title: Coimmunization with an optimized IL15 plasmid adjuvant enhances humoral immunity via stimulating B cells induced by genetically engineered DNA vaccines expressing consensus JEV and WNV E DIII.
abstract: The Japanese encephalitis virus (JEV) and West Nile virus (WNV) are responsible for a large proportion of viral encephalitis in humans. Currently, there is no FDA approved specific treatment for either, though there are attempts to develop vaccines against both viruses. In this study, we proposed novel genetically engineered DNA vaccines against these two neurotrophic flaviviruses. The structural domain III (DIII) of E protein from these viruses is reported to carry dominant epitopes that induce neutralizing antibodies. Therefore we created consensus sequence of DIII domain across numerous strains of JEV and WNV. Based on the consensus amino acid sequence, synthetic codon and RNA optimized DIII-expressing DNA vaccine constructs with an efficient leader sequence were synthesized for immunization studies. In addition, we also constructed a genetically engineered IL15 DNA vaccine molecular adjuvant for co-stimulating the immune response against DIII clones. Vaccine constructs were delivered into BALB/C mice intramuscularly followed by electroporation using the CELLECTRA in vivo electroporator. We have observed that the combined delivery of both WNV DIII and IL15-ECRO DNA vaccine constructs resulted in not only the highest level of antibody against DIII, but also enhanced cross reactivity with two other antigens tested. Also, coimmunization with IL15 plasmid further increased the immune response by four- to five-fold. Importantly, we have shown that IL15 coimmunization adjuvanted humoral responses against DIII antigens by elevating the level of antibody secreting B cells. Such a DNA vaccine approach may better help to control potential travel related infectious agents such as JEV.
authors.affiliation: VGX Pharmaceuticals, Inc., 450 Sentry Parkway, Blue Bell, PA 19422, USA.
authors.forename: Mathura P
authors.initials: MP
authors.lastname: Ramanathan
authors.forename: Michele A
authors.initials: MA
authors.lastname: Kutzler
authors.forename: Yuan-Chia
authors.initials: YC
authors.lastname: Kuo
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.forename: Harrison
authors.initials: H
authors.lastname: Liu
authors.forename: Vidhi
authors.initials: V
authors.lastname: Shah
authors.forename: Amrit
authors.initials: A
authors.lastname: Bawa
authors.forename: Bernard
authors.initials: B
authors.lastname: Selling
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.forename: J Joseph
authors.initials: JJ
authors.lastname: Kim
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology*; D003062:Codon; D016384:Consensus Sequence; D003429:Cross Reactions; D018274:Electroporation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007273:Injections, Intramuscular; D019409:Interleukin-15 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D022321:Japanese Encephalitis Vaccines / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D053060:West Nile Virus Vaccines / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D003062:Codon; D019409:Interleukin-15; D022321:Japanese Encephalitis Vaccines; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D053060:West Nile Virus Vaccines; C065696:glycoprotein E, Flavivirus