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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

Immunohistochemistry staining for LASV antigen in selected tissues of mock-vaccinated or ELGEN-MID-vaccinated guinea pigs. (A) Viral antigen staining of a mock-vaccinated lymph node (40×); (B) lymph node of a ELGEN-MID-vaccinated animal showing lymphoid hyperplasia and a lack of viral staining (20×); (C) Viral antigen staining of a mock-vaccinated spleen (40×); (D) Splenic white pulp hyperplasia in a ELGEN-MID-vaccinated guinea pig (40×); (E) Viral antigen staining of a mock-vaccinated adrenal gland (10×); (F) A lack of viral antigen staining of a ELGEN-MID-vaccinated adrenal gland (10×); (G) Viral antigen staining of a mock-vaccinated liver (20×); (H) A lack of viral antigen staining of a ELGEN-MID-vaccinated liver (10×); (I) Viral antigen staining of a mock-vaccinated kidney (20×); (J) A lack of viral antigen staining of a ELGEN-MID-vaccinated kidney (10×).
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vaccines-01-00262-f004: Immunohistochemistry staining for LASV antigen in selected tissues of mock-vaccinated or ELGEN-MID-vaccinated guinea pigs. (A) Viral antigen staining of a mock-vaccinated lymph node (40×); (B) lymph node of a ELGEN-MID-vaccinated animal showing lymphoid hyperplasia and a lack of viral staining (20×); (C) Viral antigen staining of a mock-vaccinated spleen (40×); (D) Splenic white pulp hyperplasia in a ELGEN-MID-vaccinated guinea pig (40×); (E) Viral antigen staining of a mock-vaccinated adrenal gland (10×); (F) A lack of viral antigen staining of a ELGEN-MID-vaccinated adrenal gland (10×); (G) Viral antigen staining of a mock-vaccinated liver (20×); (H) A lack of viral antigen staining of a ELGEN-MID-vaccinated liver (10×); (I) Viral antigen staining of a mock-vaccinated kidney (20×); (J) A lack of viral antigen staining of a ELGEN-MID-vaccinated kidney (10×).

Mentions: Necropsies were performed on animals that met criteria for euthanasia or who survived to the study endpoint with the exception of four of the ELGEN-MID-vaccinated animals. These four animals will be described in the next section. Pathologic findings in virus only or mock-vaccinated animals were consistent with previous reports of the disease process in strain 13 guinea pigs [24]. There was no observed difference in lesion type or severity between the animals in the virus only group and the mock-vaccinated animals. Only mild lymphoid hyperplasia (cervical lymph node or mesenteric lymph node) and/or splenic white pulp hyperplasia was noted in some pLASV-GPC-vaccinated animals at the study endpoint. These findings are consistent with recent viral infection. None of the tissues collected from pLASV-GPC-vaccinated animals, regardless of EP method, were positive for the presence of viral antigen by immunohistochemistry at the study endpoint. Figure 4 illustrates the differences observed in antigen staining for a selection of tissues. As shown, positive LASV antigen staining was present in the lymph node, spleen, adrenal gland, liver, and kidney (Figure 4A,C,E,G,I, respectively) of a mock-vaccinated animal and absent in the corresponding tissues (Figure 4B,D,F,H,J) of a ELGEN-MID-vaccinated animal.


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)

Immunohistochemistry staining for LASV antigen in selected tissues of mock-vaccinated or ELGEN-MID-vaccinated guinea pigs. (A) Viral antigen staining of a mock-vaccinated lymph node (40×); (B) lymph node of a ELGEN-MID-vaccinated animal showing lymphoid hyperplasia and a lack of viral staining (20×); (C) Viral antigen staining of a mock-vaccinated spleen (40×); (D) Splenic white pulp hyperplasia in a ELGEN-MID-vaccinated guinea pig (40×); (E) Viral antigen staining of a mock-vaccinated adrenal gland (10×); (F) A lack of viral antigen staining of a ELGEN-MID-vaccinated adrenal gland (10×); (G) Viral antigen staining of a mock-vaccinated liver (20×); (H) A lack of viral antigen staining of a ELGEN-MID-vaccinated liver (10×); (I) Viral antigen staining of a mock-vaccinated kidney (20×); (J) A lack of viral antigen staining of a ELGEN-MID-vaccinated kidney (10×).
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vaccines-01-00262-f004: Immunohistochemistry staining for LASV antigen in selected tissues of mock-vaccinated or ELGEN-MID-vaccinated guinea pigs. (A) Viral antigen staining of a mock-vaccinated lymph node (40×); (B) lymph node of a ELGEN-MID-vaccinated animal showing lymphoid hyperplasia and a lack of viral staining (20×); (C) Viral antigen staining of a mock-vaccinated spleen (40×); (D) Splenic white pulp hyperplasia in a ELGEN-MID-vaccinated guinea pig (40×); (E) Viral antigen staining of a mock-vaccinated adrenal gland (10×); (F) A lack of viral antigen staining of a ELGEN-MID-vaccinated adrenal gland (10×); (G) Viral antigen staining of a mock-vaccinated liver (20×); (H) A lack of viral antigen staining of a ELGEN-MID-vaccinated liver (10×); (I) Viral antigen staining of a mock-vaccinated kidney (20×); (J) A lack of viral antigen staining of a ELGEN-MID-vaccinated kidney (10×).
Mentions: Necropsies were performed on animals that met criteria for euthanasia or who survived to the study endpoint with the exception of four of the ELGEN-MID-vaccinated animals. These four animals will be described in the next section. Pathologic findings in virus only or mock-vaccinated animals were consistent with previous reports of the disease process in strain 13 guinea pigs [24]. There was no observed difference in lesion type or severity between the animals in the virus only group and the mock-vaccinated animals. Only mild lymphoid hyperplasia (cervical lymph node or mesenteric lymph node) and/or splenic white pulp hyperplasia was noted in some pLASV-GPC-vaccinated animals at the study endpoint. These findings are consistent with recent viral infection. None of the tissues collected from pLASV-GPC-vaccinated animals, regardless of EP method, were positive for the presence of viral antigen by immunohistochemistry at the study endpoint. Figure 4 illustrates the differences observed in antigen staining for a selection of tissues. As shown, positive LASV antigen staining was present in the lymph node, spleen, adrenal gland, liver, and kidney (Figure 4A,C,E,G,I, respectively) of a mock-vaccinated animal and absent in the corresponding tissues (Figure 4B,D,F,H,J) of a ELGEN-MID-vaccinated animal.

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