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ABSTRACT
Melioidosis is a severe infectious disease with a high mortality that is endemic in South-East Asia and Northern Australia. The causative pathogen, Burkholderia pseudomallei, is listed as potential bioterror weapon due to its high virulence and potential for easy dissemination. Currently, there is no licensed vaccine for prevention of melioidosis. Here, we explore the use of rapid plasmid DNA vaccination against B. pseudomallei flagellin for protection against respiratory challenge.
We tested three flagellin DNA vaccines with different subcellular targeting designs. C57BL/6 mice were vaccinated via skin tattoo on day 0, 3 and 6 before intranasal challenge with B. pseudomallei on day 21. Next, the most effective construct was used as single vaccination on day 0 by tattoo or intranasal formulation. Mice were sacrificed 72 hours post-challenge to assess bacterial loads, cytokine responses, inflammation and microscopic lesions.
A construct encoding a cellular secretion signal resulted in the most effective protection against melioidosis via tattooing, with a 10-fold reduction in bacterial loads in lungs and distant organs compared to the empty vector. Strikingly, a single intranasal administration of the same vaccine resulted in >1000-fold lower bacterial loads and increased survival. Pro-inflammatory cytokine responses were significantly diminished and strong reductions in markers for distant organ damage were observed.
A rapid vaccination scheme using flagellin DNA tattoo provides significant protection against intranasal challenge with B. pseudomallei, markedly improved by a single administration via airway mucosa. Hence intranasal vaccination with flagellin-encoding DNA may be applicable when acute mass vaccination is indicated and warrants further testing.
Abbreviations
| ALT | = | alanine aminotransferase |
| AST | = | aspartate aminotransferase |
| BSA | = | bovine serum albumin |
| CFA | = | Complete Freund's Adjuvant |
| CFU | = | colony forming units |
| FliC | = | flagellin |
| HE | = | haematoxylin/eosin |
| IFN | = | interferon |
| IL | = | interleukin |
| LDH | = | lactate dehydrogenase |
| PBS | = | phosphate-buffered saline |
| PEI | = | polyethylenimine |
| TNF | = | tumor necrosis factor |
| TPA | = | tissue plasminogen activator |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
The authors would like to thank Marieke ten Brink, Joost Daalhuisen and Regina de Beer for their indispensable technical assistance in these experiments. Onno J. de Boer, pathologist, was of great help in the analysis of the neutrophil stainings.
Funding
This work was supported by the Netherlands Organization for Scientific Research (NWO; VIDI grant tot WJW, grant number: 91716475; VENI grant to JWH, grant number 91611065; and VENI grant to ADB, grant number 91610005). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.