Immunogenicity and protective efficacy of a DNA vaccine against Venezuelan equine encephalitis virus aerosol challenge in nonhuman primates

Dupuy, Lesley C.; Richards, Michelle J.; Reed, Douglas S.; Schmaljohn, Connie S.

doi:10.1016/j.vaccine.2010.09.005

Cited by 46 publications

(39 citation statements)

References 28 publications

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“…In our previous studies, we demonstrated that a DNA vaccine expressing the wild-type structural proteins of VEEV IAB elicited partial protective immunity against a homologous viral aerosol challenge when administered by PMED in macaques (12). In an attempt to rationally design an improved VEEV DNA vaccine, we generated a construct expressing codon-optimized envelope glycoprotein genes.…”

Section: Resultsmentioning

confidence: 99%

“…Cynomolgus macaques vaccinated with this VEEV DNA vaccine by PMED developed detectable levels of VEEV IAB-neutralizing antibodies, but only partial protection was observed upon aerosol challenge (12). As our ultimate goal is to develop an effective human vaccine for encephalitic alphaviruses, we subsequently tested directed molecular evolution or "gene shuffling" of the envelope protein genes as a means to improve the neutralizing antibody response to VEEV and eastern equine encephalitis virus (EEEV) and western equine encephalitis virus (WEEV) DNA vaccines.…”

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confidence: 99%

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A DNA Vaccine for Venezuelan Equine Encephalitis Virus Delivered by Intramuscular Electroporation Elicits High Levels of Neutralizing Antibodies in Multiple Animal Models and Provides Protective Immunity to Mice and Nonhuman Primates

Dupuy

Richards

Ellefsen

et al. 2011

Clin. Vaccine Immunol.

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We evaluated the immunogenicity and protective efficacy of a DNA vaccine expressing codon-optimized envelope glycoprotein genes of Venezuelan equine encephalitis virus (VEEV) when delivered by intramuscular electroporation. Mice vaccinated with the DNA vaccine developed robust VEEV-neutralizing antibody responses that were comparable to those observed after administration of the live-attenuated VEEV vaccine TC-83 and were completely protected from a lethal aerosol VEEV challenge. The DNA vaccine also elicited strong neutralizing antibody responses in rabbits that persisted at high levels for at least 6 months and could be boosted by a single additional electroporation administration of the DNA performed approximately 6 months after the initial vaccinations. Cynomolgus macaques that received the vaccine by intramuscular electroporation developed substantial neutralizing antibody responses and after an aerosol challenge had no detectable serum viremia and had reduced febrile reactions, lymphopenia, and clinical signs of disease compared to those of negative-control macaques. Taken together, our results demonstrate that this DNA vaccine provides a potent means of protecting against VEEV infections and represents an attractive candidate for further development.Venezuelan equine encephalitis virus (VEEV) is a nonsegmented, positive-sense RNA virus of the genus Alphavirus in the family Togaviridae (17). Naturally transmitted by mosquitoes through rodent hosts, VEEV is highly pathogenic for equines and humans and has sporadically caused widespread epidemics in North, Central, and South America (48). While most equine and human outbreaks have been caused by the epizootic IAB and IC subtypes of VEEV, isolated cases of disease caused in equines and humans by infection with the enzootic ID and IE subtypes have also been reported (10,32,50). Regardless of the variety, human infection with VEEV typically results in an acute, incapacitating, but self-limiting disease characterized by fever, headache, lymphopenia, myalgia, and malaise (3). Severe neurological disease, including fatal encephalitis, can also result from VEEV infection of humans, although the case fatality rate is estimated to be low (Յ1%) (45). However, numerous documented laboratory accidents and the results of animal studies have demonstrated that VEEV is also highly infectious in aerosols, and infection with aerosolized VEEV could potentially result in higher mortality than that observed with natural infection (15,18,26). In addition to producing incapacitating or lethal infections and being infectious in aerosols, VEEV is also easily grown to high titers in inexpensive and unsophisticated cell culture systems and is relatively stable (45). As a result, VEEV represents a significant potential biological defense threat and is classified as a category B priority biodefense agent by both the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases.There are no licensed human vaccines for VEEV. While live-attenuated...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

A DNA Vaccine for Venezuelan Equine Encephalitis Virus Delivered by Intramuscular Electroporation Elicits High Levels of Neutralizing Antibodies in Multiple Animal Models and Provides Protective Immunity to Mice and Nonhuman Primates

Dupuy

Richards

Ellefsen

et al. 2011

Clin. Vaccine Immunol.

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“…The potential for reversion makes the hurdle of safety much more difficult to achieve with approaches using live attenuated vaccines, particularly given public perception of adverse events associated with biological products and the associated risk/benefit of the product. A DNA vaccine has shown promise against aerosol challenge with VEEV in macaques although neutralizing antibody responses were low (13). In a number of systems, replicon-based vaccines have been shown to induce stronger immune responses than DNA or subunit approaches but are safer than approaches using live attenuated vaccines due to the limited replication that can occur in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Subunit vaccines derived from a variety of expression systems have shown efficacy in rodent models (8)(9)(10)(11). DNA vaccines, administered by several means, have also shown efficacy in rodents and nonhuman primates (12)(13)(14). Live attenuated vaccines developed using modern molecular techniques provided good immunogenicity, safety, and protection in rodents and nonhuman primates although in phase I clinical trials mild fever responses were seen at very low dosages (15)(16)(17).…”

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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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“…For both the hantavirus and VEEV DNA vaccines, gene optimization was found to increase expression and to improve antibody responses in animals and humans. 28,[30][31][32][33][34][35] For the 2 hantavirus vaccines, optimization also mitigated immune interference, which we observed when using non-optimized constructs. 27,29 Although we did not have nonoptimized constructs for the SUDV or RAVV DNA vaccines, we Figure 6.…”

Section: Discussionmentioning

confidence: 71%

Codon-optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges

Grant-Klein

Altamura

Badger

et al. 2015

Human Vaccines & Immunotherapeutics

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Cynomolgus macaques were vaccinated by intramuscular electroporation with DNA plasmids expressing codonoptimized glycoprotein (GP) genes of Ebola virus (EBOV) or Marburg virus (MARV) or a combination of codon-optimized GP DNA vaccines for EBOV, MARV, Sudan virus and Ravn virus. When measured by ELISA, the individual vaccines elicited slightly higher IgG responses to EBOV or MARV than did the combination vaccines. No significant differences in immune responses of macaques given the individual or combination vaccines were measured by pseudovirion neutralization or IFN-g ELISpot assays. Both the MARV and mixed vaccines were able to protect macaques from lethal MARV challenge (5/6 vs. 6/6). In contrast, a greater proportion of macaques vaccinated with the EBOV vaccine survived lethal EBOV challenge in comparison to those that received the mixed vaccine (5/6 vs. 1/6). EBOV challenge survivors had significantly higher pre-challenge neutralizing antibody titers than those that succumbed.

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Immunogenicity and protective efficacy of a DNA vaccine against Venezuelan equine encephalitis virus aerosol challenge in nonhuman primates

Cited by 46 publications

References 28 publications

A DNA Vaccine for Venezuelan Equine Encephalitis Virus Delivered by Intramuscular Electroporation Elicits High Levels of Neutralizing Antibodies in Multiple Animal Models and Provides Protective Immunity to Mice and Nonhuman Primates

A DNA Vaccine for Venezuelan Equine Encephalitis Virus Delivered by Intramuscular Electroporation Elicits High Levels of Neutralizing Antibodies in Multiple Animal Models and Provides Protective Immunity to Mice and Nonhuman Primates

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

Codon-optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges

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