University of Zaragoza

TB kills 1.3 million people a year and sickens more than 10 million people annually. A new TB vaccine is needed to reach the global End TB goals. MTBVAC is a highly promising vaccine candidate that has the potential to be used as an alternative to BCG vaccination in infants and for prevention of TB disease in adolescents and adults. Grant from the Bill & Melinda Gates Foundation to IAVI will support efficacy trial. NEW YORK, NY and PORRIÑO, SPAIN / ACCESSWIRE / December 18, 2023 / IAVI, a global nonprofit scientific research organization, and Spanish biopharmaceutical company Biofabri, a subsidiary of Zendal, today announced that the Bill & Melinda Gates Foundation has awarded IAVI US$55 million to conduct a Phase IIb trial assessing the safety and efficacy of the tuberculosis (TB) vaccine candidate MTBVAC to prevent active TB lung disease in adolescents and adults. This funding has been made possible in part through a grant provided by Open Philanthropy, a grant-making organization that aims to use its resources to help others as much as it can. This trial is also supported by additional funding provided by the German Federal Ministry of Education and Research (BMBF) through the KfW Development Bank, which provides funding to IAVI and partners in support of developing MTBVAC. It is anticipated that the trial will begin enrolling participants in mid-2024. "We're thrilled to have secured the investment needed to advance this promising vaccine candidate into an efficacy study," said Mark Feinberg, M.D., Ph.D., president and CEO of IAVI. "The world urgently needs a new, effective vaccine that can prevent TB disease in adults and adolescents, and we are hopeful that MTBVAC will be part of the solution to finally end the TB epidemic. We are grateful to the Bill & Melinda Gates Foundation for their support of our late-stage development work on MTBVAC and to Open Philanthropy, whose visionary investment could accelerate the availability of MTBVAC by several years, if it is shown to be safe and efficacious in the upcoming efficacy trial." "This is a historic opportunity to learn whether this promising TB vaccine candidate, MTBVAC, can prevent active TB disease in adolescents and adults, the population among whom most TB disease and transmission occurs," said Lewis Schrager, M.D., senior leader of TB vaccine development efforts at IAVI. "If MTBVAC were shown to safely prevent TB disease in this population, this vaccine could prove to be critically important in global strategies to suppress the TB pandemic given its ease of use, low cost, and anticipated widespread availability." Previous Phase Ib/IIa dose-ranging studies of MTBVAC in adults and neonates demonstrated favorable immunogenicity and safety pro In addition to this Phase IIb trial, Biofabri is conducting a Phase III trial of MTBVAC (NCT04975178) in neonates in South Africa, Madagascar, and Senegal, with support from the European & Developing Countries Clinical Trials Partnership (EDCTP). Biofabri and the HIV Vaccine Trials Network are planning a Phase IIa trial (NCT0547890) evaluating the safety and immunogenicity of MTBVAC in people living with HIV whose viral loads are well controlled on antiretroviral therapy, scheduled to begin in South Africa in mid-January 2024. Only a handful of TB vaccine candidate efficacy trials have ever been conducted. This study of MTBVAC to prevent TB disease will be conducted in approximately 4,300 people who have latent TB infection. Participants will be between the ages of 14 and 45, living in South Africa and select other sub-Saharan African countries in areas with high TB burden. Participants at 15-20 trial sites will receive either a single dose of MTBVAC or placebo and be observed for two to three years. Kundai Chinyenze, M.D., MPH, IAVI Africa director, said, "We are gratified to be able to begin working on this efficacy trial in a region of the world where TB is a leading contributor to morbidity and mortality, especially for people living with HIV. IAVI's long history in conducting clinical trials in Africa and our strong network of regional and global partners provide a solid foundation for the successful conduct of this important trial." MTBVAC, designed by the Spanish researcher Carlos Martin, Ph.D., from the University of Zaragoza, and Brigitte Gicquel, Ph.D., of Institut Pasteur, was in-licensed by Biofabri (Zendal Group). The only available TB vaccine, bacille Calmette-Guérin (BCG), is derived from Mycobacterium bovis, a bacterium that causes a TB-like disease in cows. BCG is largely ineffective in preventing TB in adolescents and adults. MTBVAC is the only live, attenuated vaccine derived from Mycobacterium tuberculosis, the bacterium that causes TB disease in humans, in the pipeline. Given its derivation from the human, rather than the bovine, TB-causing organism, MTBVAC has the potential to generate a broad protective immune response against TB. The vaccine is administered as a single dose via intradermal delivery and does not require the use of an adjuvant. Esteban Rodriguez, CEO, Biofabri, said, "We are delighted by the fantastic opportunity - through the tremendous efforts of IAVI, and the valuable support provided by the Bill & Melinda Gates Foundation, Open Philanthropy, and the German Federal Ministry of Education and Research (BMBF) through the KfW Development Bank - to now evaluate the efficacy of MTBVAC in adolescents and adults. The outcome of the efficacy studies in neonates as well as those in adolescents and adults will provide us with a pathway to license MTBVAC for all age groups." Should MTBVAC be shown to be safe and efficacious, Biofabri, in partnership with IAVI and other collaborators, will ensure that MTBVAC is manufactured and supplied in sufficient quantities globally and is accessible at affordable prices in low- and middle-income countries. TB Since the COVID-19 emergency has ended, TB is on track once again to be the deadliest infectious disease in the world. TB killed an estimated 1.3 million people in 2022, about 16% of whom were children. Around 10.6 million people fell ill with TB in 2022, and the disease is one of the 10 leading causes of death worldwide. Drug-resistant/multi-drug resistant TB (DR/MDR TB) is becoming an increasing threat, with about 410,000 cases in 2022. Treating DR/MDR TB is lengthy and expensive, often causes debilitating side effects, and is not always successful. A vaccine that prevents TB disease would play an important role in reducing the incidence of DR/MDR TB, by reducing the transmission of DR/MDR TB and reducing the use of TB drugs and the emergence of drug-resistant strains. MTBVAC MTBVAC is being developed for two purposes: as a more effective and potentially longer-lasting vaccine than BCG for newborns, and for the prevention of TB disease in adults and adolescents, for whom there is currently no effective vaccine. Two Phase II trials have been completed, one supported by EDCTP and sponsored by Biofabri in infants in South Africa, and one sponsored by IAVI and supported by the U.S. National Institutes of Health and the U.S. Department of Defense through its Congressionally Directed Medical Research Program. Results are expected to be published in early 2024. IAVI. IAVI is a nonprofit scientific research organization with headquarters in the U.S. and locations in Europe, Africa, and India that develops vaccines and antibodies for HIV, tuberculosis, emerging infectious diseases (including COVID-19), and neglected diseases, with the goal of providing global access. It has contributed to efforts to evaluate most of the leading TB vaccine candidates now in clinical development and has a highly experienced TB vaccine clinical research team in South Africa. Biofabri. Biofabri is a biopharmaceutical company created in 2008 with the aim of researching, developing, and manufacturing vaccines for humans. Biofabri has a solid technical and scientific capacity in vaccines and immunotherapy. Biofabri belongs to the Zendal group, a Spanish pharmaceutical business group made up of six companies specialised in the development, manufacture and marketing of vaccines and other biotechnological products for human and animal health. UNIZAR. The University of Zaragoza in Spain is the main center for technological innovation in the Ebro Valley. It participates in different exchange programs, collaborating with universities and research centers in Europe, Latin America, and the United States. Microbiologists from the university associated with Centro de Investigación Biomédica en Red Enfermadades Respiratorias (CIBERES) led the research and subsequent discovery of the experimental vaccine MTBVAC. Within the TuBerculosis Vaccine Initiative (TBVI) consortium, the MTBVAC discovery phase has included rigorous clinical characterization by independent laboratories and research groups. IAVI Media Contact Karie Youngdahl +1 212 847 1051 kyoungdahl@iavi.org Zendal Media Contact Beatriz Díaz Lorenzo +34 619 085 074 b.diaz@zendal.com SOURCE: IAVI View the original press release on accesswire.com

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects neurons in the brain and spinal cord causing loss of muscle control. Scientists have now suggested a potential therapeutic strategy to tackle this pathology that has no treatment to date. It is a molecular trap that prevents one of the most common genetic ALS-causing peptide compounds, the Poly-GR dipeptide, from causing its toxic effects in the body. The results show that this strategy reduces the death of neurons in patients and in an animal model (vinegar flies) of the disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects neurons in the brain and spinal cord causing loss of muscle control. A study by the University of Barcelona has designed a potential therapeutic strategy to tackle this pathology that has no treatment to date. It is a molecular trap that prevents one of the most common genetic ALS-causing peptide compounds, the Poly-GR dipeptide, from causing its toxic effects in the body. The results show that this strategy reduces the death of neurons in patients and in an animal model (vinegar flies) of the disease. The first authors of this international research study published in the journal Science Advances are the experts Juan Alberto Ortega Cano, from the Faculty of Medicine and Health Sciences and the UB Institute of Neurosciences (UBneuro), and Ivan Sasselli, from the Materials Physics Centre (CSIC-UPV/EHU). Researchers from the University of Zaragoza and Northwestern University (United States) have also participated in the study. One of the most frequent causes of ALS is the mutation in the C9orf72 gene, found in approximately 33% of patients affected by familial ALS (FALS) and 5% of those affected by sporadic ALS in Spain. In these patients, dipeptides with a large number of positive charges are generated and they provoke highly toxic effects on motor neurons. In the first part of the study, the researchers combined computational and experimental techniques to improve the molecular understanding of these dipeptides and how they produce this pathological process. A toxic union for neurons The results showed that the toxicity of these compounds is partly due to those that bind to ribosomal RNA (rRNA), a molecule involved in the process of translation of genetic information and protein synthesis in the cell. "We have observed that these dipeptides, specially those rich in the amino acid arginine (poly-glycine-arginine or Poly-GR), bind to a specific region of rRNA, affecting the biosynthesis of ribosomes (small structures responsible for synthesising proteins in our body) and protein translation in human motor neurons, leading to their death," says Professor Juan Alberto Ortega Cano. "Moreover -- the researcher adds -- this interaction between Poly-GR and the rRNA is stronger than the interaction between the Poly-GR with other ribosomal proteins that had been previously described in other studies, and it tells us why these dipeptides have a high affinity for binding to ribosomes in cells." Given these results, the researchers designed an innovative strategy to trick the Poly-GR dipeptides and reduce their toxicity. They created a trap, a molecule that mimicked the specific rRNA sequence to which Poly-GR dipeptides bin during the pathological process, in order to avoid the neurotoxic effects of this binding. The application of this strategy in neurons derived from in vitro patient tissue and in in vivo models of the disease (vinegar flies) shows that "it reduces the defects in ribosome biosynthesis in protein translation and toxicity in cells expressing Poly-GR, as well as death in motor neurons of ALS patients with mutations in the C9orf72 gene," notes the researcher. Although much research remains to be done to validate and fully understand how this strategy works, the researchers note that these promising results reinforce the idea that the use of RNA traps is useful "not only to study RNA-protein interactions, but also to protect neurons from the detrimental effects of abnormal proteins generated in other neurodegenerative diseases."

Gold is a precious metal that has always fascinated humans. From Priam's Treasure to the legend of El Dorado, gold --regarded as the noblest of metals-- has been a symbol of splendour and wealth in many civilizations. Historically, gold deposits were known to form when metal was transported dissolved by hot aqueous solution flows --hydrothermal fluids-- until it accumulated in some areas in the Earth's upper crust. The recent discovery of gold nanoparticles in such mineral deposits has brought some doubts on the validity of the classical model. Gold is a precious metal that has always fascinated humans. From Priam's Treasure to the legend of El Dorado, gold -- regarded as the noblest of metals -- has been a symbol of splendour and wealth in many civilizations. Historically, gold deposits were known to form when metal was transported dissolved by hot aqueous solution flows -- hydrothermal fluids -- until it accumulated in some areas in the Earth's upper crust. The recent discovery of gold nanoparticles in such mineral deposits has brought some doubts on the validity of the classical model. Now, a paper published in the Nature group's journal Scientific Reports reopens the scientific debate on the validity of traditional models for the transport of this precious metal in nature. The new study reveals for the first time that gold nanoparticles exposed to hydrothermal fluids have the ability to melt and produce gold nanomelts at temperatures lower (<500°C) than the melting temperature of macroscopic gold (1064°C). According to this discovery, gold could be remobilized by gold nanomelts in aqueous fluids, allowing more gold to be transported more efficiently to form economically interesting accumulations. The study is led by experts from the Faculty of Earth Sciences and the Institute of Nanoscience and Nanotechnology (IN2UB) of the University of Barcelona, the Andalusian Institute of Earth Sciences (IACT-CSIC) and the Department of Mineralogy and Petrology of the University of Granada. It also has the collaboration of the Scientific and Technological Centres of the UB (CCiTUB) and the Centre for Scientific Instrumentation of the University of Granada (CIC). Gold, the most precious noble metal In the 8th century, Jabir ibn Hayyan, the great alchemist of the Islamic world, described the purification of gold and the obtaining of pure mercury from cinnabar. In the 16th century, Georgii Agricolae De ortu & causis subterraneorum already established how gold was transported in the Earth's upper crust as species dissolved in hydrothermal fluids, hot aqueous solutions -- between 50 and 500ºC -- with features that depend on the geological context and the depth at which these aqueous solutions are found (generally of the order of kilometres below the Earth's surface). Most of the world's gold deposits have been formed by this mode of transport. However, gold can also accumulate when primary gold deposits are eroded away once they are exposed to the surface by tectonic processes on land, resulting in the famous gold nuggets that prospectors found along riverbanks in the height of the gold rush. Although John Turkevich succeeded in synthesising gold nanoparticles in the 1950s, it was not until forty years later, in the early 1990s, that they were documented in natural gold deposits. Specifically, these nanoparticles were found in a type of deposit with high concentrations of gold known as the bonanza type in Nevada (United States). The discovery of these nanoparticles supported the hypothesis that states that gold could be transported as nanoparticles suspended in the fluid rather than as a dissolved species. "There is a wide variety of hydrothermal gold deposits depending on a number of factors. Globally, the most important are orogenic, Carlin and epithermal gold deposits. However, the characterisation of these mineralizing fluids has shown that their ability to dissolve gold is very low. Regardless of their nature, these fluids are incapable of transporting the amount of gold needed to explain auriferous mineralizations, especially those very rich in gold of the bonanza type," notes Professor Joaquín A. Proenza, from the UB Department of Mineralogy, Petrology and Applied Geology. "Therefore, the formation of gold deposits cannot be only caused by hydrothermal fluids transporting dissolved gold," says Proenza, member of the Research Group on Mineral Resources for Energy Transition (MinResET). When gold nanoparticles melt down This study describes for the first time the melting process of gold nanoparticles. "This process has been discovered in gold-rich samples from the Cu-Co-Ni-Au deposits of the Habana-Matanzas region (Cuba), which show a large amount of gold nanoparticles. Our research reveals how gold nanoparticles exposed to hydrothermal fluids have the ability to melt and produce gold nanomelts," says Diego Domínguez-Carretero (UB), who is the first author of the article and is working on his doctoral thesis under the supervision of Joaquín A. Proenza and Antonio García Casco (University of Granada). "Our study describes for the first time the whole formation process of the gold nanoparticles: specifically, the release of the nanoparticles from the mineral in which they were included, the exposure to the hydrothermal fluid and subsequent melting, and finally, the remobilisation by auriferous nanofusions immiscible with the hydrothermal fluid," say the researchers. To obtain these results, the team has applied a combination of classical techniques (optical microscopy and field emission scanning electron microscopy) together with other more innovative techniques (hydro-separation, focused ion beam, high-resolution transmission electron microscopy). These analytical techniques are available at the CCiTUB, at the Advanced Microscopy Laboratory of the University of Zaragoza and at the CIC. "To date, -- they continue -- the only example of the formation of gold nanomelts required other elements, such as bismuth (Bi), tellurium (Te) or antimony (Sb), which are not always concentrated together with gold in many mineral deposits. The study details for the first time the sequence of transformation of gold nanoparticles to gold nanocrystals without requiring other elements, such as Bi, Te or Sb." According to the authors, "this paradigm shift provides a better understanding of the origin of gold and, consequently, helps to establish more realistic genetic models." "Establishing the genesis, that is, to understand the complex geological processes involved and the factors that condition the formation of a mineral deposit, is an essential aim for a mineral deposit geologist." "Gold mining, like any other type of mining, feeds on these genetic models to establish exploration campaigns to find new deposits," concludes the research team. This is an innovative line at a national and European level, dedicated to the investigation of the influence of metallic nanoparticles in the formation of critical mineral deposits, developed in collaboration with the researcher José María González Jiménez, from the Andalusian Institute of Earth Sciences.