Category Archives: Immunology

Immunology

Late great engineers: Edward Jenner | The Engineer The Engineer – The Engineer

This months late great engineer was actually a scientist and surgeon rather than an engineer. But his discoveries have shaped our world significantly and, as the world scrambles for a COVID-19 vaccine, are particularly worthy of note at the current time. Meet father of immunology Edward Jenner. Written by Nick Smith.

Towards the end of the 18th century an English doctor by the name of Edward Jenner conducted an experiment on an eight-year-old boy that was to change the world. The experiment had its critics. The clergy said that Jenners work was repulsive and ungodly, while satirical cartoons appeared showing humans sprouting cows heads. But the advantages of using cowpox pus to inoculate against smallpox the deadliest disease in human history soon became clear, and Jenners pioneering work in the field became the rock upon which the fight against smallpox and other infectious human diseases was built. While Jenner wasnt alone in realising that inoculation with cowpox provided immunity to smallpox, he was the first to publish proof of its efficacy and to develop a reliable vaccine. Today, the physician from Berkley in Gloucester is known throughout the world as the father of immunology. Napoleon called Jenner one of the greatest benefactors of mankind.

Born in the mid-18th century on 17th May 1749, Jenner came into a world of fundamental change, so much so that Britain was just about to adopt the new Gregorian calendar that corrected errors in the former Julian calendar. It was a time when British medical practice and education was undergoing a quiet revolution in which the old demarcation between the Oxbridge physicians and the more hands-on apothecaries was becoming blurred. It was a time when practical experimentation and hospital work came to be regarded as being on an equal footing with academic research. It was also at time when the smallpox virus was killing 400,000 people per year in Europe. In Britain alone smallpox accounted for the lives of ten percent of the population, with this figure doubling in urban areas where infection spread more easily.

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By Jenners time variolation treatment of a disease with the same disease to create immunity to itself was the widespread method of addressing smallpox. While it had some impact on reducing the effect of the virus, especially among the wealthy, the process was fraught with risk, not least in that those inoculated with the disease became carriers and could infect those around them. It wasnt until Jenners cowpox-based vaccination became common practice by the end of the 19th century that any significant reduction in incidence in Europe and North America occur. Even then the disease remained largely unchecked in other parts of the world, notably Africa, well into the 20th century, before intensive containment measures and scientific surveillance eventually led to its formal eradication on 9th December 1979. Four decades on, smallpox remains, in the words of World Health Organization Director-General Tedros Adhanom Ghebreyesus, the only human disease ever eradicated.

The part Jenner was to play in this eradication could not necessarily be predicted from his conventional background. The eighth of nine children, his father was the vicar of Berkley, which meant that he was destined for a robust provincial education in both Wooton-under-Edge and Cirencester. By the age of 14 he had been inoculated against smallpox by variolation and he had left school, apprenticed to the surgeon Daniel Ludlow for seven years, and from whom he gained sufficient experience to become a surgeon himself. At the age of 21, Jenner undertook a further apprenticeship in surgery and anatomy at St Georges Hospital in London. It was at this time that Jenner fell under the influence of surgeon John Hunter, who offered the young doctor the characteristic Age of Enlightenment advice: dont think; try. With this presumably still ringing in his ears in 1773, at the age of 24, Jenner returned to his Gloucester home where he became a practicing doctor and surgeon.

Meanwhile, English physician John Frewster had discovered that prior infection with cowpox rendered a person immune to smallpox. Also, in the 1770s, at least five simultaneous investigations were underway in Europe and Britain testing cowpox vaccination on humans against smallpox. In Britain, during the 1774 smallpox epidemic, Dorset farmer Benjamin Jesty successfully vaccinated his wife and two children with cowpox, and it is thought that Jenner may have been aware of Jestys work. Where Jenner comes into the story is that he managed to tie up some of the unknowns in his own research.

It had long been common knowledge that milkmaids were somehow immune to smallpox due to their routine proximity to cows and cowpox. Jenners hypothesis was that the well-known folklore of milkmaid immunity stemmed from the pus in the blisters they received from the less dangerous cowpox. To test this, on 14th May 1796, Jenner inoculated James Phipps, the eight-year-old son of his gardener. Jenner got pus samples from cowpox blisters on the hands of milkmaid Sarah Nelmes who had caught the disease from a cow called Blossom. Phipps presented with fever, but no full-blown cowpox infection, and so Jenner went to the next step of challenging the boys supposed immunity with the variolous material (ie smallpox itself) that had to date been the standard basis of inoculation. As no disease followed, Phippss immunity to smallpox was challenged repeatedly. The significance of these procedures is that they made significant inroads into proving not just that cowpox could provide immunity to smallpox, but that the protective cowpox pus could be effectively inoculated from person to person and not just directly from cattle. Jenner coined the term vaccination that linguistically has its roots in the Latin adjective vaccinus, meaning of, or related to, cows.

Jenner pressed on with his research and in 1798 published a monograph entitled An Inquiry into the Causes and Effects of the Variol Vaccinn, which was followed in annual succession by three further papers developing his ideas on vaccination. But it was to be a long and difficult road to having the concept of vaccination accepted as an alternative to variolation as the standard for smallpox prevention, with the medical establishment dithering for decades over the idea. Eventually, some 17 years after Jenners death, the British government banned variolation and provided optional vaccination using cowpox free of charge under the Vaccination Act 1840. It would be a further 12 years before vaccination became compulsory. Despite not living to see the full effects of his work, Jenner knew enough of his success to reflect that, the joy I felt as the prospect before me of being the instrument destined to take away from the world one of its greatest calamities was so excessive that I found myself in a kind of reverie.

Although Jenner might have cashed in on his success, having been widely honoured for his pioneering role in the emerging field of immunology, his single-minded focus on his work on the understanding of vaccination and vaccines meant that his country medical practice fell into neglect and suffered financially. To ensure his research into vaccination could continue, in 1802 Jenners colleagues, with the support of King George III, petitioned the British government for a grant of 10,000 (approximately 1m today), which was followed five years later by a further 20,000 after the Royal college of Physicians had confirmed the widespread efficacy of vaccination. In 1803 he became president of the Jennerian Society established to promote vaccination to eradicate smallpox, and in 1805 he became a founding member of the Medical and Chirurgical Society, that was to become the Royal Society of Medicine. By 1821 such was his influence that he became physician to the new king George IV and mayor of his hometown of Berkeley, where he is buried having died of stroke in 1823.

Although the disease may have been eradicated, there remain two official samples of the virus known to cause smallpox kept in tightly controlled WHO-sanctioned government laboratories in the United States and Russia. Their existence periodically raises the ethical debate over whether they should be destroyed, with the current position of both countries being outlined by the former Secretary of the U.S. Department of Health and Human Services, Kathleen Sebelius, who says that the dangers of destroying the samples outweigh the minuscule risk attached to keeping them. Their destruction, she says, would be purely symbolic and could leave the world vulnerable should we ever need to conduct further scientific research into the virus.

Jenners legacy is best articulated in the opening sentences of a resolution by the World Health Assembly published on 8th May 1980 that declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake

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Immunology

INmune Bio, Inc. Receives Regulatory Approval from UK MHRA to Initiate Phase I Trial of INKmune in Patients with High-risk MDS – BioSpace

Study will be the first-in man trial for INKmune a novel therapy to prime the patients own NK cells to attack their cancer

LA JOLLA, Calif., June 11, 2020 (GLOBE NEWSWIRE) -- INmune Bio, Inc.(NASDAQ: INMB) (the Company), a clinical-stage immunology company focused ondeveloping treatments that harness the patients innate immune system to fight disease, announced that the Medicines and Healthcare products Regulatory Agency (MHRA; the UK equivalent of the FDA) has given approval to initiate a Phase I clinical trial of INKmune, a novel therapy to prime the patients own NK cells to attack their cancer, in patients with high-risk Myelodysplastic Syndrome (MDS) (EUDRACT 2019-004820-40). This single center Phase I trial will be the first-in-man study using INKmune. Based on the current environment and timetable of its clinical site, INmune Bio is targeting the study initiation in the 2ndhalf of this year.

Patients with MDS are mostly elderly; in this population high-dose chemotherapy or bone marrow transplant are usually too toxic, said Dr. Marion Wood, consultant hematologist and the medical director for this INKmune program. With this clinical trial, we hope to show that INKmune will provide an effective and better tolerated therapeutic option for those patients who are poorly served by current therapies. Patients with high-risk MDS will be enrolled to receive at least 3 doses of INKmune therapy via intravenous infusion, without the need for any type of conditioning therapy or pretreatment. The Phase I trial, calledLaurel,will include at least 9 patients enrolled at a single center in the UK and has the capacity for an extension cohort.

Recent research has shown that MDS patients who survive beyond two years are those with good NK cell activity (Tsirogianni et al 2019). INKmune has been shown to boost the function of NK cells from MDS patients in laboratory experiments. We will target those patients whose NK cells demonstrate a response to INKmune in the laboratory. This is part of our precision approach to immunotherapy, said Dr. Mark Lowdell, CSO of INmune Bio and discoverer of the science behind INKmune. We are excited to be able to test it as a treatment in this group of patients facing an unmet therapeutic need.

Professor Lowdell and his team in the UK have worked closely with the MHRA to get this trial through regulatory approval, despite the challenges of the COVID-19 pandemic, said RJ Tesi MD, CEO of INmune. The INKmune program is the second oncology platform entering the clinic for INmune Bio.

About INKmune

INKmune is a suspension of replication incompetent tumor cells from our proprietary tumor cell line, INB16; cryopreserved and shipped to the clinical site for local storage at -70oC. INKmune is delivered intravenously and binds to resting NK cells where it provides critical activating signals to initiate NK killing of tumor cells which are resistant to chemotherapy. NK cells activated by INKmune are able to activate other resting NK cells and thus magnify the effect. INKmune-primed NK cells have been shown to kill multiple tumor types including MDS, leukemias, myeloma, breast cancer and ovarian cancer cellsin vitroandin vivo(North et al 2007, Sabry et al 2011, Kottaridis et al 2015).

Kottaridis PD, et al. Two-stage priming of allogeneic Natural Killer cells for the treatment of patients with acute myeloid leukemia; a phase I trial. PLoS One 2015; Jun 10;10(6):e0123416. doi: 10.1371

North J, et al. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence for a two-stage process in resting NK cell activation. Journal of Immunology 2007; 178:85-94.

Sabry M, et al. Leukemic priming of resting NK cells is KIR independent but requires CD15-mediated CD2 ligation and natural cytotoxicity receptors. J.Immunology 2011; 187:6227-6234.

Tsirogianni M, et al.Natural killer cell cytotoxicity is a predictor of outcome for patients with high risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia treated with azacytidine.Leuk Lymphoma. 2019 Apr 5:1-7.

About high-risk MDS

Myelodysplastic syndrome (MDS) describes a range of blood malignancies characterised by anemias, clotting disorders and increased risk of infection all of which often result in death. In the group of MDS patients in this trial there is a high risk of progression to leukemia with rapidly fatal outcome. MDS is predominantly a disease of the elderly with the median age at diagnosis in the UK and USA of 76 years and is incurable in more than 90% of patients; over half of whom will die within 2 years of diagnosis. NK cell activity in these patients is predictive of overall survival beyond two years (Tsirogianni et al 2019).

About INmune Bio, Inc.

INmune Bio, Inc. is a publicly traded (NASDAQ: INMB), clinical-stage biotechnology company focused on developing treatments that target the innate immune system to fight disease. INmune Bio has two product platforms. The DN-TNF product platform utilizes dominant-negative technology to selectively neutralize soluble TNF, a key driver of innate immune dysfunction and mechanistic target of many diseases. DN-TNF is currently being developed for COVID-19 complications (Quellor), cancer (INB03), Alzheimers (XPro595), and NASH (LIVNate). The Natural Killer Cell Priming Platform includes INKmune aimed at priming the patients NK cells to eliminate minimal residual disease in patients with cancer. INmune Bios product platforms utilize a precision medicine approach for the treatment of a wide variety of hematologic malignancies, solid tumors and chronic inflammation. To learn more, please visitwww.inmunebio.com.

Forward Looking Statements

Clinical trials are in early stages and there is no assurance that any specific outcome will be achieved. Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any forward-looking statements contained herein are based on current expectations but are subject to a number of risks and uncertainties. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties. INB03, XPro1595, LIVNate, Quelloer and INKmune are still in clinical trials or preparing to start clinical trials and have not been approved and there cannot be any assurance that they will be approved or that any specific results will be achieved. Our two platforms are beginning clinical trials and there cannot be any assurance of the success of these trials. The factors that could cause actual future results to differ materially from current expectations include, but are not limited to, risks and uncertainties relating to the Companys ability to produce more drug for clinical trials; the availability of substantial additional funding for the Company to continue its operations and to conduct research and development, clinical studies and future product commercialization; and, the Companys business, research, product development, regulatory approval, marketing and distribution plans and strategies. These and other factors are identified and described in more detail in the Companys filings with the Securities and Exchange Commission, including the Companys Annual Report on Form 10-K, the Companys Quarterly Reports on Form 10-Q and the Companys Current Reports on Form 8-K. The Company assumes no obligation to update any forward-looking statements in order to reflect any event or circumstance that may arise after the date of this release.

INmune Bio Contact:David Moss, CFO (858) 964-3720DMoss@INmuneBio.com

Investor Contact:James Carbonara (646) 755-7412James@haydenir.com

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INmune Bio, Inc. Receives Regulatory Approval from UK MHRA to Initiate Phase I Trial of INKmune in Patients with High-risk MDS - BioSpace

Immunology

Some cells serve as unlikely heroes to defend the brain from viral invaders – STAT

Scientists have discovered the important role of microglia cells in protecting a mouse brains central nervous system from viral infections that entered the brain through the nose.

Despite entering the body through the nose which gives a pathogen a direct route to the brain via olfactory neurons many viruses rarely manage to cause fatal damage in the brain. Researchers at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health wanted to figure out why thats the case. In a new study published recently in Science Immunology, they infected mice with a respiratory virus called vesicular stomatitis virus to track the immune systems response.

Youre not trying to find out why the system [is] broken the system usually works, said Ashley Moseman, an assistant professor at Duke University School of Medicine and a co-author of the study. Past studies have shown that the brain can expel a virus without killing many of its own finite number of neurons, but they wanted to pinpoint how that process occurs.

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Their research found an unlikely hero: microglia. Microglial cells in the brain are not infected themselves by invading viruses. Rather, the study found that microglia actually find antigens the toxins a virus gives off in the brain and present them to the T cells that need to kill them.

We dont want T cells to go into the brain and kill things that they arent supposed to kill, said Moseman. So, he said, the microglia acquire antigen in a way that allows them to present antigen in the area, but avoid some of these tricky situations.

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The team observed the process between microglia and T cells by using a virus that would leave a stain to show everywhere its been, allowing them to see all the cells that survived infection. They used microscopes to observe the live cells interacting red-colored T cells flashed green when they came in contact with microglia and killed the antigen.

Later in the study, the team infected mice again, this time after reducing microglia in their brain. Under the microscope, they observed that T cells were less likely to recognize antigens when microglia were fewer. The mice also had reduced survival rates with lower counts of microglia, demonstrating how critical a role this cell type plays in the brains protection.

The researchers do not know how microglia are affected after a T cell kills the antigen. The encounter might kill microglia, too, but the stakes are lower, according to Moseman. Microglia can regenerate in ways that central nervous system neurons cannot. But its still an important question to ask, Moseman said, because what happens to microglia could have implications about how in control they are of T cells during this process.

The research has no immediate clinical implications, but scientists hope it will spark more study of how the brain protects itself and how those natural defenses could be enhanced. Many researchers are particularly interested in a possible connection to SARS-CoV-2, the virus that leads to Covid-19.

Loss of smell and taste are major symptoms of Covid-19, demonstrating a potential interference in the brain when infected. But experts said its also still unclear whether SARS-CoV-2 can enter the brain through neurons in the nose and, if so, how that might be prevented.

The findings are an important step toward researching possible interventions for when the brains defense system doesnt work, said Ari Waisman, chair and professor of immunology at University Medical Center of the Johannes Gutenberg University of Mainz, who wasnt involved in the research. He said there is now a question of whether the mechanism this study revealed, which occurs after the virus has infected the central nervous system, could be manipulated to happen earlier to protect the brain from other pathogen invasions.

Microglia has a lot of roles in antiviral infection that were not appreciated before, said Waisman.

While the study sheds light on the brains successful self-defense, its important to emphasize that this process occurs when the virus is already in the body and in the brain, Moseman said.

If youre trying to prevent invasion in the first place, you should consider the surface that is going to be invaded, he said. Once you get infected, you have to deal with the consequences one way or the other.

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Immunology

Bold Therapeutics Expands COVID-19 Consortium – PharmiWeb.com

VANCOUVER, BC, June 11, 2020 /PRNewswire/ --Bold Therapeutics, a clinical-stage biopharmaceutical company, has expanded its COVID-19 collaborations to include four more academic researchers: Francois Jean, PhD and Ted Steiner, MD, both researchers from the University of British Columbia; Stephen Barr, PhD, a researcher at Western University; and Len Seymour, PhD, a researcher at the University of Oxford in the United Kingdom. These new collaborations significantly expand Bold Therapeutics' COVID-19 consortium. In April, the company announced a collaboration with Marc-Andr Langlois, Faculty Professor of Medicine at the University of Ottawa and Canada Research Chair in Molecular Virology and Intrinsic Immunity.

BOLD-100 is a first-in-class anti-resistance ruthenium-based small molecule drug which selectively inhibits stress-induced upregulation of GRP78 an important resistance, survival and proliferation pathway common across cancers. In addition, there is extensive and rapidly growing literature suggesting that GRP78 plays a critical role in host recognition, viral entry and viral replication.

"Our research team, supported by some of the brightest scientific minds in the space, continue to generate data elucidating the potentially broad antiviral utility of BOLD-100," added E. Russell McAllister, CEO of Bold Therapeutics. "In the past couple of months, we have engaged with numerous potential COVID-19 development and commercialization partners and generated significant positive feedback on our innovative antiviral program. BOLD-100 appears to have potentially broad application not only against SARS-CoV-2, but against other single-strand RNA viruses such as Dengue, West Nile, and Zika and, potentially other yet-to-be-discovered pathogens."

In collaboration with Franois Jean, PhD, Associate Professor in the Department of Microbiology and Immunology and founder of the UBC Facility for Infectious Disease and Epidemic Research (FINDER), one of the largest university-based containment level-3 (CL3) facilities in the world, Bold Therapeutics has initiated a Mitacs Accelerate project entitled: "Antiviral properties and mechanism of actions of BOLD-100 against SARS-CoV-2 in 2D and 3D cell culture systems."

Bold Therapeutics has also initiated a parallel Mitacs Accelerate project with Theodore Steiner, MD, Professor and Division Head, Division of Infectious Diseases at UBC entitled: "Cellular inflammatory and antiviral effects of BOLD-100, a novel therapeutic agent in development for COVID-19."

Bold Therapeutics also established a collaboration with Stephen Barr, PhD, Associate Professor in the Department of Microbiology and Immunology at Western University. Dr. Barr is testing BOLD-100 against SARS-CoV-2 isolates using in vitro assays, with initial data expected later this month.

Extending its consortium of COVID-19 researchers outside of North America, Bold Therapeutics is also collaborating with Len Seymour, PhD, Director of Clinical Pharmacology at the University of Oxford, who will be testing BOLD-100 against different isolates of SARS-CoV-2 using in vitro assays.

"We are focused on a data-driven COVID-19 development strategy, and this impressive international network of collaborators allows us to generate the data necessary to support our further clinical development of BOLD-100 as an antiviral," stated Jim Pankovich, Executive Vice President, Clinical Development. "We expect initial data from these partnerships in the next month, and, in parallel, we are working to secure funding so that BOLD-100 can progress rapidly into human clinical trials."

For more information, please visit the COVID-19 section on Company's website at http://www.bold-therapeutics.com/covid-19.

Media contact: E. Russell McAllister 241540@email4pr.com(604) 262-9899

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Immunology

Researchers are developing statistical tools to analyze the spread and evolution of coronavirus – News-Medical.Net

For as much as the scientific community has learned about the novel coronavirus, SARS-CoV-2, since it emerged in China last year, many key aspects of the pandemic remain a mystery.

And for that reason, COVID-19 has been an especially tricky disease to contain.

For example, how did the virus travel from country to country, or region to region? Do weather patterns affect its ability to spread? What demographic or socioeconomic factors put certain populations at higher risk?

The problem is that existing tools for analyzing infectious diseases cant see how all of these factors are interconnected, says Kristian Andersen, PhD, professor in the Department of Immunology and Microbiology at Scripps Research.

Even the most advanced tools either arent capable of dealing with the amount of data we have today or arent appropriate for the types of questions were trying to answer.

Thats why Andersen and his collaborators Lauren Gardner, PhD, of Johns Hopkins University and Marc Suchard, MD, PhD, of University of California, Los Angelesare now working to develop better statistical models and visualization software.

The project has won a $1.3 million grant from the National Institutes of Health, with operations based out of the Scripps Research-led Center for Viral Systems Biology.

The funding supplements an initial $15 million NIH grant that enabled Andersen to launch the center in 2018, with the goal of helping eradicate infectious diseases such as Ebola and Lassa.

The team has already started its effort to build tools that can show how SARS-CoV-2 is moving around the world and what factors may be driving its spread and evolution. The idea is to be able to analyze everything at the same time, Andersen says.

Everything encompasses diverse factors such as airline traffic patterns, socioeconomic and demographic data, and weather conditions. It also includes genomic data from virus genomes sequenced from COVID-19 patients. "

"Every day, hundreds of new genomes are shared openly on research databases; Andersen and others use that data to look for mutations, or slight changes in the genetic sequence, that show how the virus moved from person to person. "

Once the new tools are developed, the genomic data and the other information will build on the Johns Hopkins COVID-19 Dashboard data and Scripps Researchs Outbreak.info website, both of which are available to the public. The Johns Hopkins dashboard, developed by Lauren Gardner, has become the worlds most accessed resource for real-time COVID-19 information.

For this project, Gardner draws from her expertise in epidemiological risk and mathematical modeling to integrate new layers of information, such as climate, land use and mobility.

Our goal is to weave together rich data layers that we will continuously analyze, creating real-time updates on the rapidly evolving pandemic. From a public health perspective, its essential to see how the virus is really spreading and how mitigation efforts are working.

Lauren Gardner, PhD., Associate Professor, Department of Civil and Systems Engineering, Johns Hopkins Univresity

Another key collaborator is statistician Marc Suchard, a professor in UCLAs Departments of Biomathematics and Human Genetics. He is the senior developer of an open-source software program thats used by more than 1,000 research groups worldwide to understand, on a genomic level, how infectious diseases spread.

Through the creation of new, scalable statistical models, well be able to more clearly identify the factors that affect viral transmission and virulence for SARS-CoV-2, Suchard says.

Not only will this allow us to understand whether certain public health measures are working, but it also will help predict how the disease could spread under different circumstances.

At its highest level, the project seeks to make complex information easier to understand, revealing patterns that would otherwise go unnoticed.

By fostering a greater understanding of the virus among researchers and the public, the team hopes that governments around the world can improve their response to the COVID-19 pandemic and minimize future outbreaks.

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Immunology

Quell Therapeutics strengthens its Board with the appointments of Dr Dhaval Patel and Sir Robert Lechler and hires Dr Natalie Belmonte as SVP Research…

London June 11th 2020 Quell Therapeutics, a biotechnology company developing engineered T regulatory (Treg) cell therapies, today announced the appointments of seasoned industry expert, Dr Dhaval Patel, Executive Vice President and Chief Scientific Officer UCB S.A. (Brussels, Belgium), and Senior Clinical Academic, Professor Sir Robert Lechler, Senior Vice President/Provost (Health) and Executive Director of King's Health Partners Academic Health Sciences Centre, to its Board of Directors.

Additionally, the Company announced today, the appointment of Dr Natalie Belmonte as SVP Research & Translation. Dr Belmonte has extensive R&D experience in the fields of Treg cell and Mesenchymal Stem Cell based therapies.

Both Dhaval and Robert are highly experienced leaders who bring a wealth of drug development and translational immunology expertise to Quell Therapeutics, said Iain McGill, Chief Executive Officer of Quell Therapeutics. We have made great progress as we work towards building out a pipeline of cell therapies leveraging our engineered Treg platform. We have already selected our first product candidate targeting tolerance in liver transplantation and Natalie, in her role as SVP Research & Translation, will play a pivotal role in helping us broaden our pipeline in auto-immune and inflammatory disorders.

I speak for both myself and Robert when I say how pleased we are to be joining the Board of Quell Therapeutics, said Dhaval Patel. The Company is at an exciting stage in its evolution as it develops CAR-Treg products in autoimmune and inflammatory diseases, which could offer patients transformative therapies to resolve chronic diseases.

Dr Dhaval Patel is Executive Vice President and Chief Scientific Officer of UCB where he is a member of the UCB Executive Committee and leads the Companys research organisation with the main goal of bringing scientific innovation to patients. He joined UCB from Novartis, where, over a period of 11 years he led various biomedical research teams in areas of neurology, autoimmunity, transplantation, and inflammation. In 2010, he became the Head of Research for the Novartis Institutes for BioMedical Research (NIBR) Europe. For 12 years prior to crossing into industry, Dhaval made a strong mark in the halls of academia and research, specifically at Duke University Medical Center and the University of North Carolina (UNC) at Chapel Hill in North Carolina in the US. Dhaval is a medical doctor and holds a PhD in Microbiology and Immunology.

Professor Sir Robert Lechler is currently Provost and Senior Vice-President (Health) at Kings College London, Executive Director of Kings Health Partners and President of the Academy of Medical Sciences. His clinical and research career have been focused on the pursuit of clinical transplantation tolerance. Prior to his roles at Kings College London, Robert was Head of the Division of Medicine, Imperial College London, Dean of the Hammersmith Campus of Imperial College, and Professor and Director of Immunology. In 2012 Robert was awarded a Knighthood for Services to Academic Medicine and in 2015 was elected as the President of the UK Academy of Medical Sciences. Robert graduated in Medicine at Manchester University and was awarded his PhD by the University of London. He continues to direct a research group in transplantation immunology, with a primary focus on transplantation and immune tolerance.

Dr Natalie Belmonte has over 15 years of experience working in the field of cell therapy in both academic and biotech environment and has extensive experience with the development of Treg cell and Mesenchymal Stem Cell based therapies. Before joining Quell Therapeutics, Nathalie served as Chief Operating Officer at Promethera Biosciences. Prior to that, she served as VP R&D at TxCell developing Treg cell-based therapy for autoimmune and inflammatory diseases. She also has experience working with stem cells in a number of academic institutes including the San Raffaele Hospital at the Telethon Institute for Gene Therapy (TIGET) in Milan. She holds a PhD in Cellular and Molecular Biology from the University of Nice Sophia Antipolis.

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Quell Therapeutics strengthens its Board with the appointments of Dr Dhaval Patel and Sir Robert Lechler and hires Dr Natalie Belmonte as SVP Research...

Immunology

What will it take to produce a COVID-19 vaccine? – University of California

Immunology and infectious disease expert Joel Ernst, M.D., addresses key questions about how vaccine development works and why vaccines are especially important in the case of COVID-19.

First, this disease is highly transmissible. Its transmitted by the respiratory route, so people spread it easily in crowded places. Obviously, its incapacitating and deadly. Finally, effective vaccines are the most economical means to control a transmissible infectious disease.

Another reason that vaccines have a particularly special role is that this disease can be transmitted by asymptomatic and presymptomatic individuals. In other words, somebody doesnt have to have a fever or be coughing in order to infect the people around them.

Without a vaccine and without broad immunity in a population, COVID-19 could very well become an endemic infection. That means it remains steady in the population, like chicken pox, and unlike other pathogens that cause outbreaks and then recede, such as Ebola or Zika.

Finally, as were experiencing, the economic and human impacts of COVID-19 are huge.

Thats pretty unlikely. There would be a lot of lives lost before we achieved a percentage of immune people in the population sufficient to prevent community transmission. In so-called herd immunity, if a high proportion (70 percent to 95 percent) of the population is immune, then a person with the disease is unlikely to cause an outbreak. To achieve that level of immunity to COVID-19 in a community through natural infection, it would mean that nearly everyone in the community would need to be infected, and with a 1 percent mortality rate for COVID-19, thats unacceptable.

Part of what we know or what we think we know is derived from the experience with SARS, which is the most closely related coronavirus to SARS-CoV-2, the virus that causes COVID-19.

It would probably be safe to extrapolate a few things from SARS.

The first is that the protective immunity that results from infection may be transient. In people who were infected with the first SARS coronavirus, their protective immunity began waning between one and two years postinfection, as indicated by repeated checking of their antibody levels. Unlike diseases like measles or smallpox, where infection confers lifelong protective immunity, coronavirus infections may not confer long-lasting immunity.

The second thing we think we know is that neutralizing antibodies are likely to contribute to protection.

When we get an infection, our immune systems respond to fight off that is, neutralize that specific invading virus or bacteria. These responses generally protect us against future infections from the same pathogen, unless the pathogen mutates to avoid recognition by those immune responses.

One of the immune responses that can provide protection is the production of antibodies, proteins that recognize an infectious pathogen, with the goal of eliminating the infection. Antibodies are generally easy to measure, but the presence of antibodies does not guarantee protection. That is because the routine tests we have dont measure the quantity or quality of antibodies.

By quality, I mean that some antibodies bind to the pathogen, but they dont contribute to protection. They can be there, they can be detected, but they dont possess the activities needed to eliminate the pathogen. For example, people infected with HIV generate antibodies to HIV proteins, but the HIV infection still persists.

At the extreme end, some antibodies can actually be harmful. For example, in the case of another viral disease, dengue, which is transmitted by mosquitoes, people can have antibodies that make the infection more severe and the symptoms more critical.

What all this means is: The right antibodies are needed. Thats the goal of vaccination to confer immunity that is superior to what is conferred by infection itself.

Multiple approaches to developing a COVID-19 vaccine are underway. Some are based on inactivating the virus, essentially making it noninfectious while preserving its ability to provoke an immune response; other approaches modify the virus so it can grow but not cause severe disease. Another alternative is to use a purified pathogen protein to stimulate the immune system to provoke immune responses that block the disease an approach thats been successful with tetanus, diphtheria, and hepatitis B vaccines.

Finally, some approaches use more advanced techniques. They work at the genetic level, embedding instructions in DNA or RNA, or they use benign viruses, called viral vectors, to deliver an antigen the pathogen protein that induces a protective immune response directly to cells in our immune system.

The goals of vaccine development are first of all, safety, and second, to induce the kind of immune response that is necessary to prevent infection and disease due to the specific pathogen; distinct pathogens can require different mechanisms to provide protective immunity.

And especially in a pandemic, rapid, large-scale production is absolutely essential. We need billions of doses of any COVID-19 vaccine. For the same reason, we need them to be economical on a global scale.

Another goal, especially in the case of COVID-19, is a vaccine that blocks the infection where the virus enters the body. Since we know that SARS-CoV-2 ordinarily enters through the respiratory tract, via the mouth or nose, we want immunity that operates right there at the portal of entry and not just in the bloodstream.

Vaccines need to generate long-lived immunological memory. Ideally, vaccines will induce immune responses that recognize viral targets that cant mutate to escape, like the flu virus does, which forces us to modify the flu vaccine every year.

Finally, vaccines need to be stable enough for distribution to clinics worldwide. In other words, a vaccine that requires refrigeration is not going to reach everyone.

There are at least 90 groups worldwide working to develop COVID-19 vaccines. Roughly 20 of them are working on DNA- or RNA-based vaccines, about 25 groups are working on viral-vector vaccines, and numerous groups are working on protein-based vaccines. A smaller number of groups are working on viruslike protein particles, which are a bit more difficult and expensive to produce. Here at UCSF, there are many experts in immunology and virology working to assure that new COVID-19 vaccines have the properties that are most important.

To have a global impact, a vaccine needs to work in large, diverse populations. And those steps can only be combined or rushed to a limited extent.Joel Ernst, M.D.

The next stage is human studies. They address the question, Is the new vaccine safe? Can you give it to people without causing undue toxicity? The next question is, Does the vaccine stimulate immune responses in humans? Next, Does the vaccine protect humans from disease in a so-called efficacy trial? Finally, Does the vaccine protect humans in the real world? That is called vaccine effectiveness. The difference between efficacy and effectiveness is that in efficacy studies, the conditions and subjects are chosen to be ideal for the study. Effectiveness means that the vaccine protects people who arent preselected, who might have medical conditions that could make it more challenging for a vaccine to work. To have a global impact, a vaccine needs to work in large, diverse populations. And those steps can only be combined or rushed to a limited extent.

A recent clinical trial led by the pharmaceutical company Moderna showed promising but very preliminary results. Can you interpret their findings?

This was a safety trial of an RNA vaccine. It was designed to test how well 45 healthy volunteers tolerated different doses of the vaccine. But supplemental data showed that the volunteers produced antibodies similar to those in people who have recovered from the virus, suggesting the vaccine achieved the sought-after immune response. While finding antibodies is good news, it does not tell us if the vaccine is effective.

An expanded safety trial. In 45 subjects, youre only going to see the most common side effects things like pain at the injection site, a fever. To capture rare side effects, its necessary to expand the number of study participants. It would also be expanded into different groups, including older people. The upper age cutoff of these volunteers was 55 years. We know that older people are more susceptible to bad outcomes from COVID-19, so its important to determine whether the same vaccine at the same dose also produces an immune response in them.

Through efficacy studies, which follow safety studies. Efficacy studies can be done in one of two main ways. They can be done in very large populations at risk you vaccinate some and dont vaccinate others and compare the rates of infection in the two groups. Those are expensive, they take a long time, and they can be complicated by fluctuations in the frequency of the disease in question. For example, if a flu vaccine trial was started after the peak of flu season, the rate of infection in both groups might be too low to find a difference in infection rates.

The other alternative is a human challenge study. In that case, people are vaccinated or not and then actually challenged with the pathogen of interest. Challenge studies are generally done with pathogens for which theres curative therapy malaria, for example. You watch for evidence that a person develops a fever and treat them immediately with that therapy. We dont have that advantage in the case of the new coronavirus, since we dont currently have a highly effective treatment.

I think were roughly 12 to 18 months from being able to roll out a vaccine thats accessible to a significant slice of the population.

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What will it take to produce a COVID-19 vaccine? - University of California

Immunology

CSL Behring Buys Vitaeris, Picks Up Transplant Rejection Therapeutic – BioSpace

CSL Behring, based in King of Prussia, Pennsylvania, is acquiring Vancouver, British Columbia-based Vitaeris. The two companies inked a strategic partnership in 2017 to accelerate the development of Vitaeriss clazakizumab. At that time, CLS Behring also had an option to acquire Vitaeris, the therapeutic, and the rest of Vitaeriss assets.

No financial details were disclosed. In the 2017 deal, Vitaeris retained control of projects through the end of Phase III development. There was an upfront cash payment of $15 million, with research-and-development milestone payments over that period, which included future sales-related payments, as well as a royalty to Alder BioPharmaceuticals, who originated clazakizumab.

Clazakizumab is an anti-interleukin-6 (IL-6) monoclonal antibody for the treatment of chronic active antibody-mediated rejection (AMR), which is the top cause of long-term rejection in kidney transplant patients. There are currently no treatments approved for transplant recipients who develop antibody-mediated rejection.

Clazakizumab will join CLS842 and CSL964 as part of CSL Behrings late-stage program related to transplants.

Clazakizumab has been a promising monoclonal antibody in the Transplant therapeutic area since we started working with Vitaeris several years ago, said Bill Mezzanotte, executive vice president, Head of R&D, CSL Behring. Acquiring Vitaeris and their associate expertise helps us to continue to grow our strategic scientific platform of recombinant proteins and antibodies. We look forward to continuing to advance this treatment candidate as a potential option for people experiencing rejectionan area where current treatment options for transplant recipients are limited, at best.

Also today, CSL Behring announced results from a Phase II clinical trial of garadacimab (formerly CSL312), an investigational novel Factor XIIa-inhibitory monoclonal antibody to prevent hereditary angioedema (HAE). The company presented results at the European Academy of Allergy and Immunology (EAACI) Digital Congress 2020.

The trial met the primary endpoint, showing a decreased number of attacks compared to placebo in patients with HAE. HAE is a rare, genetic and potentially life-threatening disease. HAE is one of two types of bradykinin-mediated angioedema, with the other being nonhereditary or acquired angioedema. HAE is the result of deficient or dysfunctional C1-INH, a blood protein that helps control inflammation.

Last month, the U.S. Food and Drug Administration (FDA) granted garadacimab orphan drug designation for bradykinin-mediated angioedema.

The attacks that HAE patients experience can be very frightening, and clinicians want to do anything in their power to reduce the frequency of these attacks, lessen the need for rescue medicine and simplify treatment, said Timothy Craig, lead study investigator with Allergy, Asthma and Immunology, Department of Medicine and Pediatrics, Penn State Hershey, Hershey, Pennsylvania. The findings of this study are very encouraging and we look forward to further research assessing the safety and efficacy of garadacimab.

CSL Behring has been quite busy recently. On June 2 the company announced a strategic alliance with Seattle Childrens Research Institute to develop stem cell gene therapies for primary immunodeficiency diseases. The initial focus will be on Wiskott-Aldrich Syndrome and X-linked Agammaglobulinemia.

The company is also working on several fronts to develop treatments and preventions for COVID-19. The company is part of the CoVIg-19 Plasma Alliance, which is working to develop an unbranded anti-SARS-CoV-2 polyclonal hyperimmune immunoglobulin therapy. The Alliance is also working with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) to test the hyperimmune therapy in adult patients with COVID-19. CSL Behring Australia is developing an anti-SARS-COV-2 plasma product for the Australian market. CSL Behring is also partnered with the Coalition for Epidemic Preparedness Innovations (CEPI) and The University of Queensland (UQ) to speed the development, manufacture and distribution of a COVID-19 vaccine, as well as other initiatives in this space.

And on May 27, 2020, CSL Limited entered into a strategic partnership with Thermo Fisher Scientific to meet the growing demand for biologic therapies while also accelerating CSLs broader manufacturing objectives. Thermo Fisher will leverage its pharma services network to support CSLs product portfolio, and via a long-term lease deal, will operate a new state-of-the-art biologics manufacturing facility in Lengnau, Switzerland, which is being built now and is expected to be completed in mid-2021.

Of the acquisition by CSL Behring, Kevin Chow, president and chief executive officer of Vitaeris, stated, Were pleased to become part of CSL Behring, a well-established, global industry leader, and know that the future of clazakizumab is in excellent hands. Together, we have already achieved much progress through our partnership over the past few years and are now in an even stronger position to realize our collective goal of addressing one of the greatest unmet needs in the organ transplant community.

Originally posted here:
CSL Behring Buys Vitaeris, Picks Up Transplant Rejection Therapeutic - BioSpace

Immunology

European Academy of Allergy and Clinical Immunology: Launch of the EAACI Guidelines for the Use of Biologicals in Patients With Severe Asthma -…

ZRICH, June 8, 2020 /PRNewswire/ -- EAACI has launched its Guidelines for the use of Biologicals in Patients with Severe Asthma at the EAACI Digital Congress 2020.

Prof. Marek Jutel, EAACI President began by highlighting the significant burden of severe asthma on patients, families and healthcare systems. "Management of severe asthma proves to be difficult due to disease heterogeneity, coexisting comorbidities and especially because of complexities in care pathways and differences in national and regional healthcare systems. Better understanding of the mechanisms of the disease has enabled a stratified approach to the management of severe asthma, supporting the use of targeted treatments with biologicals. However, many unmet needs remain: how to select a certain biological as they all target overlapping disease phenotypes? How to enhance response? What are the best strategies to enhance the respondent's rate? What is the optimal duration of treatment and its cost-effectiveness? And what is the appropriate regimen - in the clinic or home-based?"

What is novel in the EAACI guidelines for the management of severe asthma is the inclusion of the GRADE approach in formulating recommendations for each biological and asthma outcome, separate recommendations for exacerbations, for lung function and more.

"It is clear that biologicals in the context of severe asthma is a very rapidly evolving field. After the first EAACI position paper on Biologicals and allergic diseases, these EAACI Guidelines for the use of Biologicals in Patients with Severe Asthma represent a desk reference tool of utmost importance for healthcare providers, patients, regulators and healthcare systems providing specific recommendations for each biological in the context of each independent outcome," says Prof. Oscar Palomares, Complutense University of Madrid, Past Chair of EAACI Biologicals Working Group, current EAACI ExCom member and Biologicals Guidelines Project Co-Chair.

A management algorithm for the use of biologicals in the clinic is further proposed, together with future approaches and research priorities. "EAACI advocates for a triple decision chart based on phenotypic traits, biomarkers and outcomes, added to this is shared decision making to reset individual goals and define response together with the patient. Efficacy is tested after 4-6 months - if there is a response, intervention is to be continued according to the preset target and while continuously monitoring for safety. Real life evidence must be collected through registries, real world trials and health economics indicators as the basis for the next steps. If the response is suboptimal it is important to look at the airway inflammation and to the airway hyperreactvity. If the eosinophilic inflammation persists, several factors can be improved, for example adherence to background controller treatment or other options can be considers such as switching to a biological targeting a different path, or checking for other immune mechanisms. If neutrophilic inflammation is present macrolides can be considered. If there is no inflammation non-T2 asthma approaches like dual bronchodilators and in very selective cases bronchial thermoplasty can be considered," says Prof. Dr. Ioana Agache, University of Brasov Romania, Biologicals Guidelines Project Co-Chair and EAACI Past President.

The rising use of biologicals (monoclonal antibodies) in modern medicine, their remarkable potential and possible challenges were also discussed at the EAACI Digital Congress 2020 by its Special Guest, Sir Gregory Paul Winter, Nobel Prize Winner for Biochemistry in 2018.

"For inflammatory disease monoclonal antibodies are finding their place on the front line. Although inflammatory diseases such as severe asthma can be treated with chemical drugs such as corticosteroids their broad mechanism of action may also bring a range of undesirable side effects including fluid retention, hypertension and bone loss, particularly with extended use. Ideally treatments should have a more specific mode of action and avoid these side effects. That is why monoclonal antibodies which have such specific modes of action in blocking the interaction of key proteins or receptors are so attractive. And the availability of a range of therapeutic monoclonal antibodies against proteins involved in inflammation provides the opportunity to identify in the clinic those targets which are most relevant. Over the last 30 years biologicals have become increasingly important in medicine. The limitations in early use of biologicals were overcome by the recombinant DNA technology leading to a tsunami of therapeutic monoclonal antibodies. These biologicals are of high efficiency and exquisite specificity, they have a long half-life in serum and properties and functions can be tailored to order. Their impact has already been immense and likely to become greater still," says Sir Gregory Winter, University of Cambridge, Nobel Prize Laureate 2018.

Under these promising auspices, EAACI hopes its new Guidelines will be a cornerstone for clinicians, researchers, scientific societies and medical agencies in the years to come.

About EAACI:

The European Academy of Allergy and Clinical Immunology (EAACI) is an association of clinicians, researchers and allied health professionals founded in 1956. EAACI is dedicated to improving the health of people affected by allergic diseases. With more 12 000 members from 124 countries and over 75 National Allergy Societies, EAACI is the primary source of expertise in Europe and worldwide for all aspects of allergy.

Logo - https://mma.prnewswire.com/media/1177661/EAACI_Digital_Congress_2020_Logo.jpg

Contact: EAACI Headquarters Hagenholzstrasse 111, 3rd Floor 8050 Zurich CH- Switzerland Tel: +41799561865 communications@eaaci.org http://www.eaaci.org

Link:
European Academy of Allergy and Clinical Immunology: Launch of the EAACI Guidelines for the Use of Biologicals in Patients With Severe Asthma -...

Immunology

Immune modulation can cure severe and often fatal fungal infection in children – News-Medical.Net

In the June 11 issue of the New England Journal of Medicine, a team of UCLA physicians and scientists describes the first case of immune modulation being used to cure a severe and often fatal fungal infection. The team "retuned" a 4-year-old's immune system so that it could fight off disseminated coccidioidomycosis.

The case, originally reported by UCLA in 2019, could pave the way for a new treatment for the infection, which affects hundreds of Americans each year, primarily in the Southwest, and kills approximately 40% of the people who contract it.

The technique described in the study could also suggest a new paradigm for treating other severe fungal infections, bacterial infections such as tuberculosis, and severe viral infections such as influenza and COVID-19.

"Immune modulation isn't currently part of the strategy with any of these severe infections," said Dr. Manish Butte, the report's senior author, who holds the E. Richard Stiehm Endowed Chair in Pediatric Allergy, Immunology and Rheumatology at the David Geffen School of Medicine at UCLA.

"Our case suggests that rather than hoping to get the upper hand with more and more antibiotics or antifungals, we can have some success by combining these established approaches with the new idea of programming the patient's immune response to better fight the infection."

Each year, more than 100,000 people are infected with Coccidioides fungi, which reside in the soils of California, Arizona and West Texas. Most people who are infected are asymptomatic, and about 20,000 experience the minor respiratory illness commonly known as Valley fever.

The vast majority of people with Valley fever respond well to antifungal medications, but approximately 1% of the infections progress to disseminated coccidioidomycosis, in which the infection spreads rapidly throughout the body, leading to bone and tissue damage, and in many cases death.

Historically, severe infections have been seen as bad luck. Doctors haven't looked at how we can harness the immune systems of these patients to fight the infection."

Dr Manish Butte, Study Senior Author, University of California Los Angeles (UCLA) Health Sciences

According to a 2019 study in the International Journal of Environmental Research and Public Health, California spends between $700 million and $900 million a year in direct and indirect costs related to the care of people infected by the cocci fungus, including more than $300 million to care for the approximately 200 people with disseminated coccidioidomycosis.

The boy who was treated by Butte and his team had previously been treated with high doses of multiple antifungal medicines, but by the time he arrived at UCLA, he could barely walk or talk and required a feeding tube to eat.

When UCLA physicians homed in on the patient's immune system, they concluded that his T cells -; the white blood cells that play a key role in the body's immune response -; were failing to properly recognize the invading fungus. The T cells were responding as though the infection was a parasitic infection rather than a fungal one.

That prompted the team to supplement the boy's antifungal medications with an immune stimulator called interferon-gamma. And Dr. Maria Garcia-Lloret, a pediatric allergist and immunologist, suggested adding yet another medication, dupilumab, which was developed as a medication for allergic diseases and had never before been used to treat infections.

Dupilumab is a prescription drug that has not been approved by the FDA as a treatment for disseminated coccidioidomycosis.

The combination of immune modulators restored the proper programming to the patient's T cells -; and the boy's infection went away in a month.

The UCLA research team cites that the immunomodulatory approach has the potential to enhance the ability of patients to clear other types of fungal, bacterial, and viral infections that are not responding to established therapies.

In partnership with the Bakersfield, California-based Valley Fever Institute and the drugs' manufacturers -; Horizon Therapeutics, Regeneron Pharmaceuticals and Sanofi Genzyme -; the UCLA researchers are planning to test the two drugs on other people with disseminated coccidioidomycosis. They also plan to study the approach for treating other types of severe infections.

Source:

Journal reference:

Tsai, M., et al. (2020) Disseminated Coccidioidomycosis Treated with Interferon- and Dupilumab. The New England Journal of Medicine. doi.org/10.1056/NEJMoa2000024.

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Immune modulation can cure severe and often fatal fungal infection in children - News-Medical.Net