Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.
Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.
We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”
Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study
However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.
“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.
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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.
McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.
Findings from the study include:
Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.
This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.
Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).
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Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine.doi.org/10.1126/scitranslmed.adf3309.
Researchers at NYU Grossman School of Medicine and Janssen Biotech, Inc. have shown in early tests that a bioengineered drug candidate can counter infection with Staphylococcus aureus – a bacterial species widely resistant to antibiotics and a major cause of death in hospitalized patients.
Experiments demonstrated that SM1B74, an antibacterial biologic agent, was superior to a standard antibiotic drug at treating mice infected with S. aureus, including its treatment-resistant form known as MRSA.
Published online April 24 in Cell Host & Microbe,the new paper describes the early testing of mAbtyrins, a combination molecule based on an engineered version of a human monoclonal antibody (mAb), a protein that clings to and marks S. aureus for uptake and destruction by immune cells. Attached to the mAb are centyrins, small proteins that prevent these bacteria from boring holes into the human immune cells in which they hide. As the invaders multiply, these cells die and burst, eliminating their threat to the bacteria.
Together, the experimental treatment targets ten disease-causing mechanisms employed by S. aureus, but without killing it, say the study authors. This approach promises to address antibiotic resistance, say the researchers, where antibiotics kill vulnerable strains first, only to make more space for others that happen to be less vulnerable until the drugs no longer work.
To our knowledge, this is the first report showing that mAbtyrins can drastically reduce the populations of this pathogen in cell studies, and in live mice infected with drug-resistant strains so common in hospitals. Our goal was to design a biologic that works against S. aureus inside and outside of cells, while also taking away the weapons it uses to evade the immune system.”
Victor Torres, PhD, Lead Study Author, the C.V. Starr Professor of Microbiology and director of the NYU Langone Health Antimicrobial-Resistant Pathogen Program
One-third of the human population are carriers of S. aureus without symptoms, but those with weakened immune systems may develop life-threatening lung, heart, bone, or bloodstream infections, especially among hospitalized patients.
Inside out
The new study is the culmination of a five-year research partnership between scientists at NYU Grossman School of Medicine and Janssen to address the unique nature of S. aureus.
The NYU Langone team together with Janssen researchers, published in 2019 a study that found that centyrins interfere with the action of potent toxins used by S. aureus to bore into immune cells. They used a molecular biology technique to make changes in a single parental centyrin, instantly creating a trillion slightly different versions of it via automation. Out of this “library,” careful screening revealed a small set of centyrins that cling more tightly to the toxins blocking their function.
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Building on this work, the team fused the centyrins to a mAb originally taken from a patient recovering from S. aureus infection. Already primed by its encounter with the bacteria, the mAb could label the bacterial cells such that they are pulled into bacteria-destroying pockets inside of roving immune cells called phagocytes. That is unless the same toxins that enable S. aureus to drill into immune cells from the outside let it drill out of the pockets to invade from the inside.
In a “marvel of bioengineering,” part of the team’s mAbtyrin serves as the passport recognized by immune cells, which then engulf the entire, attached mAbtyrin, along with its centyrins, and fold it into the pockets along with bacteria. Once inside, the centyrins block the bacterial toxins there. This, say the authors, sets their effort apart from antibody combinations that target the toxins only outside of cells.
The team made several additional changes to their mAbtyrin that defeat S. aureus by, for instance, activating chain reactions that amplify the immune response, as well by preventing certain bacterial enzymes from cutting up antibodies and others from gumming up their action.
In terms of experiments, the researchers tracked the growth of S. aureus strains commonly occurring in US communities in the presence of primary human immune cells (phagocytes). Bacterial populations grew almost normally in the presence of the parental antibody, slightly less well in the presence of the team’s engineered mAb, and half as fast when the mAbtyrin was used.
In another test, 98% of mice treated with a control mAb (no centyrins) developed bacteria-filled sores on their kidneys when infected with a deadly strain of S. aureus, while only 38% of mice did so when treated with the mAbtyrin. Further, when these tissues were removed and colonies of bacteria in them counted, the mice treated with the mAbtyrin had one hundred times (two logs) fewer bacterial cells than those treated with a control mAb.
Finally, the combination of small doses of the antibiotic vancomycin with the mAbtyrin in mice significantly improved the efficacy of the mAbtyrin, resulting in maximum reduction of bacterial loads in the kidneys and greater than 70% protection from kidney lesions.
“It is incredibly important,” said Torres, “that we find new ways to boost the action of vancomycin, a last line of defense against MRSA.”
Along with Torres, authors from the Department of Microbiology at NYU Langone were Rita Chan, Ashley DuMont, Keenan Lacey, Aidan O’Malley, and Anna O’keeffe. The study authors included 13 scientists from Janssen Research & Development (for details see the study manuscript).
This work was supported by Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, under the auspices of an exclusive license and research collaboration agreement with NYU. Torres has recently received royalties and consulting compensation from Janssen and related entities. These interests are being managed in accordance with NYU Langone policies and procedures.
Buckley, P. T., et al. (2023). Multivalent human antibody-centyrin fusion protein to prevent and treat Staphylococcus aureus infections. Cell Host & Microbe. doi.org/10.1016/j.chom.2023.04.004.
Memory B cells play a critical role to provide long-term immunity after a vaccination or infection. In a study published in the journal Immunity, researchers describe a distinct and novel subset of memory B cells that predict long-lived antibody responses to influenza vaccination in humans.
These effector memory B cells appear to be poised for a rapid serum antibody response upon secondary challenge one year later, Anoma Nellore, M.D., Fran Lund, Ph.D., and colleagues at the University of Alabama at Birmingham and Emory University report. Evidence from transcriptional and epigenetic profiling shows that the cells in this subset differ from all previously described memory B cell subsets.
The UAB researchers identified the novel subset by the presence of FcRL5 receptor protein on the cell surface. In immunology, a profusion of different cell-surface markers is used to identify and separate immune-cell types. In the novel memory B cell subset, FcRL5 acts as a surrogate marker for positive expression of the T-bet transcription factor inside the cells. Various transcription factors act as master regulators to orchestrate the expression of many different gene sets as various cell types grow and differentiate.
Nellore, Lund and colleagues found that the FcRL5+ T-bet+ memory B cells can be detected seven days after immunization, and the presence of these cells correlates with vaccine antibody responses months later. Thus, these cells may represent an early, easily monitored cellular compartment that can predict the development of a long-lived antibody response to vaccines.
This could be a boon to the development of a more effective yearly influenza vaccine. “New annual influenza vaccines must be tested, and then manufactured, months in advance of the winter flu season,” Lund said. “This means we must make an educated guess as to which flu strain will be circulating the next winter.”
Why are vaccine candidates made so far in advance? Pharmaceutical companies, Lund says, need to wait many weeks after vaccinating volunteers to learn whether the new vaccine elicits a durable immune response that will last for months. “One potential outcome of the current study is we may have identified a new way to predict influenza vaccine durability that would give us an answer in days, rather than weeks or months,” Lund said. “If so, this type of early ‘biomarker’ could be used to test flu vaccines closer to flu season -; and moving that timeline might give us a better shot at predicting the right flu strain for the new annual vaccine.”
Seasonal flu kills 290,000 to 650,000 people each year, according to World Health Organization estimates. The global flu vaccine market was more than $5 billion in 2020.
To understand the Immunity study, it is useful to remember what happens when a vaccinated person subsequently encounters a flu virus.
Following exposure to previously encountered antigens, such as the hemagglutinin on inactivated influenza in flu vaccines, the immune system launches a recall response dominated by pre-existing memory B cells that can either produce new daughter cells or cells that can rapidly proliferate and differentiate into short-lived plasmablasts that produce antibodies to decrease morbidity and mortality. These latter B cells are called “effector” memory B cells.
“The best vaccines induce the formation of long-lived plasma cells and memory B cells,” said Lund, the Charles H. McCauley Professor in the UAB Department of Microbiology and director of the Immunology Institute. “Plasma cells live in your bone marrow and make protective antibodies that can be found in your blood, while memory B cells live for many years in your lymph nodes and in tissues like your lungs.
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“Although plasma cells can survive for decades after vaccines like the measles vaccine, other plasma cells wane much more quickly after vaccination, as is seen with COVID-19,” Lund said. “If that happens, memory B cells become very important because these long-lived cells can rapidly respond to infection and can quickly begin making antibody.”
In the study, the UAB researchers looked at B cells isolated from blood of human volunteers who received flu vaccines over a span of three years, as well as B cells from tonsil tissue obtained after tonsillectomies.
They compared naïve B cells, FcRL5+ T-bet+ hemagglutinin-specific memory B cells, FcRL5neg T-betneg hemagglutinin-specific memory B cells and antibody secreting B cells, using standard phenotype profiling and single-cell RNA sequencing. They found that the FcRL5+ T-bet+ hemagglutinin-specific memory B cells were transcriptionally similar to effector-like memory cells, while the FcRL5neg T-betneg hemagglutinin-specific memory B cells exhibited stem-like central memory properties.
Antibody-secreting B cells need to produce a lot of energy to churn out antibody production, and they also must turn on processes that protect the cells from some of the detrimental side effects of that intense metabolism, including controlling the dangerous reactive oxygen species and boosting the unfolded protein response.
The FcRL5+ T-bet+ hemagglutinin-specific memory B cells did not express the plasma cell commitment factor, but did express transcriptional, epigenetic and metabolic functional programs that poised these cells for antibody production. These included upregulated genes for energy-intensive metabolic processes and cellular stress responses.
Accordingly, FcRL5+ T-bet+ hemagglutinin-specific memory B cells at Day 7 post-vaccination expressed intracellular immunoglobulin, a sign of early transition to antibody-secreting cells. Furthermore, human tonsil-derived FcRL5+ T-bet+ memory B differentiated more rapidly into antibody-secreting cells in vitro than did FcRL5neg T-betneg hemagglutinin-specific memory B cells.
Lund and Nellore, an associate professor in the UAB Department of Medicine Division of Infectious Diseases, are co-corresponding authors of the study, “A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans.”
Co-authors with Lund and Nellore are Esther Zumaquero, R. Glenn King, Betty Mousseau, Fen Zhou and Alexander F. Rosenberg, UAB Department of Microbiology; Christopher D. Scharer, Tian Mi, Jeremy M. Boss, Christopher M. Tipton and Ignacio Sanz, Emory University School of Medicine, Atlanta, Georgia; Christopher F. Fucile, UAB Informatics Institute; John E. Bradley and Troy D. Randall, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; and Stuti Mutneja and Paul A. Goepfert, UAB Department of Medicine Division of Infectious Diseases.
Funding for the work came from National Institutes of Health grants AI125180, AI109962 and AI142737 and from the UAB Center for Clinical and Translational Science.
Nellore, A., et al. (2023). A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans. Immunity. doi.org/10.1016/j.immuni.2023.03.001.
A new UCLA-led study suggests that advanced genome editing technology could be used as a one-time treatment for the rare and deadly genetic disease CD3 delta severe combined immunodeficiency.
The condition, also known as CD3 delta SCID, is caused by a mutation in the CD3D gene, which prevents the production of the CD3 delta protein that is needed for the normal development of T cells from blood stem cells.
Without T cells, babies born with CD3 delta SCID are unable to fight off infections and, if untreated, often die within the first two years of life. Currently, bone marrow transplant is the only available treatment, but the procedure carries significant risks.
In a study published in Cell, the researchers showed that a new genome editing technique called base editing can correct the mutation that causes CD3 delta SCID in blood stem cells and restore their ability to produce T cells.
The potential therapy is the result of a collaboration between the laboratories of Dr. Donald Kohn and Dr. Gay Crooks, both members of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and senior authors of the study.
Kohn’s lab has previously developed successful gene therapies for several immune system deficiencies, including other forms of SCID. He and his colleagues turned their attention to CD3 delta SCID at the request of Dr. Nicola Wright, a pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute in Canada, who reached out in search of a better treatment option for her patients.
CD3 delta SCID is prevalent in the Mennonite community that migrates between Canada and Mexico.
Because newborns are not screened for SCID in Mexico, I often see babies who have been diagnosed late and are returning to Canada quite sick.”
Dr. Nicola Wright, pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute
When Kohn presented Wright’s request to his lab, Grace McAuley, then a research associate who joined the lab at the end of her senior year at UCLA, stepped up with a daring idea.
“Grace proposed we try base editing, a very new technology my lab had never attempted before,” said Kohn, a distinguished professor of microbiology, immunology and molecular genetics, and of pediatrics.
Base editing is an ultraprecise form of genome editing that enables scientists to correct single-letter mutations in DNA. DNA is made up of four chemical bases that are referred to as A, T, C and G; those bases pair together to form the “rungs” in DNA’s double-helix ladder structure.
While other gene editing platforms, like CRISPR-Cas9, cut both strands of the chromosome to make changes to DNA, base editing chemically changes one DNA base letter into another -; an A to a G, for example -; leaving the chromosome intact.
“I had a very steep learning curve in the beginning, when base editing just wasn’t working,” said McAuley, who is now pursuing an M.D.-Ph.D. at UC San Diego and is the study’s co-first author. “But I kept pushing forward. My goal was help get this therapy to the clinic as fast as was safely possible.”
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McAuley reached out to the Broad Institute’s David Liu, the inventor of base editing, for advice on how to evaluate the technique’s safety for this particular use. Eventually, McAuley identified a base editor that was highly efficient at correcting the disease-causing genetic mutation.
Because the disease is extremely rare, obtaining patient stem cells for the UCLA study was a significant challenge. The project got a boost when Wright provided the researchers with blood stem cells donated by a CD3 delta SCID patient who was undergoing a bone marrow transplant.
The base editor corrected an average of almost 71% of the patient’s stem cells across three laboratory experiments.
Next, McAuley worked with Dr. Gloria Yiu, a UCLA clinical instructor in rheumatology, to test whether the corrected cells could give rise to T cells. Yiu used artificial thymic organoids, which are stem cell-derived tissue models developed by Crooks’ lab that mimic the environment of the human thymus -; the organ where blood stem cells become T cells.
When the corrected blood stem cells were introduced into the artificial thymic organoids, they produced fully functional and mature T cells.
“Because the artificial thymic organoid supports the development of mature T cells so efficiently, it was the ideal system to show that base editing of patients’ stem cells could fix the defect seen in this disease,” said Yiu, who is also a co-first author of the study.
As a final step, McAuley studied the longevity of the corrected stem cells by transplanting them into a mouse. The corrected cells remained four months after transplant, indicating that base editing had corrected the mutation in true, self-renewing blood stem cells. The findings suggest that corrected blood stem cells could persist long-term and produce the T cells patients would need to live healthy lives.
“This project was a beautiful picture of team science, with clinical need and scientific expertise aligned,” said Crooks, a professor of pathology and laboratory medicine. “Every team member played a vital role in making this work successful.”
The research team is now working with Wright on how to bring the new approach to a clinical trial for infants with CD3 delta SCID from Canada, Mexico and the U.S.
This research was funded by the Jeffrey Modell Foundation, the National Institutes of Health, the Bill and Melinda Gates Foundation, the Howard Hughes Medical Institute, the V Foundation and the A.P. Giannini Foundation.
The therapeutic approach described in this article has been used in preclinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The technique is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Kohn and McAuley listed as co-inventors.
McAuley, G.E., et al. (2023) Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing. Cell.doi.org/10.1016/j.cell.2023.02.027.
Thought LeadersProfessor Roberto La RagioneChair of TrusteesHumanimal Trust
In this interview, News-Medical speaks to Professor Roberto La Ragione, Chair of Trustees at Humanimal Trust, about the concept of One Medicine and how human and veterinary medicine can collaborate, share knowledge, and initiate research for the benefit of both humans and animals.
Please can you introduce yourself, tell us about your professional background, and your role at Humanimal Trust?
I am Professor Roberto La Ragione, Chair of Trustees at Humanimal Trust.
I graduated in 1995 and then studied for a postgraduate degree in veterinary microbiology at the Royal Veterinary College (University of London). In 1996, I moved to the government’s Veterinary Laboratories Agency (VLA) to undertake a Ph.D. on the pathogenesis of E. coli in poultry. Upon completing my Ph.D. studies, I commenced a post-doctoral position at Royal Holloway, University of London, studying E. coli virulence factors and vaccine development.
Since 2001, my work has focused largely on understanding the pathogenesis of zoonotic bacterial pathogens to develop control strategies. I have led several commercial, Defra, research councils (BBSRC, MRC, EPSRC, AHRC, Innovate) and EU projects in this area.
My current research interests focus on the pathogenesis of food-borne pathogens with a particular interest in Antimicrobial Resistance (AMR) and the development of intervention strategies, including vaccines, rapid diagnostic, pre, and probiotics. I have published over 190 papers in the area of host-microbe interaction, with a particular emphasis on E. coli,Salmonella, vaccines, probiotics, and AMR.
In 2005, I was appointed Head of Pathogenesis and Control at the AHVLA, and in 2010, I was appointed Professor of Veterinary Microbiology and Pathology at the University of Surrey. I gained the FRCPath in 2010, and in 2012, I was appointed the Associate Dean for Veterinary Strategy in the new School of Veterinary Medicine at the University of Surrey. In 2014, I was appointed to the position of Head of the Department of Pathology and Infectious Diseases and Director of the Veterinary Pathology Centre. In 2019 I was appointed Deputy Head of the School of Veterinary Medicine at the University of Surrey, and then in 2021, I was appointed Head of the School of Biosciences and Medicine.
I am the past president of the Med-Vet-Net Association and the Veterinary Research Club, the current Chair of Humanimal Trust, a member of the FSA ACMSF AMR sub-committee, a Trustee of the Houghton Trust, a member of the APHA Science Advisory Board and Chair of the Royal College of Pathologists Veterinary Pathology SAC. I am an Associate member of the European College of Veterinary Microbiology, and in 2020, I was awarded an Honorary Associateship of the Royal College of Veterinary Surgeons.
Humanimal Trust is a unique organization. Please could you tell us about the organization’s origin, purpose, and values?
Humanimal Trust is the only organization in the UK with the sole and specific purpose of progressing One Medicine.
It was founded in May 2014 by world-renowned orthopedic-neuro veterinary surgeon Professor Noel Fitzpatrick – otherwise known as the TV Supervet. As a vet, Noel Fitzpatrick experienced personally the deep divide between human and animal medicine and saw how unfair this was.
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Frustrated by the lack of opportunities to share what he was learning from veterinary practice or to benefit from relevant learning from human medicine, he decided to create the platform himself. This laid the foundations for the work Humanimal Trust does today, removing barriers and seeking to close the divide between human and animal medicine.
Our five areas of work spell out I-CARE, which sums up the way we feel, our supporters feel, and we hope everybody will one day feel about One Medicine:
Influence – we care about bringing together everyone who cares about One Medicine to create a road map for change in public policy, education, and at the clinical coalface.
Collaboration – we care about creating opportunities for human and veterinary professionals and students to learn from one another (in person and virtually) by demonstrating One Medicine at work.
Awareness – we care that people should know and understand the benefits of One Medicine for humans and animals, about non-animal alternatives to laboratory models, and how much human and animal medicine can learn from one another’s clinical practice – saving time, money, and lives.
Research – we care about research – funding it, facilitating it, shouting about it – that could benefit humans and animals without using laboratory animal models.
Education – we care about learning – every child learning about the connections between humans and animals; veterinary and human medical students learning with and from one another; practitioners learning continuously from their peers.
Humanimal Trust advocates for One Medicine. What is One Medicine, when did this concept originate, and how has the understanding of it evolved in recent years?
The origins of One Medicine date back to the nineteenth century when Rudolf Virchow linked human and animal health. Sir William Osler, Dr. Calvin Schwabe, Lord Lawson Soulsby, and others have since continued to expand the One Medicine concept, identifying the connections, commonalities, and synergies between human and veterinary medicine.
It was whilst studying the history of medicine that Professor Fitzpatrick came upon a term used to describe human and veterinary medicine working with one another: One Medicine. The third edition of Dr. Calvin Schwabe’s seminal publication in 1984 of ‘Veterinary Medicine and Human Health’ which spoke of One Medicine, laid the foundation for what we now know as One Health, but in considering this text, Fitzpatrick identified a need to move away from a public health agenda to a common health agenda focusing on infectious and non-infectious diseases.
Moreover, when reviewing the three Rs (refinement, reduction, and replacement) in relation to animal use in research, it became clear that a fourth R was missing from the 3Rs principle – the principle of reciprocity so that not only do medical practitioners and allied researchers benefit, but also patients, regardless of their species.
By considering the contribution that animals can make to research by studying their lives and their responses to naturally occurring, spontaneous diseases rather than using experimental animal models in research, the use of animals in research can be significantly reduced.
One Medicine and the ‘Biology of the Future’ (Biology Week 2020)
Why is it currently the case that human and veterinary medicine are kept separate, and why would it be beneficial to change this?
Although the practice of bringing veterinary and human medical and research professionals together is thought to stimulate new and innovative research, historically, this has been challenging. A number of studies have investigated why this could be, and different levels of awareness and priorities may be one reason. A 2020 study, which surveyed vets and GPs in Australia, found that vets generally had more awareness and felt more confident in engaging in zoonoses management compared to GPs, and were also more likely to initiate cross-professional referrals.
The Trust believes that education is key to One Medicine. Only by learning about the similarities between humans and animals from the earliest stage to collaboration in the most advanced science and clinical practice will we promote change. Therefore, we must ensure that the best research, clinical practice and learning, benefiting both humans and animals, are accessible, funded, encouraged, and promoted.
A study published in 2017 by a group of scientists in The Netherlands noted that having a clear common goal (like One Medicine) can help to stimulate collaboration. The study also suggested that professional organizations could be important facilitators of collaboration in this area.
With this in mind, in 2020, the Trust launched the Humanimal Hub, a free online platform for all human and animal medical and veterinary professionals to meet, collaborate, share knowledge, and initiate research for the benefit of both humans and animals.
While still in its infancy, the Hub already has over 250 members. It provides a much-needed virtual space for connections to be made and conversations to be initiated, which the Trust actively seeks to nurture. For example, Anna Radford, a Consultant in Paediatric Surgery at Hull University NHS Trust and Leeds Children’s Hospital, was looking to collaborate with an individual or group in veterinary medicine with a specialty in problems with urinary tract or kidneys and/or antimicrobial resistance. Through the Hub, we were able to identify a suitable professional, and as a result, an interdisciplinary group has been set up to identify common urological conditions affecting both humans and companion animals.
Anna was also introduced to a diagnostics company working in the animal medical care field at the Trust’s inaugural global ‘One Medicine Symposium: Stronger Together’ in May 2021. Through them, Anna has set up a new collaboration to determine whether this diagnostic technology developed with companion animal medicine in mind could potentially also be useful to help diagnose urinary, joint, and cerebrospinal fluid infections in a busy NHS hospital setting.
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These are just two examples of how we know that great things can happen when animal and human health professionals and scientists come together.
Which areas of medicine do you currently focus on, and what benefits does One Medicine provide to this particular area?
I believe One Medicine has transformative potential across all areas of medicine where physiological and genetic similarities exist between humans and animals. There are five main pillars of research that the Trust currently seeks to fund, namely infection control and antimicrobial resistance; cancer; bone and joint disease; brain and spinal disease; and regenerative medicine.
In line with this, the Trust began an important collaboration with the children’s charity Action Medical Research in 2020 to help support two child-focused medical research projects. The first study, led by Professor Hall-Scraggs at University College London, focuses on juvenile idiopathic arthritis (JIA). Patients with JIA have a disease that causes inflammation of their joints. This leads to pain, joint deformity, disability, and reduced quality of life. There are newer drugs now available that suppress joint inflammation, but these are expensive and can have side effects, the most serious being life-threatening infection. Magnetic resonance imaging (MRI) scans can show inflammation of joints. By measuring inflammation in patients with juvenile idiopathic arthritis, the study could help optimize their treatment by showing how much inflammation is present and whether it changes with treatment.
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The second study, which is ongoing, is investigating infection prevention and its impact on antimicrobial resistance in critically ill children, led by Dr. Nazima Pathan, Lecturer in Paediatric Intensive Care at the University of Cambridge. The transferable data from both studies has real potential to help improve the lives of humans and animals with similar conditions.
Another example of research the Trust has funded concerns liquid biopsies for canine patients. This research was undertaken by Professor Joanna Morris and Dr. Tomoko Iwata at the University of Glasgow and is a great example of reciprocity whereby human and animal bladder cancer patients may benefit from this research.
Are there any particular examples of where either human or veterinary medicine has led to advances in the other?
Cancer research is perhaps the area for which One Medicine is most well-known. For example, dogs, long considered our best friends, don’t just share our lives but also risk factors for certain diseases. Many diseases also share genetic similarities between humans and dogs. Canine lymphoma, the second most common cancer in dogs, has relatively similar characteristics to human non-Hodgkin lymphoma. Around 1 in 8 golden retrievers will develop canine lymphoma, and CRUK estimates that 1 in 39 males and 1 in 51 females are at risk of being diagnosed with non-Hodgkin lymphoma. Both species need better, more effective ways to treat the disease, and clinical trials with canine veterinary patients have been helping to fast-track the development of new treatments in this area for several years.
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The US-based DISCO initiative recognizes the value of aligning veterinary and human drug development projects and explains why it can be worthwhile to include veterinary patients at an early stage in cancer drug development trials. From shortening drug development times to encouraging cross-collaboration between the disciplines for the benefit of both human and veterinary patients, the potential advantages of this approach are clearly laid out in a landmark 2019 paper, which came about from a workshop of the World Small Animal Veterinary Association’s One Health committee.
What is the one thing you wish people knew about One Medicine?
One Medicine is about human and animal healthcare advancing hand in hand, in an equitable and sustainable way, and not at the expense of an animal’s life.
How can people, both medical professionals and the general public, get involved with Humanimal Trust and support the One Medicine cause?
Human and animal medical professionals, students, and researchers can join the Humanimal Hub for free and use it as an opportunity to collaborate, share knowledge, and initiate research with other like-minded individuals. The Trust also holds an annual One Medicine Day event that brings together researchers, doctors, vets, allied healthcare professionals, and students from around the world to discuss practical ways forward for One Medicine. The year’s ‘One Medicine Day Seminar: One Medicine in Action’ talks can be found here.
There are also opportunities to join our team as a volunteer Ambassador, write articles for us, present at events or act as a moderator for the Hub.
There are many ways that members of the public interested in One Medicine can get involved too, from signing The Humanimal Pledge or organizing a Paws for a Picnic fundraiser with family and friends to leaving a gift in your will or becoming a volunteer speaker in your local community.
What is next for yourself and Humanimal Trust?
We recognize the need to present One Medicine consistently through an education lens. Our absolute priority is to improve understanding at every level – from pre-school to professional training (veterinary and medical undergraduates) and development – of the relationship between human and animal health and the need for collaboration and reciprocity of benefit to humans and animals.
With this in mind, our focus for the next twelve months is on four key areas of activity:
Focused awareness building among key audiences
Developing partnerships, networks, and collaborations
Education
Research funding, engagement, and influencing activity
To help drive this, we have appointed a new CEO, Joe Bailey, who will be joining us in November from RSPCA Assured, together with a new Trustee, Anna Radford, whom I referred to earlier. I have no doubt that their understanding of and passion for our purpose will help take Humanimal Trust to the next level.
We are expanding our Science Committee, which will strengthen our ability to draw on the best available expertise to make better-informed decisions about which research activities we prioritize for funding or support. In addition, to support the strategic development of our educational program, we have created a new role – Schools Education Manager – which will enable us to initiate the long-term development of a One Medicine curriculum.
We will soon launch our new Podcast series, which I’m very excited about. This will follow the Trust’s previous series, Humanimal Connection, but with a very different feel to it, so watch this space.
About Professor Roberto La Ragione, BSc (Hons) MSc Ph.D. FRSB CBiol FIBMS CSci AECVM FRCPath HonAssocRCVS
I am a Professor of Veterinary Microbiology and Pathology in the School of Veterinary Medicine and the Head of the School of Biosciences and Medicine at the University of Surrey. My role includes delivering and overseeing teaching and research in the School and running my own research group, which consists of vets, doctors, and scientists. My current research interests focus on Antimicrobial Resistance (AMR) and understanding the pathogenesis of zoonotic bacterial pathogens (those that can be transmitted from animals to humans and, in some cases, from humans to animals). I also have a particular interest in developing control and intervention strategies, including rapid diagnostics, vaccines and probiotics for controlling bacterial pathogens in companion and food-producing animals. I have published over 190 peer-reviewed papers in the area of microbiology and pathology.
My role includes delivering and overseeing teaching and research in the School and running my own research group, which consists of vets, doctors, and scientists. My current research interests focus on Antimicrobial Resistance (AMR) and understanding the pathogenesis of zoonotic bacterial pathogens (those that can be transmitted from animals to humans and, in some cases, from humans to animals). I also have a particular interest in developing control and intervention strategies, including rapid diagnostics, vaccines and probiotics for controlling bacterial pathogens in companion and food-producing animals. I have published over 190 peer-reviewed papers in the area of microbiology and pathology.