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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

Outcome of backchallenge experiment. (A) Survival curve; (B) Average weights postchallenge; and (C) Average temperatures post-challenge for animals enrolled in the backchallenge experiment.
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vaccines-01-00262-f005: Outcome of backchallenge experiment. (A) Survival curve; (B) Average weights postchallenge; and (C) Average temperatures post-challenge for animals enrolled in the backchallenge experiment.

Mentions: Four of the surviving ELGEN-MID vaccinated animals were kept at the end of the study in order to assess the ability of the vaccine to protect animals upon secondary exposure to virus after an extended period of time. These animals were maintained in the BSL-4 laboratory for 120 days after the end of the vaccine study, then were re-exposed to 1,000 pfu LASV by SC injection, along with four age/weight-matched control guinea pigs. These animals were observed daily for signs of disease. The vaccinated animals survived to the study endpoint (Figure 5A) and never developed signs of disease compared to the control animals, which lost weight (Figure 4B), were febrile (Figure 4C), and succumbed to disease (Figure 4A).


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)

Outcome of backchallenge experiment. (A) Survival curve; (B) Average weights postchallenge; and (C) Average temperatures post-challenge for animals enrolled in the backchallenge experiment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

vaccines-01-00262-f005: Outcome of backchallenge experiment. (A) Survival curve; (B) Average weights postchallenge; and (C) Average temperatures post-challenge for animals enrolled in the backchallenge experiment.
Mentions: Four of the surviving ELGEN-MID vaccinated animals were kept at the end of the study in order to assess the ability of the vaccine to protect animals upon secondary exposure to virus after an extended period of time. These animals were maintained in the BSL-4 laboratory for 120 days after the end of the vaccine study, then were re-exposed to 1,000 pfu LASV by SC injection, along with four age/weight-matched control guinea pigs. These animals were observed daily for signs of disease. The vaccinated animals survived to the study endpoint (Figure 5A) and never developed signs of disease compared to the control animals, which lost weight (Figure 4B), were febrile (Figure 4C), and succumbed to disease (Figure 4A).

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