Development of a versatile vaccination platform based on papaya mosaic virus (PapMV) nanoparticles

Over the past years, virus-like particles (VLPs) have shown great potential as highly immunogenic subunit vaccines. These non-infectious viral structures mimic the native pathogen’s organisation and conformation. VLPs contain highly repetitive and ordered viral epitopes leading to B cell activation through receptor cross-linking. By displaying heterologous epitopes on VLPs, one can mount an immune response against a different pathogen. These chimeric VLPs serve as presentation scaffold and can sometimes act as adjuvant to boost the immune response. However, VLP assembly can be affected by large epitope insertions altering intra or extra protein interactions impacting its conformation. Even if the insertion is successful, the epitopes have to be exposed at the particle surface to induce an immune response. To circumvent this problem, we have developed a new vaccine platform based on PapMV nanoparticules and sortase A (SrtA) transpeptidase. SrtA catalyzes the covalent conjugation of target antigenic epitopes to already assembled PapMV VLPs harbouring the SrtA recognition motif LPETG. Successful SrtA conjugations were achieved with peptides derived from Influenza (M2e) and HIV (T20). SrtA conjugated PapMV nanoparticles induce strong humoral responses in mice against both M2e and T20 peptides. PapMV-M2e vaccinated mice were protected against a lethal dose of Influenza H1N1 (A/WSN/33). Sera from PapMV-T20 vaccinated mice did not reduce in vitro HIV infection even with the high presence of specific antibodies. This new PapMV-SrtA platform eliminates the need for genetic fusion of the coat protein that can be difficult, time consuming and, sometime, unrealizable. The modification of PapMV VLP post-assembly facilitates its use in the rapid development of new vaccines by changing the nature of the target epitopes conjugated. This could be particularly useful when developing a pandemic vaccine or personalised vaccine for cancer therapy

Engineering of Papaya Mosaic Virus (PapMV) Nanoparticles through Fusion of the HA11 Peptide to Several Putative Surface-Exposed Sites

Papaya mosaic virus has been shown to be an efficient adjuvant and vaccine platform in the design and improvement of innovative flu vaccines. So far, all fusions based on the PapMV platform have been located at the C-terminus of the PapMV coat protein. Considering that some epitopes might interfere with the self-assembly of PapMV CP when fused at the C-terminus, we evaluated other possible sites of fusion using the influenza HA11 peptide antigen. Two out of the six new fusion sites tested led to the production of recombinant proteins capable of self assembly into PapMV nanoparticles; the two functional sites are located after amino acids 12 and 187. Immunoprecipitation of each of the successful fusions demonstrated that the HA11 epitope was located at the surface of the nanoparticles. The stability and immunogenicity of the PapMV-HA11 nanoparticles were evaluated, and we could show that there is a direct correlation between the stability of the nanoparticles at 37°C (mammalian body temperature) and the ability of the nanoparticles to trigger an efficient immune response directed towards the HA11 epitope. This strong correlation between nanoparticle stability and immunogenicity in animals suggests that the stability of any nanoparticle harbouring the fusion of a new peptide should be an important criterion in the design of a new vaccine

A Type System for Privacy Properties (Technical Report)

Mature push button tools have emerged for checking trace properties (e.g. secrecy or authentication) of security protocols. The case of indistinguishability-based privacy properties (e.g. ballot privacy or anonymity) is more complex and constitutes an active research topic with several recent propositions of techniques and tools. We explore a novel approach based on type systems and provide a (sound) type system for proving equivalence of protocols, for a bounded or an unbounded number of sessions. The resulting prototype implementation has been tested on various protocols of the literature. It provides a significant speed-up (by orders of magnitude) compared to tools for a bounded number of sessions and complements in terms of expressiveness other state-of-the-art tools, such as ProVerif and Tamarin: e.g., we show that our analysis technique is the first one to handle a faithful encoding of the Helios e-voting protocol in the context of an untrusted ballot box

Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer

Chronic inflammation plays a crucial role in bladder cancer (BCa) development and progression. To offer a unique treatment opportunity for this type of cancer, a hydrazide derivative namely, DAB-1, was recently identified in our laboratory as a potential drug to target cancer-related inflammation. In preclinical models of murine BCa, this particular compound exhibited remarkable anticancer activities. Structurally, DAB-1 is made from para-aminobenzoic acid and bears two different components, a maleimide and a hydrazide moieties, which are critical for its anti-inflammatory activity and its anticancer properties. In order to improve its biological potential, the hydrazide moiety was further modified to provide 3 ​s-generation molecules named, DAB-2-28, DAB-2-31A, and DAB-2-31B, and two third-generation molecules named, DAB-3-27 and DAB-3-33. Data from in vitro studies revealed that, among the different DAB molecules under study, DAB-2-28 has less cytotoxic activity with greater efficiency than DAB-1 to inhibit the production of nitric oxide (NO) induced by the combination of IFNγ with TNFα, as well as the activation of pro-tumoral and pro-inflammatory signaling pathways IL6/STAT3 and TNFα/NFκB. Moreover, while DAB-2-28 exhibited similar anti-inflammatory activity in vivo to DAB-1 in a model of carrageenan-induced acute inflammation, it efficiently inhibited the expression of the enzymes iNOS and COX-2 induced by the combined activation of IFNγ with LPS in peritoneal macrophages. Notably, analysis of the growth kinetics of MB49-I tumors implanted subcutaneously in C57Bl/6 mice showed that DAB-2-28 was more efficient to inhibit tumor development. In conclusion, this study provided preclinical proof-of-principle for DAB-2-28 molecule in the treatment of BCa.Fil: Oufqir, Yassine. Université du Québec a Montreal; CanadáFil: Fortin, Laurie. Université du Québec a Montreal; CanadáFil: Girouard, Julie. Université du Québec a Montreal; CanadáFil: Cloutier, Francis. Université du Québec a Montreal; CanadáFil: Cloutier, Maude. Université du Québec a Montreal; CanadáFil: Leclerc, Marie France. Université du Québec a Montreal; CanadáFil: Belgorosky, Denise. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Eijan, Ana Maria. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bérubé, Gervais. Université du Québec a Montreal; CanadáFil: Reyes-Moreno, Carlos. Université du Québec a Montreal; Canad

Supramolecular assembly of gelatin and inorganic polyanions: Fine-tuning the mechanical properties of nanocomposites by varying their composition and microstructure

A series of bionanocomposites has been synthesized through a complex coacervation process inducing the assembly of gelatin with a wide range of inorganic polyanions (IPyAs) differing by their diameter and charge and including polyoxometalates (POMs) and a polythiomolybdate cluster. The microstructure and stoichiometry of these hybrid coacervates, which are strongly dependent on the charge matching between both components, have been studied by combining Fourier transform infrared (FT-IR) spectroscopy, solid-state nuclear magnetic resonance (NMR), thermogravimetric analysis (TGA), elemental analysis, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX) elemental mapping. The mechanical properties of these materials were deeply characterized by tensile measurements at large deformation, revealing different behaviors (i.e., elastomer and ductile), depending on the nature of the IPyA. It is noteworthy that the mechanical properties of these bionanocomposites are strongly enhanced, compared to pure gelatin hydrogels. When attempting to connect structure and properties in these bionanocomposites, we have demonstrated that the density of cross-links (gelatin triple helices and IPyA) is the key parameter to control the extensibility of these materials