Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines

Abstract Self-amplifying replicon RNA (RepRNA) are large molecules (12-14 kb); their self-replication amplifies mRNA template numbers, affording several rounds of antigen production, effectively increasing vaccine antigen payloads. Their sensitivity to RNase-sensitivity and inefficient uptake by den...

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Bibliographic Details
Published in:Nanomedicine 2016-04, Vol.12 (3), p.711-722
Main Authors: Démoulins, Thomas, PhD, Milona, Panagiota, PhD, Englezou, Pavlos C., PhD, Ebensen, Thomas, PhD, Schulze, Kai, PhD, Suter, Rolf, PhD, Pichon, Chantal, PhD, Midoux, Patrick, PhD, Guzmán, Carlos A., MD, PhD, Ruggli, Nicolas, PhD, McCullough, Kenneth C., PhD
Format: Article
Language:English
Subjects:
Adjuvant
Animals
Antigens - genetics
Antigens - immunology
Blood dendritic cells
Cell Line
Dendritic Cells - immunology
Humoral and cellular immunity
Immunity, Cellular
Immunity, Humoral
Influenza vaccines
Influenza virus
Internal Medicine
Intracellular delivery
Life Sciences
Mice, Inbred BALB C
Polyethyleneimine - chemistry
Polyplexes
Protein Biosynthesis
Replicon
Replicon-RNA
RNA - administration & dosage
RNA - genetics
RNA - immunology
RNA - pharmacokinetics
Self-replicating vaccine
Swine
Vaccines - administration & dosage
Vaccines - genetics
Vaccines - immunology
Vaccines - pharmacokinetics
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Summary:Abstract Self-amplifying replicon RNA (RepRNA) are large molecules (12-14 kb); their self-replication amplifies mRNA template numbers, affording several rounds of antigen production, effectively increasing vaccine antigen payloads. Their sensitivity to RNase-sensitivity and inefficient uptake by dendritic cells (DCs) – absolute requirements for vaccine design – were tackled by condensing RepRNA into synthetic, nanoparticulate, polyethylenimine (PEI)-polyplex delivery vehicles. Polyplex-delivery formulations for small RNA molecules cannot be transferred to RepRNA due to its greater size and complexity; the N:P charge ratio and impact of RepRNA folding would influence polyplex condensation, post-delivery decompaction and the cytosolic release essential for RepRNA translation. Polyplex-formulations proved successful for delivery of RepRNA encoding influenza virus hemagglutinin and nucleocapsid to DCs. Cytosolic translocation was facilitated, leading to RepRNA translation. This efficacy was confirmed in vivo , inducing both humoral and cellular immune responses. Accordingly, this paper describes the first PEI-polyplexes providing efficient delivery of the complex and large, self-amplifying RepRNA vaccines.
ISSN:1549-9634
1549-9642
DOI:10.1016/j.nano.2015.11.001