A replication-incompetent Rift Valley fever vaccine: Chimeric virus-like particles protect mice and rats against lethal challenge

Mandell, Robert B.; Koukuntla, Ramesh; Mogler, Laura J.K.; Carzoli, Andrea K.; Freiberg, Alexander N.; Holbrook, Michael R.; Martin, Brian K.; Staplin, William R.; Vahanian, Nicholas N.; Link, Charles J.; Flick, Ramon

doi:10.1016/j.virol.2009.11.001

Cited by 70 publications

(78 citation statements)

References 125 publications

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“…The vaccine induced potentially protective (i.e., 1:40), virus neutralizing titers with single vaccination in five of the six animals within 2 weeks pv (Table 1). These results compared favorably with the outcome of recently reported vaccinations using vaccines based on RVFV glycoproteins, such as GnGc VLPs and Gne , de Boer et al 2010, Mandell et al 2010a, Kortekaas et al 2012, Oreshkova et al 2013, as well as a Newcastle disease virus-vectored vaccine (NDFL-GnGc) (Kortekaas et al 2010a, Kortekaas et al 2010b) and virus replicon particles (Dodd et al 2012, Oreshkova et al 2013, some of which have also been reported to elicit neutralizing antibodies with single vaccination in sheep (Kortekaas et al 2010a, Kortekaas, et al 2012, Oreshkova, et al 2013.…”

Section: Discussionsupporting

confidence: 61%

“…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%

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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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Section: Discussionsupporting

confidence: 61%

mentioning

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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“…IFN-γ expression from VACVs was confirmed by ELISA by a commercial ELISA (huIFNγ ELISA Ready-SET-Go!, eBioScience); bioactivity of the cytokine was confirmed by an IFN-γ bioassay (47) Plaque-Reduction Neutralization Tests. RVFV PRNT 80 assays for mouse sera after challenge were performed in the biosafety level 4 laboratory at UTMB, as previously described (51). The same procedure was used at UC Davis to analyze the prechallenge mouse and baboon sera.…”

Section: Methodsmentioning

confidence: 99%

Recombinant Rift Valley fever vaccines induce protective levels of antibody in baboons and resistance to lethal challenge in mice

Papin¹,

Verardi

Jones³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Rift Valley fever (RVF) is a zoonotic disease endemic in Africa and the Arabian Peninsula caused by the highly infectious Rift Valley fever virus (RVFV) that can be lethal to humans and animals and results in major losses in the livestock industry. RVF is exotic to the United States; however, mosquito species native to this region can serve as biological vectors for the virus. Thus, accidental or malicious introduction of this virus could result in RVFV becoming endemic in North America. Such an event would likely lead to significant morbidity and mortality in humans, and devastating economic effects on the livestock industry. Currently, there are no licensed vaccines for RVF that are both safe and efficacious. To address this issue, we developed two recombinant RVFV vaccines using vaccinia virus (VACV) as a vector for use in livestock. The first vaccine, vCOGnGc, was attenuated by the deletion of a VACV gene encoding an IFN-γ binding protein, insertional inactivation of the thymidine kinase gene, and expression of RVFV glycoproteins, Gn and Gc. The second vaccine, vCOGnGcγ, is identical to the first and also expresses the human IFN-γ gene to enhance safety. Both vaccines are extremely safe; neither resulted in weight loss nor death in severe combined immunodeficient mice, and pock lesions were smaller in baboons compared with the controls. Furthermore, both vaccines induced protective levels of antibody titers in vaccinated mice and baboons. Mice were protected from lethal RVFV challenge. Thus, we have developed two safe and efficacious recombinant vaccines for RVF.

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“…Examples of recently developed candidate vaccines include DNA-vectored (2,24,27), virus-like particle (VLP) (11,29,31), replicon particle (RRP) (23), and live attenuated (5, 13) vaccines. VLP candidates show promise and remarkable safety but generally require adjuvant and/or multiple immunizations for complete protection.…”

mentioning

confidence: 99%

Single-Dose Immunization with Virus Replicon Particles Confers Rapid Robust Protection against Rift Valley Fever Virus Challenge

Dodd

Bird

Metcalfe

et al. 2012

J Virol

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c Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. The potential for RVFV introduction outside the area of endemicity highlights the need for fast-acting, safe, and efficacious vaccines. Here, we demonstrate a robust system for the reverse genetics generation of a RVF virus replicon particle (VRP RVF ) vaccine candidate. Using a mouse model, we show that VRP RVF immunization provides the optimal balance of safety and single-dose robust efficacy. VRP RVF can actively synthesize viral RNA and proteins but lacks structural glycoprotein genes, preventing spread within immunized individuals and reducing the risk of vaccine-induced pathogenicity. VRP RVF proved to be completely safe following intracranial inoculation of suckling mice, a stringent test of vaccine safety. Single-dose subcutaneous immunization with VRP RVF , although it is highly attenuated, completely protected mice against a virulent RVFV challenge dose which was 100,000-fold greater than the 50% lethal dose (LD 50 ). Robust protection from lethal challenge was observed by 24 h postvaccination, with 100% protection induced in as little as 96 h. We show that a single subcutaneous VRP RVF immunization initiated a systemic antiviral state followed by an enhanced adaptive response. These data contrast sharply with the much-reduced survivability and immune responses observed among animals immunized with nonreplicating viral particles, indicating that replication, even if confined to the initially infected cells, contributes substantially to protective efficacy at early and late time points postimmunization. These data demonstrate that replicon vaccines successfully bridge the gap between safety and efficacy and provide insights into the kinetics of antiviral protection from RVFV infection.

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A replication-incompetent Rift Valley fever vaccine: Chimeric virus-like particles protect mice and rats against lethal challenge

Cited by 70 publications

References 125 publications

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

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

Recombinant Rift Valley fever vaccines induce protective levels of antibody in baboons and resistance to lethal challenge in mice

Single-Dose Immunization with Virus Replicon Particles Confers Rapid Robust Protection against Rift Valley Fever Virus Challenge

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