Identification of Western Equine Encephalitis Virus Structural Proteins That Confer Protection after DNA Vaccination

Gauci, Penelope J.; Wu, Josh; Rayner, George A.; Barabé, Nicole D.; Nagata, Leslie P.; Proll, David

doi:10.1128/cvi.00377-09

Cited by 14 publications

(8 citation statements)

References 12 publications

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“…The insect cell-derived McMillan E1ecto antigen presented to mice in the LANAC context (CLNC-ODN-PIC) may explain why our study differs from a previous study that immunized mice with recombinant bacterium-derived WEEV E1 antigen and reported minimal protection against two WEEV strains (3). Gauchi et al used a DNA vaccine approach to immunize mice with WEEV E1 and demonstrated protection against challenge with a low-virulence WEEV strain but not with a high-virulence WEEV strain (6,7). In both studies, WEEV challenge occurred at 2 to 3 weeks after boost.…”

Section: Discussionmentioning

confidence: 99%

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Liposome-Antigen-Nucleic Acid Complexes Protect Mice from Lethal Challenge with Western and Eastern Equine Encephalitis Viruses

Phillips

Schountz

Toth

et al. 2014

J Virol

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Alphaviruses are mosquito-borne viruses that cause significant disease in animals and humans. Western equine encephalitis virus (WEEV) and eastern equine encephalitis virus (EEEV), two New World alphaviruses, can cause fatal encephalitis, and EEEV is a select agent of concern in biodefense. However, we have no antiviral therapies against alphaviral disease, and current vaccine strategies target only a single alphavirus species. In an effort to develop new tools for a broader response to outbreaks, we designed and tested a novel alphavirus vaccine comprised of cationic lipid nucleic acid complexes (CLNCs) and the ectodomain of WEEV E1 protein (E1ecto). Interestingly, we found that the CLNC component, alone, had therapeutic efficacy, as it increased survival of CD-1 mice following lethal WEEV infection. Immunization with the CLNC-WEEV E1ecto mixture (lipid-antigennucleic acid complexes [LANACs]) using a prime-boost regimen provided 100% protection in mice challenged with WEEV subcutaneously, intranasally, or via mosquito. Mice immunized with LANACs mounted a strong humoral immune response but did not produce neutralizing antibodies. Passive transfer of serum from LANAC E1ecto-immunized mice to nonimmune CD-1 mice conferred protection against WEEV challenge, indicating that antibody is sufficient for protection. In addition, the LANAC E1ecto immunization protocol significantly increased survival of mice following intranasal or subcutaneous challenge with EEEV. In summary, our LANAC formulation has therapeutic potential and is an effective vaccine strategy that offers protection against two distinct species of alphavirus irrespective of the route of infection. We discuss plausible mechanisms as well the potential utility of our LANAC formulation as a pan-alphavirus vaccine.

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Section: Discussionmentioning

confidence: 99%

“…Subunit vaccines consisting of recombinant forms of WEEV E2 or E1 have been reported to induce significant protection in animal models (6)(7)(8). Although E2 is the major neutralizing antigen, E1 is highly conserved among alphaviruses (9,10).…”

mentioning

confidence: 99%

Liposome-Antigen-Nucleic Acid Complexes Protect Mice from Lethal Challenge with Western and Eastern Equine Encephalitis Viruses

Phillips

Schountz

Toth

et al. 2014

J Virol

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“…E1 was chosen because previous studies had shown that it can be used as a subunit vaccine to provide 100% protection in a mouse model [23, 24] and it can potentially provide cross-protection against multiple alphaviruses [24-26]. The E26KE1 polyprotein was chosen because in its native form, it is proteolytically processed to yield the E2E1 heterodimer complex, which might induce a more effective immune response than E1 alone [23, 24, 27]. Previous studies had indicated that polyprotein precursors derived from other alphaviruses could be processed when expressed under polh control in the baculovirus system [23, 28].…”

Section: Resultsmentioning

confidence: 99%

Factors affecting recombinant Western equine encephalitis virus glycoprotein production in the baculovirus system

Toth

Geisler

Aumiller

et al. 2011

Protein Expression and Purification

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In an effort to produce processed, soluble Western equine encephalitis virus (WEEV) glycoproteins for subunit therapeutic vaccine studies, we isolated twelve recombinant baculoviruses designed to express four different WEEV glycoprotein constructs under the transcriptional control of three temporally distinct baculovirus promoters. The WEEV glycoprotein constructs encoded full-length E1, the E1 ectodomain, an E26KE1 polyprotein precursor, and an artificial, secretable E2E1 chimera. The three different promoters induced gene expression during the immediate early (ie1), late (p6.9), and very late (polh) phases of baculovirus infection. Protein expression studies showed that the nature of the WEEV construct and the timing of expression both influenced the quantity and quality of recombinant glycoprotein produced. The full-length E1 product was insoluble, irrespective of the timing of expression. Each of the other three constructs yielded soluble products and, in these cases, the timing of expression was important, as higher protein processing efficiencies were generally obtained at earlier times of infection. However, immediate early expression did not yield detectable levels of every WEEV product, and expression during the late (p6.9) or very late (polh) phases of infection provided equal or higher amounts of processed, soluble product. Thus, while earlier foreign gene expression can provide higher recombinant glycoprotein processing efficiencies in the baculovirus system, in the case of the WEEV glycoproteins, earlier expression did not provide larger amounts of high quality, soluble recombinant glycoprotein product.

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“…Although cell-mediated immune responses against the E2 and E1 antigens were elicited by this DNA vaccine as measured by lymphocyte proliferation assays, no virus-specific antibody responses were detected by ELISA. In a subsequent report by this group, DNA vaccines expressing the C-E3-E2-6K-E1, E3-E2-6K-E1, or 6K-E1 proteins of WEEV strain 71V-1658 from the wild-type genes administered in three 2 μ g doses by PMED provided complete protection against homologous intranasal challenge with the same 1.5 × 10 3 PFU (25 LD 50 ) dose of virus, while a DNA vaccine expressing the E3-E2 proteins did not provide any protection [ 47 ]. Although the DNA vaccines expressing the C-E3-E2-6K-E1, E3-E2-6K-E1, or 6K-E1 proteins provided significant protection against a similar challenge with the CBA87 strain, only the DNA vaccines expressing the C-E3-E2-6K-E1 and E3-E2-6K-E1 proteins provided significant protection against the Fleming strain.…”

Section: Discussionmentioning

confidence: 99%

A Multiagent Alphavirus DNA Vaccine Delivered by Intramuscular Electroporation Elicits Robust and Durable Virus-Specific Immune Responses in Mice and Rabbits and Completely Protects Mice against Lethal Venezuelan, Western, and Eastern Equine Encephalitis Virus Aerosol Challenges

Dupuy

Richards

Livingston

et al. 2018

Journal of Immunology Research

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There remains a need for vaccines that can safely and effectively protect against the biological threat agents Venezuelan (VEEV), western (WEEV), and eastern (EEEV) equine encephalitis virus. Previously, we demonstrated that a VEEV DNA vaccine that was optimized for increased antigen expression and delivered by intramuscular (IM) electroporation (EP) elicited robust and durable virus-specific antibody responses in multiple animal species and provided complete protection against VEEV aerosol challenge in mice and nonhuman primates. Here, we performed a comparative evaluation of the immunogenicity and protective efficacy of individual optimized VEEV, WEEV, and EEEV DNA vaccines with that of a 1 : 1 : 1 mixture of these vaccines, which we have termed the 3-EEV DNA vaccine, when delivered by IM EP. The individual DNA vaccines and the 3-EEV DNA vaccine elicited robust and durable virus-specific antibody responses in mice and rabbits and completely protected mice from homologous VEEV, WEEV, and EEEV aerosol challenges. Taken together, the results from these studies demonstrate that the individual VEEV, WEEV, and EEEV DNA vaccines and the 3-EEV DNA vaccine delivered by IM EP provide an effective means of eliciting protection against lethal encephalitic alphavirus infections in a murine model and represent viable next-generation vaccine candidates that warrant further development.

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Identification of Western Equine Encephalitis Virus Structural Proteins That Confer Protection after DNA Vaccination

Cited by 14 publications

References 12 publications

Liposome-Antigen-Nucleic Acid Complexes Protect Mice from Lethal Challenge with Western and Eastern Equine Encephalitis Viruses

Liposome-Antigen-Nucleic Acid Complexes Protect Mice from Lethal Challenge with Western and Eastern Equine Encephalitis Viruses

Factors affecting recombinant Western equine encephalitis virus glycoprotein production in the baculovirus system

A Multiagent Alphavirus DNA Vaccine Delivered by Intramuscular Electroporation Elicits Robust and Durable Virus-Specific Immune Responses in Mice and Rabbits and Completely Protects Mice against Lethal Venezuelan, Western, and Eastern Equine Encephalitis Virus Aerosol Challenges

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