(30)(31)(32)(33)(34). We report here efforts to develop a combination vaccine that would protect against all three encephalitic alphaviruses (VEEV, WEEV, and EEEV).…”

mentioning

confidence: 99%

Combined Alphavirus Replicon Particle Vaccine Induces Durable and Cross-Protective Immune Responses against Equine Encephalitis Viruses

Reed

Glass

Bakken

et al. 2014

J Virol

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Alphavirus replicons were evaluated as potential vaccine candidates for Venezuelan equine encephalitis virus (VEEV), western equine encephalitis virus (WEEV), or eastern equine encephalitis virus (EEEV) when given individually or in combination (V/W/E) to mice or cynomolgus macaques. Individual replicon vaccines or the combination V/W/E replicon vaccine elicited strong neutralizing antibodies in mice to their respective alphavirus. Protection from either subcutaneous or aerosol challenge with VEEV, WEEV, or EEEV was demonstrated out to 12 months after vaccination in mice. Individual replicon vaccines or the combination V/W/E replicon vaccine elicited strong neutralizing antibodies in macaques and demonstrated good protection against aerosol challenge with an epizootic VEEV-IAB virus, Trinidad donkey. Similarly, the EEEV replicon and V/W/E combination vaccine elicited neutralizing antibodies against EEEV and protected against aerosol exposure to a North American variety of EEEV. Both the WEEV replicon and combination V/W/E vaccination, however, elicited poor neutralizing antibodies to WEEV in macaques, and the protection conferred was not as strong. These results demonstrate that a combination V/W/E vaccine is possible for protection against aerosol challenge and that cross-interference between the vaccines is minimal. IMPORTANCE Three related viruses belonging to the genus Alphavirus cause severe encephalitis in humans: Venezuelan equine encephalitis virus (VEEV), western equine encephalitis virus (WEEV), and eastern equine encephalitis virus (EEEV).Normally transmitted by mosquitoes, these viruses can cause disease when inhaled, so there is concern that these viruses could be used as biological weapons. Prior reports have suggested that vaccines for these three viruses might interfere with one another. We have developed a combined vaccine for Venezuelan equine encephalitis, western equine encephalitis, and eastern equine encephalitis expressing the surface proteins of all three viruses. In this report we demonstrate in both mice and macaques that this combined vaccine is safe, generates a strong immune response, and protects against aerosol challenge with the viruses that cause Venezuelan equine encephalitis, western equine encephalitis, and eastern equine encephalitis.

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An alphavirus replicon-derived candidate vaccine against Rift Valley fever virus

Cited by 46 publications

References 31 publications

A Determinant of Sindbis Virus Neurovirulence Enables Efficient Disruption of Jak/STAT Signaling

A Determinant of Sindbis Virus Neurovirulence Enables Efficient Disruption of Jak/STAT Signaling

A Glycoprotein Subunit Vaccine Elicits a Strong Rift Valley Fever Virus Neutralizing Antibody Response in Sheep

Combined Alphavirus Replicon Particle Vaccine Induces Durable and Cross-Protective Immune Responses against Equine Encephalitis Viruses

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