Abstract
Antibodies generated against West Nile virus (WNV) during infection are essential for controlling dissemination. Recent studies have demonstrated that epitopes in all three domains of the flavivirus envelope protein (E) are targets for neutralizing antibodies, with determinants in domain III (DIII) eliciting antibodies with strong inhibitory properties. In order to increase the magnitude and quality of the antibody response against the WNV E protein, DNA vaccines with derivatives of the WNV E gene (full length E, truncated E, or DIII region, some in the context of the pre-membrane [prM] gene) were conjugated to the molecular adjuvant P28. The P28 region of the complement protein C3d is the minimum CR2-binding domain necessary for the adjuvant activity of C3d. Delivery of DNA-based vaccines by gene gun and intramuscular routes stimulated production of IgG antibodies against the WNV DIII region of the E protein. With the exception of the vaccine expressing prM/E given intramuscularly, only mice that received DNA vaccines by gene gun produced protective neutralizing antibody titers (FRNT80 titer >1/40). Correspondingly, mice vaccinated by the gene gun route were protected to a greater level from lethal WNV challenge. In general, mice vaccinated with P28-adjuvated vaccines produced higher IgG titers than mice vaccinated with non-adjuvanted vaccines.
Highlights
West Nile virus (WNV) is a single-stranded positive polarity enveloped RNA virus and member of the Flavivirus genus of the Flaviviridae family
Administered naïve sera succumbed to virulent WNV infection. Discussion it has been a decade since the emergence of WNV in North America, there remains no effective, licensed vaccine to combat WNV induced disease in humans
Since neutralizing antibodies may serve as a primary protective function against challenge [5], recent vaccine strategies have focused on using the ectodomain of E or different domains within E to elicit neutralizing anti-WNV antibodies [23,24,26,29,30,31,32,33]
Summary
West Nile virus (WNV) is a single-stranded positive polarity enveloped RNA virus and member of the Flavivirus genus of the Flaviviridae family. The host immune response is critical for limiting virus spread and disease. Results from genetically engineered mice indicate that both the innate (e.g., interferon) and the adaptive (B and T cells) immune responses control WNV infection [4]. The primary target of the neutralizing antibody response is the E protein, which is the most accessible structural glycoprotein on the surface of the virion [7]. Structural analysis of the soluble ectodomain of flavivirus E proteins reveals three domains [8,9]. Domain II, which contains 12 β-strands, has important roles in dimerization, trimerization, and virus-mediated fusion [10,11,12].
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