UniVax

While vaccination is the cornerstone of Flu prophylaxis, current inactivated vaccines provide only moderate protection requiring annual updating due to poor long-term immunity and antigenic drift.

UniVax will solve this restriction by generating multimeric, self-replicating, universal Flu RNA (RepRNA) vaccines delivered by synthetic, biocompatible, biodegradable carriers. It is targeted to DC receptors due to the essential role of these cells in efficient immune defence development. Co-formulation with novel mucosal adjuvants - also applicable for parenteral vaccination - potentiates development of humoral and cellular immune responses. The latter includes both cytotoxic and the multifunctional T cells related to robust protective T-lymphocyte immunity. Together with the RepRNA providing several rounds of antigen production within DCs, UniVax creates the means for efficacious induction of robust humoral and cell mediated immune (CMI) defences in an SME-dominated concept.

UniVax core technologies are based on is synthetic RepRNA encoding multimeric Flu virus antigens. The multimeric approach derives from current knowledge on combining antigens important for inducing robust immune response. Our unique synergistic approach combines technologies and SME potential to protect RNA from nucleases and enhance delivery efficiency due to the https://univax-fp7.eu/index.php?id=1293 collective knowledge on polysaccharide, lipid and polyester biotechnologies.

UniVax will generate essential data on integrating innovative technologies for RepRNA, synthetic delivery, ligand-based targeting of DCs and mucosal adjuvanting. The prototype of synthetic RepRNA vaccines with innovative mucosal adjuvants will be evaluated pre-clinically and clinically, providing data on efficacy of vaccine delivery for breadth and duration of protection.

UniVax publications

2019

Neutral lipopolyplexes for in vivo delivery of conventional and replicative RNA vaccine
Perche F., Clemençon R., Schulze K., Ebensen T., Guzmán CA., Pichon C.
Molecular Therapy 1, Nature Publishing Group, 20/02/2019, 1-10

2018

Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells
Le Moignic A, Malard V, Benvegnu T, Lemiègre L, Berchel M, Jaffrès PA, Baillou C, Delost M, Macedo R, Rochefort J, Lescaille G, Pichon C, Lemoine FM, Midoux P, Mateo V
Journal of Controlled Release, 278, Elsevier, 08/05/2018, 110-121

Dendritic Cell Targeting mRNA Lipopolyplexes Combine Strong Antitumor T-Cell Immunity with Improved Inflammatory Safety
Van der Jeught K, De Koker S, Bialkowski L, Heirman C, Tjok Joe P, Perche F, Maenhout S, Bevers S, Broos K, Deswarte K, Malard V, Hammad H, Baril P, Benvegnu T, Jaffrès PA, Kooijmans SAA, Schiffelers R, Lienenklaus S, Midoux P, Pichon C*, Breckpot K*, Thielemans K*
ACS Nano, 12, American Chemical Society, 23/10/2018, 9815-9829

Impact of pre-existing immunity on the induction of functional cross-reactive anti-hemagglutinin stalk antibodies following vaccination with an AS03 adjuvanted pandemic H1N1 vaccine
Tete SM, Jul-Larsen Å, Rostami S, Felli Lunde TH, Søland H, Krammer F, Cox RJ.
Vaccine 2018 018 Apr 12;36(16):2213-2219; DOI:10.1016/j.vaccine.2018.02.022

Immune responses after live attenuated influenza vaccination
Mohn KG, Smith I, Sjursen H, Cox RJ.

2017

Self-replicating RNA vaccine functionality modulated by fine-tuning of polyplex delivery vehicle structure
Thomas Démoulins, Thomas Ebensen, Kai Schulze, Pavlos C. Englezou, Maria Pelliccia, Carlos A. Guzmán Nicolas Ruggli, Kenneth C. McCullough
Journal of Controlled Release, Vol. 266, Elsevier, Netherlands, 01/11/2017, 256-271
dx.doi.org/10.1016/j.jconrel.2017.09.018

Revisiting Boronate/Diol Complexation as a Double Stimulus-Responsive Bioconjugation
Arianna Gennari, Chirag Gujral, Erwin Hohn, Enrique Lallana, Francesco Cellesi, Nicola Tirelli
Bioconjugate Chemistry, Vol. 28/Issue 5, American Chemical Society, United States, 17/05/2017, 1391-1402
dx.doi.org/10.1021/acs.bioconjchem.7b00080

The CD44-Mediated Uptake of Hyaluronic Acid-Based Carriers in Macrophages
Julio M. Rios de la Rosa, Annalisa Tirell , Arianna Gennari, Ian J. Stratford, Nicola Tirelli
Advanced Healthcare Materials, Vol. 6/Issue 4, WILEY-VCH Verlag GmbH & Co, 01/02/2017, 1601012
dx.doi.org/10.1002/adhm.201601012

Self-Replicating RNA Vaccine Delivery to Dendritic Cells
Démoulins T, Englezou PC, Milona P, Ruggli N, Tirelli N, Pichon C, Sapet C, Ebensen T, Guzmán CA, McCullough K.
Molecular Biology, 1499, Maik Nauka-Interperiodica Publishing, 01/05/2017, 37-75

Chitosan/Hyaluronic Acid Nanoparticles: Rational Design Revisited for RNA Delivery
Enrique Lallana, Julio M. Rios de la Rosa, Annalisa Tirella, Maria Pelliccia, Arianna Gennari, Ian J. Stratford, Sanyogitta Puri, Marianne Ashford, Nicola Tirelli
Molecular Pharmaceutics, Vol. 14/Issue 7, American Chemical Society, United States, 03/07/2017, 2422-2436
10.1021/acs.molpharmaceut.7b00320

The CD44-Mediated Uptake of Hyaluronic Acid-Based Carriers in Macrophages
Julio M. Rios de la Rosa, Annalisa Tirella, Arianna Gennari, Ian J. Stratford, Nicola Tirelli
Advanced Healthcare Materials, Vol. 6/Issue 4, WILEY-VCH Verlag GmbH & Co, 2017; 10.1002/adhm.201601012

Distinct T and NK cell populations may serve as immune correlates of protection against symptomatic pandemic influenza A(H1N1) virus infection during pregnancy
Savic M, Dembinski JL, Laake I, Hungnes O, Cox RJ, Oftung F, Trogstad L, Mjaaland S
PLOS ONE 2017 12(11): e0188055.
doi.org/10.1371/journal.pone.0188055

A DNA Vaccine That Targets Hemagglutinin to Antigen-Presenting Cells Protects Mice against H7 Influenza
Andersen TK, Zhou F, Cox R, Bogen B, Grødeland G
December 2017 Volume 91 Issue 23 e01340-17; DOI:10.1128/JVI.01340-17

High prevalence of humoral and cellular immunity to influenza viruses in pre-school children living in Addis Ababa, Ethiopia
Dembinski JL, Mihret A. Yimer SA, Tessema B, Trieu MC, Tarekegn A, Getachew N, Cox RJ, Oftung F, Haneberg B, Aseffa A, Mjaaland S .
Open Forum Infect Dis. 2017 Feb 11;4(1):ofx026.
doi: 10.1093/ofid/ofx026.

Mucosal Administration of Cycle-Di-Nucleotide-Adjuvanted Virosomes Efficiently Induces Protection against Influenza H5N1 in Mice
Ebensen T, Debarry J, Pedersen GK, Blazejewska P, Weissmann S, Schulze K, McCullough KC, Cox RJ, Guzmán CA.
Front Immunol. 2017 Sep 28;8:1223; DOI:10.3389/fimmu.2017.01223

Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for In Vivo Protection in a Serum Transfer Mouse Challenge Model.
Jacobsen H, Rajendran M, Choi A, Sjursen H, Brokstad KA, Cox RJ, Palese P, Krammer F, Nachbagauer R.
MBio. 2017 Sep 19;8(5). pii: e01463-17. DOI:10.1128/mBio.01463-17

Boosting of Cross-Reactive and Protection-Associated T Cells in Children After Live attenuated influenza vaccination in children.
Mohn KG, Zhou F, Brokstad KA, Sridhar S, Cox RJ.
J Infect Dis. 2017 Mar 27. doi: 10.1093/infdis/jix165

Influenza A haemagglutinin specific IgG responses in children and adults after seasonal trivalent live attenuated influenza vaccination.
Islam S, Mohn KG, Krammer F, Sanne M, Bredholt G, Jul-Larsen Å, Tete SM, Zhou F, Brokstad KA, Cox RJ.
Vaccine. 2017 Oct 9;35(42):5666-567; DOI:10.1016/j.vaccine.2017.08.044

Long-term maintenance of the influenza-specific cross-reactive memory CD4+ T-cell responses following repeated annual influenza vaccination.
Trieu MC, Zhou F, Lartey S, Jul-Larsen Å, Mjaaland S, Sridhar S, Cox RJ.
J Infect Dis (2017) 215 (5): 740-749; DOI:10.1093/infdis/jiw619

Self-replicating RNA vaccine functionality modulated by fine-tuning of polyplex delivery vehicle structure
Démoulins T, Ebensen T, Schulze K, Englezou PC, Pelliccia M, Guzmán CA, Ruggli N, McCullough KC
J Control Release 2017 Nov 28;266:256-271; DOI:10.1016/j.jconrel.2017.09.018

Self-Replicating RNA Vaccine Delivery to Dendritic Cells
Démoulins T, Englezou PC, Milona P, Ruggli N, Tirelli N, Pichon C, Sapet C, Ebensen T, Guzmán CA, McCullough KC
Methods Mol Biol 2017;1499:37-75; DOI:10.1007/978-1-4939-6481-9_3

2016

Intracellular Availability of pDNA and mRNA after Transfection: A Comparative Study among Polyplexes, Lipoplexes, and Lipopolyplexes
Gonçalves C, Akhter S, Pichon C, Midoux P.
Molecular Pharmaceutics, 13(9), American Chemical Society, 02/05/2016, 3153-3163

Linear, Star, and Comb Oxidation-Responsive Polymers: Effect of Branching Degree and Topology on Aggregation and Responsiveness
Richard d'Arcy, Arianna Gennari, Roberto Donno, Nicola Tirelli
Macromolecular Rapid Communications; Vol. 37/Issue 23, 2016; Wiley-VCH Verlag; 10.1002/marc.201600481

Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines
Démoulins T, Milona P, Englezou PC, Ebensen T, Schulze K, Suter R, Pichon C, Midoux P, Guzmán CA, Ruggli N, McCullough KC.
Nanomedicine 2016 Apr;12(3):711-722.; DOI: 10.1016/j.nano.2015.11.001

Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination
Sarah M Tete, Florian Krammer, Sarah Larte, Geir Bredholt, John Wood, Steinar Skrede, Rebecca J Cox
D.O.I. 10.1038/npjvaccines. 2016.1 Nature

Antibody response to seasonal influenza vaccination in multiple sclerosis patients receiving immunomodulatory therapy
Olberg H, Eide G, Cox RJ, Jul-Larsen, Å, Lartey S, Vedeler C, Myhr KM.
European Journal of Neurology 2018 Mar;25(3):527-534; DOI:10.1111/ene.13537

Humoral, T-cell and B-cell immune responses to seasonal influenza vaccine in solid organ transplant recipients receiving anti-T cell therapies
Delphine Héquet, Manuel Pascual, Sarah Lartey, Rishi D. Pathirana, Geir Bredholt, Katja Hoschler , Roger Hullin , Pascal Meylan , Rebecca J. Cox , Oriol Manuel
10.1016/j.vaccine.2016.05.021 Vaccine, 2016

Hyaluronan/Tannic Acid Nanoparticles Via Catechol/Boronate Complexation as a Smart Antibacterial System
Elita Montanari, Arianna Gennari, Maria Pelliccia, Charlotte Gourmel, Enrique Lallana,
Pietro Matricardi, Andrew J. McBain, Nicola Tirelli
DOI: 10.1002/mabi.201600311 Macromolecular Bioscience, 2016

Mannosylation Allows for Synergic (CD44/C-Type Lectin) Uptake of Hyaluronic Acid Nanoparticles in Dendritic Cells, but Only upon Correct Ligand Presentation
Arianna Gennari, Maria Pelliccia, Roberto Donno, Ian Kimber, Nicola Tirelli
DOI: 10.1002/adhm.201500941 Advanced Healthcare Materials, 2016

2015

Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines
Desmoulins T, Milona P, Englezou PC, Ebensen T, Schulze K, Suter R, Pichon C, Midoux P, Guzmán CA, Ruggli N, McCullough KC
Nanomedicine: Nanotechnology, Biology, and Medicine
Dec 1. pii: S1549-9634(15)00203-8 Elsevier Inc., 04/05/2015
10.1016/j.nano.2015.11001

Lipid-based mRNA vaccine delivery systems
Midoux P and Pichon C.
Expert Review of Vaccines, 14, Expert Reviews Ltd., 18/05/2015, 221-234

Dendritic Cell Targets for Self-Replicating RNA Vaccines
Kenneth C. McCullough, Panagiota Milona, Thomas Démoulins, Pavlos Englezou, Nicolas Ruggli
Blood, 2015

Influence of Primary Structure on Responsiveness. Oxidative, Thermal, and Thermo-Oxidative Responses in Polysulfides
Richard d’Arcy Alessandro Siani Enrique Lallana and Nicola Tirelli
Macromolecules, 2015, 48 (22), pp 8108–8120
DOI: 10.1021/acs.macromol.5b02007

2014

Self-replicating Replicon-RNA Delivery to Dendritic Cells by Chitosan-nanoparticles for Translation In Vitro and In Vivo
McCullough KC, Bassi I, Milona P, Suter R, Thomann-Harwood L, Englezou P, Démoulins T, Ruggli N.
Molecular Therapy, 2014

Alginate-coated chitosan nanogels differentially modulate class-A and class-B CpG-ODN targeting of dendritic cells and intracellular delivery
Démoulins T, Milona P, McCullough KC.
Nanomedicine: Nanotechnology, Biology, and Medicine, 2014

Intranasal formulations: promising strategy to deliver vaccines
Peggy Riese , Priya Sakthivel , Stephanie Trittel , Carlos A Guzmán
Expert Opinion on Drug Delivery, Vol. 11/Issue 10, 2014

Self-Amplifying Replicon RNA Vaccine Delivery to Dendritic Cells by Synthetic Nanoparticles
McCullough KC, Milona P, Thomann-Harwood L, Démoulins T, Englezou P, Suter R, Ruggli N.
Open Vaccine Journal, 2014

Induction of Broadly Reactive Anti-Hemagglutinin Stalk Antibodies by an H5N1 Vaccine in Humans
R. Nachbagauer, T. J. Wohlbold, A. Hirs, R. Hai, H. Sjursen, P. Palese, R. J. Cox, F. Krammer
D.O.I. 10.1128/JVI.02133-14 Journal of Virology, 2014

UniVax

Objectives

UniVax publications

Final Project Executive Summary and Results