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Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation.

Cashman KA, Broderick KE, Wilkinson ER, Shaia CI, Bell TM, Shurtleff AC, Spik KW, Badger CV, Guttieri MC, Sardesai NY, Schmaljohn CS - Vaccines (Basel) (2013)

Bottom Line: Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls.Together, these innovations resulted in enhanced efficacy of the vaccine.The vaccinated GPs were never ill and were not viremic at any timepoint.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. kathleen.cashman@us.army.mil.

ABSTRACT
Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development.

No MeSH data available.


Related in: MedlinePlus

Outcomes for dermal versus muscle electroporation using the codon-optimized LASV DNA construct. (A) Survival curve; (B) Serum viremia as measured by plaque assay; (C) Average body temperature changes as a function of time postinfection, and (D) Morbidity score based on observed disease signs. The grey bar indicates the normal body temperature range for guinea pigs.
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vaccines-01-00262-f003: Outcomes for dermal versus muscle electroporation using the codon-optimized LASV DNA construct. (A) Survival curve; (B) Serum viremia as measured by plaque assay; (C) Average body temperature changes as a function of time postinfection, and (D) Morbidity score based on observed disease signs. The grey bar indicates the normal body temperature range for guinea pigs.

Mentions: To evaluate the affect of codon-optimization alone on vaccine efficacy, we vaccinated a group of eight guinea pigs with 100 µg of DNA three times at 3-week intervals, using the same IMEP device as in the pilot study. We also vaccinated groups of guinea pigs with the optimized vaccine using a newly developed ELGEN-minimally invasive intradermal EP device (ELGEN-MID). For this study, we were able to monitor the development of fevers in control animals through the use of the IPTT-300 microchip transponders. These microchip transponders were not available for use in the pilot study. All guinea pigs mock-vaccinated with the empty plasmid or not vaccinated (virus only) became febrile, displayed signs of illness, lost weight, and succumbed to infection between days 15 and 18 postchallenge, whereas all guinea pigs vaccinated with the codon-optimized LASV DNA, regardless of the EP method used, survived challenge (Figure 3A). Unlike the pilot study in which guinea pigs vaccinated with the non-optimized LASV DNA vaccine demonstrated signs of illness, the guinea pigs vaccinated with the codon-optimized vaccine by ELGEN-MID EP did not develop any signs of illness, and remained afebrile (Figure 3B–D). We observed mild signs of disease in some of the guinea pigs that received the optimized LASV DNA vaccine by IMEP (4/8), including low fevers and slight viremias (Figure 3B,C), suggesting that dermal electroporation was more efficacious in this study.


Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation.

Cashman KA, Broderick KE, Wilkinson ER, Shaia CI, Bell TM, Shurtleff AC, Spik KW, Badger CV, Guttieri MC, Sardesai NY, Schmaljohn CS - Vaccines (Basel) (2013)

Outcomes for dermal versus muscle electroporation using the codon-optimized LASV DNA construct. (A) Survival curve; (B) Serum viremia as measured by plaque assay; (C) Average body temperature changes as a function of time postinfection, and (D) Morbidity score based on observed disease signs. The grey bar indicates the normal body temperature range for guinea pigs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494234&req=5

vaccines-01-00262-f003: Outcomes for dermal versus muscle electroporation using the codon-optimized LASV DNA construct. (A) Survival curve; (B) Serum viremia as measured by plaque assay; (C) Average body temperature changes as a function of time postinfection, and (D) Morbidity score based on observed disease signs. The grey bar indicates the normal body temperature range for guinea pigs.
Mentions: To evaluate the affect of codon-optimization alone on vaccine efficacy, we vaccinated a group of eight guinea pigs with 100 µg of DNA three times at 3-week intervals, using the same IMEP device as in the pilot study. We also vaccinated groups of guinea pigs with the optimized vaccine using a newly developed ELGEN-minimally invasive intradermal EP device (ELGEN-MID). For this study, we were able to monitor the development of fevers in control animals through the use of the IPTT-300 microchip transponders. These microchip transponders were not available for use in the pilot study. All guinea pigs mock-vaccinated with the empty plasmid or not vaccinated (virus only) became febrile, displayed signs of illness, lost weight, and succumbed to infection between days 15 and 18 postchallenge, whereas all guinea pigs vaccinated with the codon-optimized LASV DNA, regardless of the EP method used, survived challenge (Figure 3A). Unlike the pilot study in which guinea pigs vaccinated with the non-optimized LASV DNA vaccine demonstrated signs of illness, the guinea pigs vaccinated with the codon-optimized vaccine by ELGEN-MID EP did not develop any signs of illness, and remained afebrile (Figure 3B–D). We observed mild signs of disease in some of the guinea pigs that received the optimized LASV DNA vaccine by IMEP (4/8), including low fevers and slight viremias (Figure 3B,C), suggesting that dermal electroporation was more efficacious in this study.

Bottom Line: Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls.Together, these innovations resulted in enhanced efficacy of the vaccine.The vaccinated GPs were never ill and were not viremic at any timepoint.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. kathleen.cashman@us.army.mil.

ABSTRACT
Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development.

No MeSH data available.


Related in: MedlinePlus