Background and Vector Design: The filoviruses Marburg virus and Ebola virus cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Currently there are no approved therapeutics or vaccines available despite a number of experimental approaches. Among the promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). This system was developed in our group in collaboration with Dr. Thomas Geisbert (now UTMB, Galveston) and the current status of the vaccine development was recently reviewed. (Geisbert &Feldmann, Infect Dis. 2011;204: S1075) We have developed rVSVs expressing the GP of representative strains of all species of Ebola virus Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), Bundibugyo ebolavirus (BEBOV) and Reston ebolavirus (REBOV) as well as two strains of Marburg virus Lake Victoria marburgvirus strains Musoke (LVMARV-Mus) and Angola (LVMARV-Ang). These vaccine vectors have been extensively characterized in animal models for their protective efficacy against homologous challenges (Hoenen et al. Expert Opin Biol Ther. 2012;12: 859;Geisbert &Feldmann, Infect Dis. 2011;204: S1075;Marzi et al., J Bioterror Biodef. 2011;S1(4): 2157;deWit et al Genome Med. 2011;3: 5;Falzarano et al Expert Rev Vaccines. 2011;10: 63).. One of the main concerns with all replication-competent vaccines, including the rVSV filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study in cynomolgus macaques where the vaccines were administered intrathalamically. Our data strongly suggest that rVSV filovirus GP vaccine vectors lack the neurovirulence properties associated with the VSV wild-type parent vector and support their further development as a vaccine platform for human use. (Mire et al PLoS Negl Trop Dis. 2012;6(3): e1567) Cross-Protection Using Monovalent Vaccine Vectors: Cross-protection among the different Ebola virus species and even Marburg virus is an important consideration and has been difficult to achieve due to relatively high genetic variability among genera in particular but also among species within a single genus, and the general lack of cross-protective antibodies even among species. In this regard we have previously performed a proof-of-concept study using a single-injection protocol with a blended vaccine including rVSV-SEBOVgp, rVSV-ZEBOVgp and rVSV-LVMARVMusgp to see if a cross-protective vaccine could be developed against four human pathogenic filoviruses endemic in Central Africa. Challenge was performed four weeks after immunization with MARV-Mus, SEBOV, ZEBOV and CIEBOV resulting in protection against homologous challenges as well as a heterologous challenge (CIEBOV) indicating that cross-protective vaccines are feasible. (Geisbert et al., J Virol. 2009;83:7296) More recently, we have performed another proof-of-concept study in which we evaluated cross-protection following immunization with a single vaccine vector (rVSV-ZEBOVGP or rVSV-CIEBOVGP) (Falzarano et al. J Infect Dis. 2011;204 Suppl 3: S1082). A single vaccination with the rVSV-ZEBOVgp provided cross-protection (75% survival) against a subsequent heterologous BEBOV challenge, whereas vaccination with the rVSV-CIEBOVgp resulted in no protection. This demonstrates that monovalent rVSV-based vaccines may be useful against a newly emerging species;however, heterologous protection across species remains challenging and may depend on enhancing the immune responses either through booster immunizations or through the inclusion of multiple immunogens. Overall, we can conclude that single monovalent rVSV vaccine vectors can provide partial cross-protection in cases of challenge viruses that are genetically more closely related. One approach to overcome this limitation is the use of blended monovalent rVSV vaccine vectors, which provide broader cross-protection against homologous and partial protection against certain heterologous challenges. Cross-Protection Using Multivalent Vaccine Vectors: Another approach to overcome the limitations in cross-protection is the use of multivalent rVSV vaccine vectors. A proof-of-concept study was performed in Syrian hamsters using immunization with a single bivalent rVSV vector expressing the glycoproteins of ZEBOV and Andes virus (ANDV), a New World hantavirus (rVSV-ZEBOVgp/ANDVgpc). A single immunization with rVSV-ZEBOVgp/ANDVgpc conferred complete and sterile protection against lethal ZEBOV and ANDV challenge. Complete protection was achieved with an immunization as close as 3 days prior to ZEBOV challenge, and 40% of the animals were even protected when treated with rVSV-ZEBOVgp/ANDVgpc one day postchallenge. We concluded that bivalent rVSV vectors are a feasible approach to vaccination against multiple pathogens. (Tsuda et al. J Infect Dis. 2011;204 Suppl 3: S1090) Infection of guinea pigs with non-adapted Ebola virus wild-type strains of the different species resulted in full protection of all animals against subsequent challenge with guinea pig-adapted ZEBOV, showing that cross-species protection is possible. However, cross-protection was not achieved in guinea pigs following immunization with a monovalent rVSV expressing a single Ebola virus GP against and subsequent heterologous challenge, indicating that the Ebola virus GPs alone are not sufficient to elucidate cross-protective efficacy. New bivalent rVSV vectors were generated that express a heterologous Ebola virus GP and additional heterologous Ebola virus proteins (VP40 or NP). After applying a 2-dose immunization approach, we observed an improved cross-protection rate. Our data demonstrate that cross-protection between the EBOV species can be achieved, although EBOV-GP alone cannot induce the required immune response. (Marzi et al. J Infect Dis. 2011;204 Suppl 3: S1066) Based on all our results described above, we are currently generating trivalent rVSV vectors expressing three different Ebola virus GPs, one as a transmembrane protein (replacing the VSV glycoprotein) and two as soluble proteins that will be secreted. Efficacy testing of the vectors will be performed in a rodent and non-human primate model. Alternatively, we will express two Ebola virus GPs and another Ebola virus protein (i.e. VP40) in a trivalent rVSV vector.

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Budget End
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1
Fiscal Year
2012
Total Cost
$543,939
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Marzi, Andrea; Kercher, Lisa; Marceau, Joshua et al. (2015) Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus-Based Filovirus Vaccines. J Infect Dis :
Matassov, Demetrius; Marzi, Andrea; Latham, Terri et al. (2015) Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus. J Infect Dis 212 Suppl 2:S443-51
Marzi, Andrea; Falzarano, Darryl (2015) An updated Ebola vaccine: immunogenic, but will it protect? Lancet 385:2229-30
Marzi, Andrea; Halfmann, Peter; Hill-Batorski, Lindsay et al. (2015) Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates. Science 348:439-42
Barrenas, Fredrik; Green, Richard R; Thomas, Matthew J et al. (2015) Next-generation sequencing reveals a controlled immune response to Zaire Ebola virus challenge in cynomolgus macaques immunized with vesicular stomatitis virus expressing Zaire Ebola virus glycoprotein (VSVΔG/EBOVgp). Clin Vaccine Immunol 22:354-6
Geisbert, Thomas W; Strong, James E; Feldmann, Heinz (2015) Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection. J Infect Dis :
Kurup, Drishya; Wirblich, Christoph; Feldmann, Heinz et al. (2015) Rhabdovirus-based vaccine platforms against henipaviruses. J Virol 89:144-54
Lai, Lilin; Davey, Richard; Beck, Allison et al. (2015) Emergency postexposure vaccination with vesicular stomatitis virus-vectored Ebola vaccine after needlestick. JAMA 313:1249-55
Marzi, Andrea; Feldmann, Friederike; Geisbert, Thomas W et al. (2015) Vesicular stomatitis virus-based vaccines against Lassa and Ebola viruses. Emerg Infect Dis 21:305-7
de Wit, Emmie; Marzi, Andrea; Bushmaker, Trenton et al. (2015) Safety of recombinant VSV-Ebola virus vaccine vector in pigs. Emerg Infect Dis 21:702-4

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