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. 2014 Nov 13;9(11):e112568.
doi: 10.1371/journal.pone.0112568. eCollection 2014.

Vaccine-induced Protection of Rhesus Macaques Against Plasma Viremia After Intradermal Infection With a European Lineage 1 Strain of West Nile Virus

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Free PMC article

Vaccine-induced Protection of Rhesus Macaques Against Plasma Viremia After Intradermal Infection With a European Lineage 1 Strain of West Nile Virus

Babs E Verstrepen et al. PLoS One. .
Free PMC article

Abstract

The mosquito-borne West Nile virus (WNV) causes human and animal disease with outbreaks in several parts of the world including North America, the Mediterranean countries, Central and East Europe, the Middle East, and Africa. Particularly in elderly people and individuals with an impaired immune system, infection with WNV can progress into a serious neuroinvasive disease. Currently, no treatment or vaccine is available to protect humans against infection or disease. The goal of this study was to develop a WNV-vaccine that is safe to use in these high-risk human target populations. We performed a vaccine efficacy study in non-human primates using the contemporary, pathogenic European WNV genotype 1a challenge strain, WNV-Ita09. Two vaccine strategies were evaluated in rhesus macaques (Macaca mulatta) using recombinant soluble WNV envelope (E) ectodomain adjuvanted with Matrix-M, either with or without DNA priming. The DNA priming immunization was performed with WNV-DermaVir nanoparticles. Both vaccination strategies successfully induced humoral and cellular immune responses that completely protected the macaques against the development of viremia. In addition, the vaccine was well tolerated by all animals. Overall, The WNV E protein adjuvanted with Matrix-M is a promising vaccine candidate for a non-infectious WNV vaccine for use in humans, including at-risk populations.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: SEM and LS are employees of Novavax AB and minority shareholders of Novavax Inc. JL and OL are shareholders of eMMUNITY Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Study outline.
Schematic representation of the study with two West Nile virus vaccine strategies. Group 1 received three immunizations with recombinant E protein adjuvanted with Matrix-M (red triangles) at indicated study weeks. Group 2 received one immunization of WNV-DermaVir (green triangle), followed by two immunizations with recombinant E protein adjuvanted with Matrix-M (red triangles). Nine weeks after the last immunization, all animals (including controls) were challenged intradermally with 2×105 TCID50 of WNV-Ita09. All animals were euthanized 14 days post-challenge (study week 17).
Figure 2
Figure 2. Vaccine-induced antibody responses.
Antibodies reactive against (A) the ecto-domain of the WNV E protein, and (B) inactivated WNV were measured in the individual animals at indicated time points. Humoral responses were quantified as sample:negative ratio (S/N). Vaccine-induced neutralizing capacity (PRNT50) of macaque sera was determined using the plaque reduction neutralization test (C). Individual animals are depicted as dots: group 1 (red), group 2 (green), and group 3 (blue). The median value is indicated for each group. Unpaired t-test was used to compare the responses between the groups. Statistical significant differences were defined as p<0.05 and are indicated with arches in the figure.
Figure 3
Figure 3. Vaccine-induced T-cell responses.
A. IFNγ-secreting cells in blood of the individual animals measured in ELISpot. The responses are presented in spot-forming units (SFU) per million PBMCs. The WNV-specific T-cell responses were calculated by subtraction of the background responses (mean value of triplicate assays plus two times the standard deviation, minus medium alone). Intracellular staining of IFNγ produced by CD4 T-cells (panel B), and CD8 T-cells (panel C). Background IFNγ-responses (number of IFNγ-producing cells with medium alone) were subtracted. Individual animals are depicted as dots: group 1 (red), group 2 (green), and group 3 (blue). The median value is indicated for each group. Unpaired t-test was used to compare the responses between the groups. Statistical significant differences were defined as p<0.05.
Figure 4
Figure 4. Detection of West Nile virus in tissue samples.
Tissue samples were analyzed for the presence of WNV RNA by qualitative real-time PCR (red) or a nested PCR assay (orange).

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Grant support

The project was funded by the European Community FP7 project WINGS (grant no. 261426). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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