A West Nile virus DNA vaccine utilizing a modified promoter induces neutralizing antibody in younger and older healthy adults in a phase I clinical trial

Abstract

Background: West Nile virus (WNV) is a flavivirus that causes meningitis and encephalitis. There are no licensed vaccines to prevent WNV in humans. The safety and immunogenicity of a first-generation WNV DNA vaccine was demonstrated in a clinical trial and a similar DNA vaccine has been licensed for use in horses.

Methods: A DNA vaccine encoding the protein premembrane and the E glycoproteins of the NY99 strain of WNV under the transcriptional control of the CMV/R promoter was evaluated in an open-label study in 30 healthy adults. Half of the subjects were age 18-50 years and half were age 51-65 years. Immune responses were assessed by enzyme-linked immunosorbent assay, neutralization assays, intracellular cytokine staining, and ELISpot.

Results: The 3-dose vaccine regimen was safe and well tolerated. Vaccine-induced T cell and neutralizing antibody responses were detected in the majority of subjects. The antibody responses seen in the older age group were of similar frequency, magnitude, and duration as those seen in the younger cohort.

Conclusions: Neutralizing antibody responses to WNV were elicited by DNA vaccination in humans, including in older individuals, where responses to traditional vaccine approaches are often diminished. This DNA vaccine elicited T cell responses of greater magnitude when compared with an earlier-generation construct utilizing a CMV promoter.

Clinical trials registration: NCT00300417.

Figures

Figure 1.

A. Sera from vaccinees at week 12 (4 weeks after 3rd vaccination) and at the final study visit (week 52) was assessed for the presence of antibody by enzyme-linked immunosorbent assay (ELISA) (A) and at week 12 for neutralizing antibody by a West Nile virus reporter virus particle neutralization assay (B). In each figure, the x-axis represents individual vaccine clinical trial subjects A–DD by increasing age at enrollment. The y-axis represents the log10 reciprocal endpoint titer (A) and log10 reciprocal EC50 (B).

Figure 2.

Neutralizing antibody was measured throughout the trial as is shown for the 18–50-year-old subjects (A) and the 51–65-year-old subjects (B). Peak responses occurred around week 12 and responses generally remained positive but at relatively lower magnitude by the end of the yearlong study, Vaccinations were administered at days 0, 28, and 56.

Figure 3.

CD4 (A) and CD8 (B) T cell responses over the course of the studies are shown as assessed by intracellular cytokine staining. Magnitude of response is shown for all positive responders by group. Results from the prior study, VRC 302 (all subjects, ages 18–50) are shown in comparison to VRC 303 (all subjects), which are additionally shown by age group, younger (18–50 years) and older (51–65 years).

Figure 4.

Neutralizing antibody (EC50) responses at week 12 are shown by group: VRC 303 all subjects, VRC 302 all subjects, VRC 303 younger group (ages 18–50 years), and VRC 303 older group (ages 51–65 years).