A live, attenuated recombinant West Nile virus vaccine

Abstract

West Nile (WN) virus is an important cause of febrile exanthem and encephalitis. Since it invaded the U.S. in 1999, >19,000 human cases have been reported. The threat of continued epidemics has spurred efforts to develop vaccines. ChimeriVax-WN02 is a live, attenuated recombinant vaccine constructed from an infectious clone of yellow fever (YF) 17D virus in which the premembrane and envelope genes of 17D have been replaced by the corresponding genes of WN virus. Preclinical tests in monkeys defined sites of vaccine virus replication in vivo. ChimeriVax-WN02 and YF 17D had similar biodistribution but different multiplication kinetics. Prominent sites of replication were skin and lymphoid tissues, generally sparing vital organs. Viruses were cleared from blood by day 7 and from tissues around day 14. In a clinical study, healthy adults were inoculated with 5.0 log(10) plaque-forming units (PFU) (n = 30) or 3.0 log10 PFU (n = 15) of ChimeriVax-WN02, commercial YF vaccine (YF-VAX, n = 5), or placebo (n = 30). The incidence of adverse events in subjects receiving the vaccine was similar to that in the placebo group. Transient viremia was detected in 42 of 45 (93%) of ChimeriVax-WN02 subjects, and four of five (80%) of YF-VAX subjects. All subjects developed neutralizing antibodies to WN or YF, respectively, and the majority developed specific T cell responses. ChimeriVax-WN02 rapidly elicits strong immune responses after a single dose, and is a promising candidate warranting further evaluation for prevention of WN disease.

Fig. 1.

ChimeriVax-WN02 or YF-VAX were inoculated s.c. into cynomolgus macaques. (A) Viremia mean (±SD) by day after inoculation of macaques with 5 log₁₀ PFU ChimeriVax-WN02 or YF-VAX. (B) Neutralizing Ab GMT.

Fig. 2.

Clinical trial of ChimeriVax-WN02: Viremia mean PFU/ml (±SD) by day after s.c. inoculation with 5.0 or 3.0 log₁₀ PFU ChimeriVax-WN02 or YF-VAX.

Fig. 3.

Incidence of AEs occurring at rate >10% in the ChimeriVax-WN02 or placebo groups.

Fig. 4.

Individual neutralizing Ab responses to WN virus in the 5.0 or 3.0 log₁₀ PFU ChimeriVax-WN02 treatment groups by interval after inoculation. See Table 2.

Fig. 5.

Cell-mediated immune responses after vaccination with ChimeriVax-WN02 and YF-VAX vaccines. (A) WN virus-specific IFN-γ producing T cells per million PBMC. Open diamonds, ChimeriVax-WN02 vaccine 5.0 log₁₀ PFU; open squares, ChimeriVax-WN02 vaccine 3.0 log₁₀ PFU; inverted open triangle, YF-VAX; open circle, placebo. (B) T lymphocyte proliferation responses to inactivated WN virus antigen, represented as stimulation index. (C) Correlation between IFN-γ producing WN virus-specific T cells and stimulation index in ChimeriVax-West Nile vaccines 14 and 28 days after immunization. Confidence intervals for Spearman’s rank correlation of log₁₀ IFN-γ producing PBMC per million and log₁₀ stimulation index were based on Fisher’s transformation. On day 14, the correlation was 0.491 (95% CI, 0.231–0.686); on day 28, the correlation was 0.188 (95% CI: −0.112 to 0.456).