Recombinant Isfahan Virus and Vesicular Stomatitis Virus Vaccine Vectors Provide Durable, Multivalent, Single-Dose Protection against Lethal Alphavirus Challenge

Abstract

The demonstrated clinical efficacy of a recombinant vesicular stomatitis virus (rVSV) vaccine vector has stimulated the investigation of additional serologically distinct Vesiculovirus vectors as therapeutic and/or prophylactic vaccine vectors to combat emerging viral diseases. Among these viral threats are the encephalitic alphaviruses Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV), which have demonstrated potential for natural disease outbreaks, yet no licensed vaccines are available in the event of an epidemic. Here we report the rescue of recombinant Isfahan virus (rISFV) from genomic cDNA as a potential new vaccine vector platform. The rISFV genome was modified to attenuate virulence and express the VEEV and EEEV E2/E1 surface glycoproteins as vaccine antigens. A single dose of the rISFV vaccine vectors elicited neutralizing antibody responses and protected mice from lethal VEEV and EEEV challenges at 1 month postvaccination as well as lethal VEEV challenge at 8 months postvaccination. A mixture of rISFV vectors expressing the VEEV and EEEV E2/E1 glycoproteins also provided durable, single-dose protection from lethal VEEV and EEEV challenges, demonstrating the potential for a multivalent vaccine formulation. These findings were paralleled in studies with an attenuated form of rVSV expressing the VEEV E2/E1 glycoproteins. Both the rVSV and rISFV vectors were attenuated by using an approach that has demonstrated safety in human trials of an rVSV/HIV-1 vaccine. Vaccines based on either of these vaccine vector platforms may present a safe and effective approach to prevent alphavirus-induced disease in humans.IMPORTANCE This work introduces rISFV as a novel vaccine vector platform that is serologically distinct and phylogenetically distant from VSV. The rISFV vector has been attenuated by an approach used for an rVSV vector that has demonstrated safety in clinical studies. The vaccine potential of the rISFV vector was investigated in a well-established alphavirus disease model. The findings indicate the feasibility of producing a safe, efficacious, multivalent vaccine against the encephalitic alphaviruses VEEV and EEEV, both of which can cause fatal disease. This work also demonstrates the efficacy of an attenuated rVSV vector that has already demonstrated safety and immunogenicity in multiple HIV-1 phase I clinical studies. The absence of serological cross-reactivity between rVSV and rISFV and their phylogenetic divergence within the Vesiculovirus genus indicate potential for two stand-alone vaccine

Tick-Borne Viruses

“…The members of genus Vesiculovirus are mainly arthropod-borne viruses that are transmitted by biting insects, most likely sandflies (Nasar et al 2017 ). The Isfahan virus (ISFV) is the unique member in genus Vesiculovirus that has been isolated from Hy.…”

Novel Insect-Specific Eilat Virus-Based Chimeric Vaccine Candidates Provide Durable, Mono- and Multivalent, Single-Dose Protection against Lethal Alphavirus Challenge

“…Interference has been observed with other alphavirus vaccines (44-48). However, we recently showed that this phenomenon was not observed when blended EEEV and VEEV vaccines, based on the replication-competent Isfahan virus platform, were administered to mice (49). The difference in the induction of interference may reflect the inherent biological differences in different vaccine platforms or may increase with use of three or more components in the multivalent administration.…”

“…Plaque assays. Titration of EILV chimeras was performed on ϳ80% confluent C7/10 cell monolayers seeded overnight in six-well plates as described here, while all other viruses were titrated on Vero cells as described previously (49). Duplicate wells were infected with 0.1-ml aliquots from serial 10-fold dilutions in 1ϫ DMEM supplemented with 2% penicillin-streptomycin, 0.4 ml of medium was added to each well to prevent cell desiccation, and virus was adsorbed for 1 h. Following incubation, the virus inoculum was removed and cell monolayers were overlaid with 3 ml of a 1:1 mixture of 2% tragacanth and 2ϫ minimal essential medium with 5% FBS, 2% tryptose phosphate broth solution, and 2% penicillin-streptomycin.…”

Assessment of the ability of V920 recombinant vesicular stomatitis-Zaire ebolavirus vaccine to replicate in relevant arthropod cell cultures and vector species

“…All arthropod cells were stored in a humidified incubator at 28 C in 5% CO 2 . The passage ranges of the cell cultures used during these experiments were as follows: Vero (passages 8-96), C6/36 (6)(7)(8)(9)(10)(11)(12), CuVa (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), LL-5 (94-100), 4a3b (91-121). All cell cultures tested negative for mycoplasma.…”

“…11 VSV has proven to be a successful vector in the development of several live-attenuated vaccine candidates due to its ability to accept and stably express foreign gene products from heterologous viruses. [20][21][22][23][24][25][26] To develop a safe and efficacious single-dose vaccine against ZEBOV, the G gene of VSV was replaced with the immunogenic glycoprotein (GP) gene of ZEBOV, resulting in VSV virion particles expressing ZEBOV GP as the surface antigen. [27][28][29][30] The resulting rVSVDG-ZEBOV-GP construct, also referred to as V920, is a replication competent, live-attenuated vaccine that has attenuated replication and a narrower host-cell tropism in vitro than wild-type VSV.…”