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mRNA vaccine

Pavlos C Englezou, Cedric Sapet, Thomas Démoulins, Panagiota Milona, Thomas Ebensen, Kai Schulze, Carlos-Alberto Guzman, Florent Poulhes, Olivier Zelphati, Nicolas Ruggli, Kenneth C McCullough
Advances in RNA technology during the past two decades have led to the construction of replication-competent RNA, termed replicons, RepRNA, or self-amplifying mRNA, with high potential for vaccine applications. Cytosolic delivery is essential for their translation and self-replication, without infectious progeny generation, providing high levels of antigen expression for inducing humoral and cellular immunity. Synthetic nanoparticle-based delivery vehicles can both protect the RNA molecules and facilitate targeting of dendritic cells-critical for immune defense development...
September 7, 2018: Molecular Therapy. Nucleic Acids
Bo Lou, Stefaan De Koker, Chun Yin Jerry Lau, Wim E Hennink, Enrico Mastrobattista
Vaccines based on messenger RNA (mRNA) have emerged as potent systems to elicit CD8+ T cell responses against various cancers and viral infectious diseases. The efficient intracellular delivery of mRNA molecules encoding antigens into the cytosol of antigen-presenting cells (APCs) is still challenging, requiring cell attachment, active uptake and subsequent endosomal escape. Here, we report a facile approach for the formulation of peptide-functionalized mRNA polyplexes using copper-free click chemistry to promote presentation of mRNA antigen by dendritic cells (DCs)...
September 6, 2018: Bioconjugate Chemistry
Wendy Ullmer, Bert L Semler
The cellular mRNA decay protein AUF1 acts as a restriction factor during infection by picornaviruses, including poliovirus, coxsackievirus, and human rhinovirus. AUF1 relocalizes from the nucleus to the cytoplasm during infection by these viruses due to the disruption of nucleocytoplasmic trafficking by viral proteinases. Previous studies have demonstrated that AUF1 binds to poliovirus and coxsackievirus B3 (CVB3) RNA during infection, with binding shown to occur within the internal ribosome entry site (IRES) of the 5' noncoding region (NCR) or the 3' NCR, respectively...
September 4, 2018: MBio
Aksel Bernhoft, Helga R Høgåsen, Grethe Rosenlund, Torfinn Moldal, Søren Grove, Marc H G Berntssen, Stein I Thoresen, Jan Alexander
Post-smolt Atlantic salmon (Salmo salar) were fed with standard feed added one of five concentrations of either pure deoxynivalenol (DON; 0.5-6 mg/kg) or pure ochratoxin A (OTA; 0.2-2.4 mg/kg), or no added toxins for up to 8 weeks. Performance effects (feed intake, feed efficiency, gain, length and condition factor), various clinical biochemical parameters, packed cell volume and vaccination response against Aeromonas salmonicidae were all inversely correlated with DON dose, whereas relative liver weight increased with DON dose...
September 1, 2018: Food and Chemical Toxicology
Stephen M Smith, O Hans Iwenofu
Sarcomas are heterogenous malignant mesenchymal neoplasms. These are often notoriously difficult to treat particularly in the metastatic setting. There is therefore an urgent need for development of better and more efficacious targeted therapies. Cancer testis antigens (CTAs) are a family of proteins in which aberrant gene-activation and subsequent high level mRNA expression, are restricted to testicular germ cells and are seen in certain malignancies. Importantly, the restriction of this class of antigens to testicular germ cells and malignancies and not somatic tissue, makes them an excellent choice for targeted immunotherapy...
August 2018: Chinese Clinical Oncology
Maria Agallou, Eleni Pantazi, Elisavet Tsiftsaki, Dimitra K Toubanaki, Catherine Gaitanaki, Despina Smirlis, Evdokia Karagouni
Leishmania elongation factor 2 (EF-2) has been previously identified as a TH 1-stimulatory protein. In this study, we assayed the protective potential of the N-terminal domain of EF-2 (N-LiEF-2, 1-357 aa) that has been predicted to contain several overlapping MHC class I and II-restricted epitopes injected in the form of dendritic cell (DC)-based vaccine. Ex vivo pulsing of DCs with the recombinant N-LiEF-2 domain along with CpG oligodeoxynucleotides (ODNs) resulted in their functional differentiation. BALB/c vaccinated with CpG-triggered DCs pulsed with N-LiEF-2 were found to be the most immune-reactive in terms of induction of DTH responses, increased T cell proliferation and IL-2 production...
August 30, 2018: Molecular Immunology
Shurong Ren, Qiubo Wang, Yanli Zhang, Yancheng Song, Xue Dong, Wendi Zhang, Xianfei Qin, Mingyue Liu, Ting Yu
Dendritic cell (DC) vaccine is a potent immunotherapeutic approach for cancer treatment, but the clinical efficacy needs to be improved. In this study, we evaluated the combinational effect of Toll-like receptor 7 (TLR7) agonist Imiquimod and BM-DC vaccine against mouse melanoma and explored the potential mechanisms. We found that topical application of Imiquimod cream caused skin inflammation and enhanced exogenous BM-DC homing to draining lymph nodes. Imiquimod treatment enhanced DC vaccine efficacy against B16-OVA melanoma...
August 24, 2018: International Immunopharmacology
Norbert Pardi, Kaela Parkhouse, Ericka Kirkpatrick, Meagan McMahon, Seth J Zost, Barbara L Mui, Ying K Tam, Katalin Karikó, Christopher J Barbosa, Thomas D Madden, Michael J Hope, Florian Krammer, Scott E Hensley, Drew Weissman
Currently available influenza virus vaccines have inadequate effectiveness and are reformulated annually due to viral antigenic drift. Thus, development of a vaccine that confers long-term protective immunity against antigenically distant influenza virus strains is urgently needed. The highly conserved influenza virus hemagglutinin (HA) stalk represents one of the potential targets of broadly protective/universal influenza virus vaccines. Here, we evaluate a potent broadly protective influenza virus vaccine candidate that uses nucleoside-modified and purified mRNA encoding full-length influenza virus HA formulated in lipid nanoparticles (LNPs)...
August 22, 2018: Nature Communications
Mahdokht Ilbeigi Khamsehnejad, Navid Dinparast Djadid, Abbasali Raz
Malaria is a vector-borne infectious disease that is considered a priority of the World Health Organization due to its enormous impacts on global health. Plasmodium spp. (Haemosporida: Plasmodiidae), Anopheles spp. (Diptera: Culicidae), and a suitable host are the key elements for malaria transmission. To disrupt the parasitic life cycle of malaria or prevent its transmission, these three key elements should be targeted by effective control strategies. Development of vaccines that interrupt malaria transmission is one of the solutions that has been recommended to the countries that aim to eliminate malaria...
August 13, 2018: Journal of Medical Entomology
E Brabants, K Heyns, S DE Smet, P Devreker, J Ingels, N DE Cabooter, V Debacker, M Dullaers, J P VAN Meerbeeck, B Vandekerckhove, K Y Vermaelen
BACKGROUND: Many efforts have been devoted to improve the performance of dendritic cell (DC)-based cancer vaccines. Ideally, a DC vaccine should induce robust type 1-polarized T-cell responses and efficiently expand antigen (Ag)-specific cytotoxic T-cells, while being applicable regardless of patient human leukocyte antigen (HLA) type. Production time should be short, while maximally being good manufacturing practice (GMP)-compliant. We developed a method that caters to all of these demands and demonstrated the superiority of the resulting product compared with DCs generated using a well-established "classical" protocol...
August 16, 2018: Cytotherapy
N Ziklo, A Colorni, L-Y Gao, S J Du, M Ucko
No vaccine is yet commercially available against Mycobacterium marinum, the etiological agent of "fish tuberculosis". The mycobacterial gene responsible for invasion and intracellular persistence, iipA, is known to moderate M. marinum pathology in zebrafish. Two doses of heat-killed, wild type virulent M. marinum and two doses of a heat-killed avirulent M. marinum iipA::kan mutant strain were used in parallel to vaccinate sea bass (Dicentrarchus labrax). The fish were then challenged with live virulent M...
August 18, 2018: Journal of Aquatic Animal Health
Jing Wang, Run-Zhen He, Ge-Ling Lu, Heng-Li Luo, Dan-Qi Lu, An-Xing Li
To effectively increase production and improve economic returns, the co-culture of Nile tilapia (Oreochromis niloticus) and marine shrimp has been adopted in many countries, including China. Although O. niloticus is an euryhaline fish that can tolerate elevated salinities and even full-strength seawater, fluctuations in salinity levels can undoubtedly induce stress and affect the immune response of this fish. Therefore, this study assessed the impact of salinity on vaccine efficacy in Nile tilapia, which used serum antibody level as a surrogate marker to detect vaccine efficacy...
August 15, 2018: Fish & Shellfish Immunology
Yujiao Zhou, Feifei Liu, Chengmin Li, Guo Shi, Xiaolei Xu, Xue Luo, Yuanling Zhang, Jingjie Fu, Aizhong Zeng, Limin Chen
Dendritic cells (DCs) harboring tumor-associated antigen are supposed to be a potential immunotherapy for hepatocellular carcinoma (HCC). Aspartate- β -hydroxylase (AAH), an overexpressed tumor-associated cell surface protein, is considered as a promising biomarker and therapeutic target for HCC. In this study, we constructed adenovirus vector encoding AAH gene by gateway recombinant cloning technology and preliminarily explored the antitumor effects of DC vaccines harboring AAH. Firstly, the total AAH mRNA was extracted from human HCC tissues; the cDNA was amplified by RT-PCR, verified, and sequenced after TA cloning...
2018: Journal of Immunology Research
Min Yong Jwa, Eun Byeol Ko, Hyun Young Kim, Sun Kyung Kim, Soyoung Jeong, Ho Seong Seo, Cheol-Heui Yun, Seung Hyun Han
Streptococcus pneumoniae is a major respiratory pathogen that can cause pneumonia, meningitis, and otitis media. Although capsular polysaccharide-based vaccines are commercially available, there is a need for broad-spectrum, serotype-independent, and cost-effective vaccines. Recently, an intranasal vaccine formulated with gamma-irradiated nonencapsulated S. pneumoniae whole cells has been developed and its immunogenicity is under investigation. Since innate immunity influences the subsequent adaptive immunity, in the present study, we investigated the immunostimulatory activity of gamma-irradiated S...
August 14, 2018: Microbial Pathogenesis
Adi Sharbi-Yunger, Mareike Grees, Cafri Gal, David Bassan, Stefan B Eichmüller, Esther Tzehoval, Jochen Utikal, Viktor Umansky, Lea Eisenbach
For many years, clinicians and scientists attempt to develop methods to stimulate the immune system to target malignant cells. Recent data suggest that effective cancer vaccination requires combination immunotherapies to overcome tumor immune evasion. Through presentation of both MHC-I and II molecules, DCs based vaccine platforms are effective in generating detectable CD4 and CD8 T cell responses against tumor associated antigens. Several platforms include DC transfection with mRNA of the desired tumor antigen...
August 14, 2018: International Journal of Cancer. Journal International du Cancer
Kristina Keidel, Fabian Amman, Ilona Bibova, Jakub Drzmisek, Vladimir Benes, David Hot, Branislav Vecerek
Bordetella pertussis is the causative agent of human whooping cough (pertussis), a highly contagious respiratory disease which despite massive vaccination programs remains the major cause of infant morbidity and mortality. The requirement of the RNA chaperone Hfq for virulence of B. pertussis suggested that Hfq-dependent small regulatory RNAs are involved in the modulation of gene expression in this re-emerging pathogen. High through-put RNA sequencing revealed hundreds of putative non-coding RNAs including the RgtA sRNA...
August 10, 2018: RNA
Ruchi Jain, Josh P Frederick, Eric Y Huang, Kristine E Burke, David M Mauger, Elizaveta A Andrianova, Sam J Farlow, Summar Siddiqui, Jeffrey Pimentel, Kahlin Cheung-Ong, Kristine M McKinney, Caroline Köhrer, Melissa J Moore, Tirtha Chakraborty
The advent of therapeutic mRNAs significantly increases the possibilities of protein-based biologics beyond those that can be synthesized by recombinant technologies (eg, monoclonal antibodies, extracellular enzymes, and cytokines). In addition to their application in the areas of vaccine development, immune-oncology, and protein replacement therapies, one exciting possibility is to use therapeutic mRNAs to program undesired, diseased cells to synthesize a toxic intracellular protein, causing cells to self-destruct...
August 8, 2018: Nucleic Acid Therapeutics
R Lama, P Pereiro, M M Costa, J A Encinar, R M Medina-Gali, L Pérez, J Lamas, J Leiro, A Figueras, B Novoa
P. dicentrarchi is one of the most threatening pathogens for turbot aquaculture. This protozoan ciliate is a causative agent of scuticociliatosis, which is a disease with important economic consequences for the sector. Neither vaccines nor therapeutic treatments are commercially available to combat this infection. Numerous antimicrobial peptides (AMPs) have demonstrated broad-spectrum activity against bacteria, viruses, fungi, parasites and even tumor cells; an example is Nk-lysin (Nkl), which is an AMP belonging to the saposin-like protein (SAPLIP) family with an ability to interact with biological membranes...
August 4, 2018: Fish & Shellfish Immunology
Sergio Gonzalez-Duque, Marie Eliane Azoury, Maikel L Colli, Georgia Afonso, Jean-Valery Turatsinze, Laura Nigi, Ana Ines Lalanne, Guido Sebastiani, Alexia Carré, Sheena Pinto, Slobodan Culina, Noémie Corcos, Marco Bugliani, Piero Marchetti, Mathieu Armanet, Marc Diedisheim, Bruno Kyewski, Lars M Steinmetz, Søren Buus, Sylvaine You, Daniele Dubois-Laforgue, Etienne Larger, Jean-Paul Beressi, Graziella Bruno, Francesco Dotta, Raphael Scharfmann, Decio L Eizirik, Yann Verdier, Joelle Vinh, Roberto Mallone
Although CD8+ T-cell-mediated autoimmune β cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by β cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known β cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein...
July 23, 2018: Cell Metabolism
Maria Carolina Accioly Brelaz-de-Castro, Thays Miranda de Almeida, Amanda Ferreira de Almeida, Marina de Assis Souza, Andresa Pereira de Oliveira Mendes, Rafael de Freitas E Silva, Maria Edileuza Felinto de Brito, Valéria Rêgo Alves Pereira
American Cutaneous leishmaniasis (ACL) is a public health problem. The immunological response is mainly dependent on T cell cytokine responses and might influence disease presentation, susceptibility and development. The understanding of the host immune response role in the control and in the pathology of leishmaniasis is relevant and has implications on diagnosis, follow-up and vaccine development. In this study, the differences in the immune response and T cell profile of patients before treatment was investigated through flow cytometry and real time PCR in peripheral blood mononuclear cells after different antigenic stimulations...
August 1, 2018: Microbial Pathogenesis
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