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A nonhuman primate scrub typhus model: protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques.

Paris DH, Chattopadhyay S, Jiang J, Nawtaisong P, Lee JS, Tan E, Dela Cruz E, Burgos J, Abalos R, Blacksell SD, Lombardini E, Turner GD, Day NP, Richards AL - J. Immunol. (2015)

Bottom Line: We investigated scrub typhus disease pathophysiology and evaluated two O. tsutsugamushi 47-kDa, Ag-based candidate vaccines, a DNA plasmid vaccine (pKarp47), and a virus-vectored vaccine (Kp47/47-Venezuelan equine encephalitis virus replicon particle) for safety, immunogenicity, and efficacy against homologous ID challenge with O. tsutsugamushi Karp.Control cynomolgus macaques developed fever, classic eschars, lymphadenopathy, bacteremia, altered liver function, increased WBC counts, pathogen-specific Ab (IgM and IgG), and cell-mediated immune responses.Vaccinated macaques receiving the DNA plasmid pKarp47 vaccine had significantly increased O. tsutsugamushi-specific, IFN-γ-producing PBMCs (p = 0.04), reduced eschar frequency and bacteremia duration (p ≤ 0.01), delayed bacteremia onset (p < 0.05), reduced circulating bacterial biomass (p = 0.01), and greater reduction of liver transaminase levels (p < 0.03) than controls.

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Affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, United Kingdom; parigi@tropmedres.ac.

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Relationship among IFN-γ–producing PBMCs, level and duration of bacteremia, and diameter of lesion postinoculation between vaccine groups. The left graph summarizes the number of Ag-specific, IFN-γ–producing PBMCs collected at 3 wk after third vaccination, as estimate of cellular immunity available before challenge with O. tsutsugamushi. Vaccinees with the pKarp47 ×3 vaccine (group 3) had the highest IFN-γ–producing PBMCs, the lowest bacteremia, and the shortest bacteremic duration. The middle graphs depict the median levels of bacteremia and duration of bacteremic dissemination phase during acute disease, and the right graph depicts the diameter of the eschar lesion at day 12 per group (and dosage regimens).
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fig07: Relationship among IFN-γ–producing PBMCs, level and duration of bacteremia, and diameter of lesion postinoculation between vaccine groups. The left graph summarizes the number of Ag-specific, IFN-γ–producing PBMCs collected at 3 wk after third vaccination, as estimate of cellular immunity available before challenge with O. tsutsugamushi. Vaccinees with the pKarp47 ×3 vaccine (group 3) had the highest IFN-γ–producing PBMCs, the lowest bacteremia, and the shortest bacteremic duration. The middle graphs depict the median levels of bacteremia and duration of bacteremic dissemination phase during acute disease, and the right graph depicts the diameter of the eschar lesion at day 12 per group (and dosage regimens).

Mentions: In group 1, the unvaccinated control macaques did not exhibit an increase in the number of Ag-specific, IFN-γ–secreting cells until day 21 after ID challenge with O. tsutsugamushi Karp. In group 2, homologous triple vaccination with Kp47/47-VRP induced few IFN-γ–producing cells, with an increase of SFUs in the ELISpot assay visible only after the third vaccination (Fig. 6B). In group 3, PBMCs from animals immunized with pKarp47(×3) produced Ag-specific IFN-γ in a dose-dependent manner. These vaccines had a significantly higher median number of IFN-γ–producing cells than controls (p = 0.043, Mann–Whitney U test). The macaques receiving the highest dose of pKarp47(×3) in group 3 showed early and strong increases in Ag-specific IFN-γ productions in the ELISpot assays (Fig. 7). The same was observed for group 4 macaques after the first two vaccines were applied (which were pKarp47), but the number of IFN-γ–secreting cells declined after administration of the boost vaccination with Kp47/47-VRP (Fig. 6B). Levels of IL-13 in vaccinated animals did not reach levels above control animals (data not shown).


A nonhuman primate scrub typhus model: protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques.

Paris DH, Chattopadhyay S, Jiang J, Nawtaisong P, Lee JS, Tan E, Dela Cruz E, Burgos J, Abalos R, Blacksell SD, Lombardini E, Turner GD, Day NP, Richards AL - J. Immunol. (2015)

Relationship among IFN-γ–producing PBMCs, level and duration of bacteremia, and diameter of lesion postinoculation between vaccine groups. The left graph summarizes the number of Ag-specific, IFN-γ–producing PBMCs collected at 3 wk after third vaccination, as estimate of cellular immunity available before challenge with O. tsutsugamushi. Vaccinees with the pKarp47 ×3 vaccine (group 3) had the highest IFN-γ–producing PBMCs, the lowest bacteremia, and the shortest bacteremic duration. The middle graphs depict the median levels of bacteremia and duration of bacteremic dissemination phase during acute disease, and the right graph depicts the diameter of the eschar lesion at day 12 per group (and dosage regimens).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4319312&req=5

fig07: Relationship among IFN-γ–producing PBMCs, level and duration of bacteremia, and diameter of lesion postinoculation between vaccine groups. The left graph summarizes the number of Ag-specific, IFN-γ–producing PBMCs collected at 3 wk after third vaccination, as estimate of cellular immunity available before challenge with O. tsutsugamushi. Vaccinees with the pKarp47 ×3 vaccine (group 3) had the highest IFN-γ–producing PBMCs, the lowest bacteremia, and the shortest bacteremic duration. The middle graphs depict the median levels of bacteremia and duration of bacteremic dissemination phase during acute disease, and the right graph depicts the diameter of the eschar lesion at day 12 per group (and dosage regimens).
Mentions: In group 1, the unvaccinated control macaques did not exhibit an increase in the number of Ag-specific, IFN-γ–secreting cells until day 21 after ID challenge with O. tsutsugamushi Karp. In group 2, homologous triple vaccination with Kp47/47-VRP induced few IFN-γ–producing cells, with an increase of SFUs in the ELISpot assay visible only after the third vaccination (Fig. 6B). In group 3, PBMCs from animals immunized with pKarp47(×3) produced Ag-specific IFN-γ in a dose-dependent manner. These vaccines had a significantly higher median number of IFN-γ–producing cells than controls (p = 0.043, Mann–Whitney U test). The macaques receiving the highest dose of pKarp47(×3) in group 3 showed early and strong increases in Ag-specific IFN-γ productions in the ELISpot assays (Fig. 7). The same was observed for group 4 macaques after the first two vaccines were applied (which were pKarp47), but the number of IFN-γ–secreting cells declined after administration of the boost vaccination with Kp47/47-VRP (Fig. 6B). Levels of IL-13 in vaccinated animals did not reach levels above control animals (data not shown).

Bottom Line: We investigated scrub typhus disease pathophysiology and evaluated two O. tsutsugamushi 47-kDa, Ag-based candidate vaccines, a DNA plasmid vaccine (pKarp47), and a virus-vectored vaccine (Kp47/47-Venezuelan equine encephalitis virus replicon particle) for safety, immunogenicity, and efficacy against homologous ID challenge with O. tsutsugamushi Karp.Control cynomolgus macaques developed fever, classic eschars, lymphadenopathy, bacteremia, altered liver function, increased WBC counts, pathogen-specific Ab (IgM and IgG), and cell-mediated immune responses.Vaccinated macaques receiving the DNA plasmid pKarp47 vaccine had significantly increased O. tsutsugamushi-specific, IFN-γ-producing PBMCs (p = 0.04), reduced eschar frequency and bacteremia duration (p ≤ 0.01), delayed bacteremia onset (p < 0.05), reduced circulating bacterial biomass (p = 0.01), and greater reduction of liver transaminase levels (p < 0.03) than controls.

View Article: PubMed Central - PubMed

Affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7FZ, United Kingdom; parigi@tropmedres.ac.

Show MeSH
Related in: MedlinePlus