Browsing by Author "Matarazzo, Laura"
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- Development of a new mRNA vaccine platform for tuberculosisPublication . Matarazzo, Laura; Taina‑González, Laura; Pinheiro, Ricardo; Pires, David; Fuente, Maria de la; Bettencourt, Paulo J. G.
- Development of a new mRNA vaccine platform for tuberculosisPublication . Matarazzo, Laura; Taina‑González, Laura; Pinheiro, Ricardo; Pires, David; de la Fuente, María; Bettencourt, Paulo J. G.Background Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is the frst cause of death by an infectious disease worldwide, killed 1.6 million people in 2021. Bacillus Calmette-Guerin (BCG) is the only approved vaccine for TB to date. However, while BCG is efective in preventing severe forms in children, its efcacy in adults is inconsistent and it does not prevent transmission, highlighting the need for new vaccine development [1]. The recent success of COVID-19 vaccines raised the interest for mRNA-based vaccines, as they are efective, safe and easy to produce. This project aims to develop a new mRNA vaccine platform for TB, based on mRNA coding for antigenic peptides from BCG and M.tb identifed by immunopeptidomics [2], and formulated with a patented technology of lipid nanoemulsions (NE) (WO2019138139A1), adapted for efcient intracellular delivery of mRNA [3]. Materials and methods We tested diferent prototypes of NE-mRNA formulations, coding for EGFP, in vitro. Human alveolar basal epithelial cells (A549), human monocytic cells (THP-1), and primary human monocyte-derived macrophages, were transfected with NE-mRNA formulations. Transfection efciency was assessed by measuring the percentage of transfected cells, and the intensity of GFP fuorescence. The cytotoxicity of the formulations was evaluated using AlamarBlue, and by 7-AAD viability staining. Results In vitro preliminary data using EGFP-mRNA-NE formulations indicate that NE formulations can efciently deliver mRNA and induce expression of the encoded protein in diferent cell types, with low cytotoxicity. Conclusions The NE technology presented here is safe, stable, and can efciently deliver mRNA to various cell types. Selected NE formulations will be used as a carrier for a new vaccine candidate against TB, based on mRNA encoding relevant antigenic peptides. These will be tested in mice for safety, immunogenicity, efcacy and dose optimization in order to generate an efective and sustained humoral and cellular immune response against TB. The mRNA vaccines are rapid and relatively simple to produce. The vaccine platform described here could be adapted to develop vaccines against other infectious diseases, particularly to quickly respond to emerging pathogens.
- mRNA vaccines: a new opportunity for malaria, tuberculosis and HIVPublication . Matarazzo, Laura; Bettencourt, Paulo J. G.The success of the first licensed mRNA-based vaccines against COVID-19 has created a widespread interest on mRNA technology for vaccinology. As expected, the number of mRNA vaccines in preclinical and clinical development increased exponentially since 2020, including numerous improvements in mRNA formulation design, delivery methods and manufacturing processes. However, the technology faces challenges such as the cost of raw materials, the lack of standardization, and delivery optimization. MRNA technology may provide a solution to some of the emerging infectious diseases as well as the deadliest hard-to-treat infectious diseases malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), for which an effective vaccine, easily deployable to endemic areas is urgently needed. In this review, we discuss the functional structure, design, manufacturing processes and delivery methods of mRNA vaccines. We provide an up-to-date overview of the preclinical and clinical development of mRNA vaccines against infectious diseases, and discuss the immunogenicity, efficacy and correlates of protection of mRNA vaccines, with particular focus on research and development of mRNA vaccines against malaria, tuberculosis and HIV.
- New mRNA - nanoemulsions vaccine platform: application for Tuberculosis vaccine developmentPublication . Matarazzo, Laura; Taina‑González, Laura; Pinheiro, Ricardo; Pires, David; Fuente, María de la; Bettencourt, Paulo J. G.Background: Tuberculosis (TB) is a deadly infectious disease caused by the airborne bacterium Mycobacterium Tuberculosis (M.tb), killing 1.6 million people every year, especially in low- and middle-income countries. The only licensed TB vaccine, a live attenuated strain of M. bovis (BCG), has variable efficacy, does not prevent transmission and is not safe in immunocompromised patients, particularly AIDS patients, who are at high risk of developing TB disease. Thus, the development of an efficient, safe and cost-effective tuberculosis vaccine remains a research priority. mRNA vaccine technology, which proved its potential during the COVID-19 pandemic, could represent a valuable alternative to conventional vaccines against TB. Objectives: We aim to establish a novel vaccine platform against TB, combining antigen identification by immunopeptidomics, mRNA design and production using advanced techniques, and a patented technology of lipid nanoemulsion (NE) adapted to efficiently deliver mRNA to target cells. Methods: Using a prototype mRNA encoding the fluorescent protein EGFP, we assessed in vitro the safety and transfection efficiency of different NE formulations on human alveolar basal epithelial cells (A549) and primary human monocyte-derived macrophages and dendritic cells. Results: Here we show that NEs can efficiently deliver mRNA to different cell types without significant cytotoxicity, and the formulation can be tailored to increase uptake by specific cells relevant for vaccination applications. Conclusion: Lipid NEs appear to be safe, easily adaptable and efficient transporters for mRNA. We will use selected NE formulations as carriers for mRNA vaccine candidates encoding relevant antigenic peptides from M.tb and other Mycobacterium species. Safety and immunogenicity studies will be performed in mice and the vaccination schedule will be optimized to generate a sustained humoral and cellular immune response against TB. This vaccine platform could be adapted to develop vaccines against other infectious diseases, particularly to quickly respond to emerging pathogens.