Clinical trial to test the safety, efficacy of bacteriophages for treating P. aeruginosa infections in CF patients
Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs and other organs in the body. Nearly 40,000 children and adults in the United States live with CF, an often difficult existence exacerbated by an opportunistic bacterium called Pseudomonas aeruginosa, which is a major cause of chronic, life-threatening lung infections.
P. aeruginosa infections are not easily treated. The pathogen can be resistant to most current antibiotics. However, an early-stage clinical trial led by scientists at University of California San Diego School of Medicine, with collaborators across the country, has launched to assess the safety and efficacy of treating P. aeruginosa lung infections in CF patients with a different biological weapon: bacteriophages.
Bacteriophages are viruses that have evolved to target and destroy specific bacterial species or strains. Phages are more abundant than all other life forms on Earth combined and are found wherever bacteria exist. Discovered in the early 20th century, they have long been investigated for their therapeutic potential, but increasingly so with the rise and spread of antibiotic-resistant bacteria.
In 2016, scientists and physicians at UC San Diego School of Medicine and UC San Diego Health used an experimental intravenous phage therapy to successfully treat and cure colleague Tom Patterson, PhD, who was near death from a multidrug-resistant bacterial infection. Patterson’s was the first documented case in the U.S. to employ intravenous phages to eradicate a systemic bacterial infection. Subsequent successful cases helped lead to creation of the Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego, the first such center in North America.
In 2020, IPATH researchers published data from 10 cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections, all at UC San Diego. In 7 of 10 cases, there was a successful outcome.
The new phase 1b/2 clinical trial advances this work. The trial is co-led by Robert Schooley, MD, professor of medicine and an infectious disease expert at UC San Diego School of Medicine who is co-director of IPATH and helped lead the clinical team that treated and cured Patterson in 2016.
It will consist of three elements, all intended to assess the safety and microbiological activity of a single dose of intravenous phage therapy in males and non-pregnant females 18 years and older, all residing in the United States.
The dose is a cocktail of four phages that target P. aeruginosa, a bacterial species commonly found in the environment (soil and water) that can cause infections in the blood, lungs and other parts of the body after surgery.
For persons with CF, P. aeruginosa is a familiar and sometimes fatal foe. The Cystic Fibrosis Foundation estimates that roughly half of all people with CF are infected by Pseudomonas. Previous studies have indicated that chronic P. aeruginosa lung infections negatively impact life expectancy of CF patients, who currently live, on average, to approximately 44 years.
In the first stage of the trial, two “sentinel subjects” will receive one of three dosing strengths of the IV bacteriophage therapy. If, after 96 hours and no adverse effects, the second stage (2a) will enroll 32 participants into one of four arms: the three doses and a placebo.
After multiple follow-up visits over 30 days and an analysis of which dosing strength exhibited the most favorable safety and microbiologic activity, i.e. most effective at reducing P. aeruginosa, stage 2b will recruit up to 72 participants to either receive that IV dose or a placebo.
Enrollment will occur at 16 cystic fibrosis clinical research sites in the United States, including UC San Diego. It is randomized, double-blind and placebo-controlled. The trial is being conducted through the Antibacterial Resistance Leadership Group and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, with additional support for the UC San Diego trial site from the Mallory Smith Legacy Fund.
Mallory Smith was born with cystic fibrosis and died in 2017 at the age of 25 from a multidrug-resistant bacterial infection following a double lung transplant.
Mallory’s death was a preventable tragedy. We are supporting the IPATH trial through Mallory’s Legacy Fund because Mark and I deeply believe in the promise of phage therapy to save lives by combatting multidrug-resistant bacteria.”
Diane Shader Smith, Mother
In an article published in 2020 in Nature Microbiology, Schooley and Steffanie Strathdee, PhD, associate dean of global health sciences and Harold Simon Professor in the Department of Medicine and IPATH co-director, describe phages as “living antibiotics.”
As such, said Schooley, researchers need to learn how to best use them to benefit patients through the same systematic clinical trials employed to evaluate traditional antibiotics.
The primary objectives of the new trial are first to determine the safety of a single IV phage dose in clinically stable patients with CF who are also infected with P. aeruginosa, said Schooley.
“Second, it’s to describe the microbiological activity of a single IV dose and third, to assess the benefit-to-risk profile for CF patients with P. aeruginosa infections. This is one study, with a distinct patient cohort and carefully prescribed goals. It’s a step, but an important one that can, if ultimately proven successful, help address the growing, global problem of antimicrobial resistance and measurably improve patients’ lives.”
Estimated study completion date is early 2025.
$2.5 million CDC contract to fund one of the largest SARS-CoV-2 surveillance programs in the U.S.
A team led by Scripps Research scientists has been awarded a contract by the U.S. Centers for Disease Control & Prevention (CDC) in support of one of the largest SARS-CoV-2 surveillance programs in the United States.
The two-year, $2.5 million contract will fund the large-scale, near real-time sequencing of SARS-CoV-2 isolates from hospitals and local public health agencies in San Diego and nearby northwestern Mexico, and the development of software for tracking the evolution and geographical spread of SARS-CoV-2 variants.
The contract, an extension of one originally awarded in 2020, will be carried out by the San Diego Epidemiology and Research for COVID Health (SEARCH) Alliance, which was co-founded by Scripps Research, the University of California San Diego (UC San Diego), and Rady Children’s Hospital-San Diego.
CDC’s support for SEARCH’s genomic surveillance program has already led to significant COVID-19 public health advances as well as new science on SARS-CoV-2, and we expect much more progress in both areas as a result of this new award.”
Kristian Andersen, PhD, Principal Investigator, Professor, Department of Immunology and Microbiology at Scripps Research
Since the start of the pandemic, SEARCH has been conducting genomic surveillance of SARS-CoV-2 using clinical samples collected at San Diego hospitals and from sources across the border in Baja California. SEARCH has also developed key protocols and analysis tools to track the emergence and spread of SARS-CoV-2 variants in wastewater. Moreover, SEARCH investigators are actively involved in understanding the emergence of SARS-CoV-2, and in several high-profile publications have found evidence for an initial spread from animals sold at the Huanan Market in Wuhan, China.
SEARCH’s efforts involve multiple collaborations, including with the CDC, San Diego County’s Health & Human Services Agency, the California Department of Public Health, Sharp Health, Scripps Health, the viral surveillance company Helix, and the Salud Digna healthcare network in Mexico. Since the start of the pandemic, these efforts have yielded publications and analyses of more than 70,000 SARS-CoV-2 sequences.
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Under the new contract, SEARCH will accelerate its virus-sequencing workflow to produce more timely and actionable information on local virus spread and evolution-;including the emergence of new variants and subvariants of concern.
“The current process of sampling, sequencing and analyzing a batch of virus samples from local hospital cases and wastewater treatment plants can take several weeks,” says Mark Zeller, PhD, project scientist in the Andersen lab. “We’re aiming to get that down to a matter of days, which would enable us to monitor the transmission chains in local outbreaks in near real-time.”
Working with the County of San Diego, the state of California and Mexican public health labs, the researchers will also continue to analyze the transmission of SARS-CoV-2 across the busy California-Baja border. Additionally, they’ll expand their genomic surveillance efforts to additional Mexican border states and popular tourist destinations, including Puerto Vallarta. The team will continue to post their analyses on SEARCH’s online dashboards.
The project includes the further development of open-source software tools to support the tracking of local SARS-CoV-2 evolution and transmission.
“The tools we’ve developed in recent years are already being used widely by the public health community for SARS-CoV-2 sequencing and analysis,” says Joshua Levy, PhD, postdoctoral research associate in the Andersen lab. “Under this new contract, we will be developing the technology to permanently transform how genomic surveillance will be used to strengthen our public health response.”
These open-source software tools are available at https://andersen-lab.com/secrets/code/. The SEARCH Alliance’s SARS-CoV-2 surveillance dashboards are at https://searchcovid.info/Dashboards/.
Source:
Duke receives federal funding for HIV vaccine research
The Duke Human Vaccine Institute (DHVI) and the Department of Surgery at Duke University School of Medicine received a grant from the National Institute of Allergy and Infectious Diseases for HIV vaccine research that could total $25.9 million with full funding over five years.
The funding supports a multi-institutional effort called The Consortium for Innovative HIV/AIDS Vaccine and Cure Research that is built around two areas of scientific focus: identification of the components and the mechanisms of protection of preventive vaccines; and the use of the newly identified preventive vaccines along with other immune therapies in advancing potential treatments and/or cures.
The grant’s principal investigators are Guido Ferrari, M.D., a professor in the Department of Surgery and research professor in the Department of Genetics and Microbiology, and Wilton Williams, Ph.D., an associate professor in the departments of Surgery and Medicine, and assistant professor in the Department of Immunology at Duke University School of Medicine.
The researchers will lead work that builds upon ongoing HIV vaccine development research at DHVI and expands investigations of vaccine strategies, including innovative mRNA approaches that induce protective immune responses in non-human primate models.
This grant is synergistic with everything going on at Duke, notably the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) initiative to design an HIV vaccine. We are excited about the wonderful science that will be done in the context of this grant. It expands the capacity at Duke, UNC and others who are collaborating on this effort to move forward with both vaccines and potential cures.”
Barton Haynes, Director of the DHVI
Combining vaccine approaches with cure efforts is designed to stimulate innovative collaborations toward both. Studies in nonhuman primates will investigate how effective HIV/AIDS vaccines protect from initial infection and systemic infection.
Vaccines and other immune interventions will also be used as cure strategies with the goal of eliminating all the infection in the cells. While advances have been made in boosting cellular and antibody immunity, it remains unclear whether the boosted immune response can prevent reinfection after antiretroviral treatments are stopped. With the newly funded grant, the researchers hope to answer that and other questions.
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“This grant enables us to do something current vaccine research is not funded to do – explore vaccines with a mission to cure,” Williams said. “Right now, it’s either prevention or cure, and we want to achieve a combination of those things.”
Ferrari said vaccine research has advanced far enough that researchers can now begin applying potential components of vaccines, as well as new technologies such as mRNA vaccine design, to explore ways of eradicating the HIV from infected cells.
“The beauty of mRNA is its ability to be adapted quickly and we can produce it in a timely manner to address new variants, which is important for HIV,” Ferrari said. “We will now focus on how we can capitalize on the current science to eradicate infection.”
“The science underpinning this program has broad applicability, spanning from the immediate goals of eliminating HIV disease, to a more generalizable harnessing of the immune system to prevent emerging infectious diseases, control cancer, and accelerate our understanding of autoimmunity and transplant biology,” said Allan D. Kirk, M.D., Ph.D., chair of the Department of Surgery.
“Our department sees the promise of basic investments like these for transformational approaches to care that do not traditionally fall within a surgical department,” Kirk said. “Drs. Williams and Ferrari are vital members of our translational science community.”
In addition to Williams and Ferrari, collaborators at Duke are Priyamvada Acharya, Mihai Azoitei, Derek Cain, Thomas Denny, Robert J. Edwards, Barton Haynes, David Montefiori, Justin Pollara, Keith Reeves, Wes Rountree, Kevin Saunders, Shaunna Shen, Rachel Spreng, Georgia Tomaras, Kevin Wiehe, Kelly Cuttle and Cynthia Nagle.
Study partners include Katharine Barr, Michael Betts, Beatrice Hahn, George Shaw, Drew Weissman at the University of Pennsylvania; Richard Dunham and David Margolis at the University of North Carolina at Chapel Hill; Sampa Santra at Harvard University; Andrew McMichael, Persephone Borrow and Geraldine Gillespie at Oxford University; Bette Korber and Kshitij Wagh at Los Alamos National Laboratory; and Mark Lewis at BIOQUAL.
Monoclonal antibody improves cat allergen immunotherapy
An experimental approach to enhancing a standard cat allergy treatment made it more effective and faster acting, and the benefits persisted for a year after treatment ended, a study supported by the National Institutes of Health has found. The findings were published Monday in the Journal of Allergy and Clinical Immunology.
Allergen immunotherapy, often called allergy shots, is a long-term treatment that decreases allergy symptoms for people with conditions such as allergic rhinitis or allergic asthma by reducing their sensitivity to allergens. Achieving persistent symptom relief requires at least three years of allergy shots, however, and does not work for everyone.
“People with chronic allergy symptoms may suffer from reduced productivity and quality of life,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of NIH. “Developing allergen immunotherapy regimens that work better and more quickly than those currently available would provide much-needed relief for many people.”
To that end, NIAID-supported investigators tested whether giving a monoclonal antibody called tezepelumab plus cat allergy shots to people with allergic rhinitis caused by cat allergens would safely provide better and faster long-lasting symptom relief than allergy shots alone. Allergic rhinitis involves inflammation of the nasal membranes and causes symptoms such as sneezing, runny nose, stuffy nose, watery eyes, problems with smell, and an itchy nose, mouth, or eyes.
The Phase 1/2 clinical trial, called CATNIP, was led by Jonathan Corren, M.D., and conducted by the NIAID-funded Immune Tolerance Network. Dr. Corren is an associate clinical professor of medicine at the David Geffen School of Medicine at UCLA in Los Angeles. Tezepelumab was donated for the trial by Amgen Inc. of Thousand Oaks, California and AstraZeneca of Gaithersburg, Maryland.
Tezepelumab blocks a protein called thymic stromal lymphopoietin (TSLP), a type of cell-signaling molecule, or cytokine, called an alarmin. Cells that cover the surface of organs like the skin and intestines or that line the inside of the nose and lungs rapidly secrete TSLP in response to signals of potential danger. In allergic disease, TSLP helps initiate an overreactive immune response to otherwise harmless substances like cat dander, provoking airway inflammation that leads to the symptoms of allergic rhinitis.
The CATNIP study enrolled 121 adults ages 18 to 65 years at nine medical centers in eight cities across the United States. The participants were assigned at random to receive either tezepelumab plus subcutaneous cat allergy shots, tezepelumab plus placebo shots, placebo plus allergy shots, or a double placebo. No one knew who received which regimen until the end of the study. The treatment period lasted 48 weeks, and the study team continued to follow participants for a year after treatment ended.
To test how well each regimen worked, the study team gave participants one spritz in each nostril of a nasal spray containing cat allergen extract six times during the two-year study period. The study team recorded participants’ level of nasal symptoms and airflow through the nose at five, 15, 30 and 60 minutes after receiving the nasal spray and hourly for up to five hours thereafter. In addition, blood and nasal cell samples were collected from participants.
The investigators found that participants’ worst nasal symptoms were 36% lower at the end of treatment in the group that received tezepelumab plus allergy shots compared to the group that received allergy shots alone, and 24% lower a year later. These results show for the first time that adding a cytokine inhibitor to allergy shots can reduce allergic rhinitis symptoms for an extended period after just one year of treatment, according to the researchers.
An analysis of blood and nasal cell samples revealed that the combination treatment caused changes in gene network activity that reduced the activation of allergy-related immune cells on the inner lining of the nose, helping suppress allergic nasal symptoms.
With the successful outcome of the CATNIP trial, plans are underway for a NIAID-supported Phase 2 trial of tezepelumab plus oral immunotherapy for food allergy. In addition, the CATNIP investigators are further analyzing the study data to understand how tezepelumab plus immunotherapy works at a cellular level, to potentially design additional trials that look at more health outcomes, and to identify the people who may benefit the most from this treatment combination.
More information:
Jonathan Corren et al, Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: a randomized controlled trial, Journal of Allergy and Clinical Immunology (2022). DOI: 10.1016/j.jaci.2022.08.029
Jonathan Corren et al, Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: a randomized controlled trial, Journal of Allergy and Clinical Immunology (2022). DOI: 10.1016/j.jaci.2022.08.029
New study identifies potential therapeutic target for colonic disorders
Colonic motility disorders, especially problems associated with constipation and diarrhea, are common in adults and children, greatly impacting quality of life. A new study in The American Journal of Pathology identifies neuropilin 2 (NRP2) as a novel regulator of distal colonic smooth muscle motility. Its ability to regulate cytoskeletal tone and restrain abnormal smooth muscle contraction may provide opportunities in the future to inhibit or activate signaling and thereby regulate smooth muscle activity in patients suffering from colonic motility disorders.
“Normal visceral smooth muscle activity is central to the function of many body systems including the gastrointestinal and urinary tracts, but it is much less studied than vascular smooth muscle,” explained co-lead investigator Maryrose P. Sullivan, Ph.D., Department of Surgery, Harvard Medical School; and Division of Urology, VA Boston Healthcare System.
“Earlier studies by our group that showed robust expression of Nrp2 in smooth muscle of the colon prompted us to understand its functional significance in contraction and colonic motility.”
The investigators found extensive NRP2 expression in the distal colon that was especially prominent in circular and longitudinal smooth muscles in both humans and mouse models. They used genetically modified mice to determine the impact of Nrp2 deletion on contractility of the colon. Having demonstrated extensive expression of Nrp2 in smooth muscle of the gastrointestinal tract, they determined the functional consequences of Nrp2 gene deletion in vitro and motility analysis in intact mice.
Their findings showed colonic tissues displayed increased evoked contraction in mice with global or smooth muscle–specific deletion of Nrp2. Mice with inducible, smooth muscle–specific Nrp2 deletion also showed an increase in colonic motility.
“We were intrigued by the emergence of functional changes as early as a week after deletion of Nrp2,” said co-lead investigator Rosalyn M. Adam, Ph.D., Urological Diseases Research Center, Boston Children’s Hospital; and Department of Surgery, Harvard Medical School, Boston.
“The relatively rapid detection of differences in contractile behavior of colonic muscle argues against major structural changes to the tissue, but rather suggests changes in cellular signaling. Delineating the signaling networks regulated by Nrp2 in smooth muscle is a major focus of our ongoing research.”
Dr. Sullivan and Dr. Adam observed that their study provides an important addition to understanding mechanisms of regulation of visceral smooth muscle and suggests that Nrp2 may be an actionable target in diseases characterized by abnormal smooth muscle contraction.
“Although studies in patients are many years away, ongoing studies in our group are focused on development of small molecule inhibitors designed to inhibit Nrp2. These efforts may provide opportunities in the future to inhibit signaling via Nrp2 and regulate smooth muscle activity in patients. This is particularly relevant for diseases in which visceral smooth muscle is impaired, since effective pharmacotherapy for these conditions is not currently available,” they noted.
Alterations in colonic motility can result from a variety of conditions, including congenital anomalies such as Hirschsprung disease, diabetes, inflammation, infection, gut dysbiosis, and nerve damage secondary to spinal injury. Furthermore, changes in the magnitude and/or coordination of contractile activity throughout the gastrointestinal tract can lead to dysfunctional motility with ensuing disturbances in intestinal flora, inflammation, and nutrient absorption, often with serious health consequences.
More information:
George Lambrinos et al, Neuropilin 2 Is a Novel Regulator of Distal Colon Contractility, The American Journal of Pathology (2022). DOI: 10.1016/j.ajpath.2022.07.013
George Lambrinos et al, Neuropilin 2 Is a Novel Regulator of Distal Colon Contractility, The American Journal of Pathology (2022). DOI: 10.1016/j.ajpath.2022.07.013
Genetically engineered bacteria make living materials for self-repairing walls and cleaning up pollution
With just an incubator and some broth, researchers can grow reusable filters made of bacteria to clean up polluted water, detect chemicals in the environment and protect surfaces from rust and mold.
I am a synthetic biologist who studies engineered living materials – substances made from living cells that have a variety of functions. In my recently published research, I programmed bacteria to form living materials that can not only be modified for different applications, but are also quick and easy to produce.
Like human cells, bacteria contain DNA that provides the instructions to build proteins. Bacterial DNA can be modified to instruct the cell to build new proteins, including ones that don’t exist in nature. Researchers can even control exactly where these proteins will be located within the cell.
Because engineered living materials are made of living cells, they can be genetically engineered to perform a broad variety of functions, almost like programming a cellphone with different apps. For example, researchers can turn bacteria into sensors for environmental pollutants by modifying them to change color in the presence of certain molecules. Researchers have also used bacteria to create limestone particles, the chemical used to make Styrofoam and living photovoltaics, among others.
A primary challenge for engineered living materials has been figuring out how to induce them to produce a matrix, or substances surrounding the cell, that allows researchers to control the physical properties of the final material, such as its viscosity, elasticity and stiffness. To address this, my team and I created a system to encode this matrix in the bacteria’s DNA.
We modified the DNA of the bacteria Caulobacter crescentus so that the bacterial cells would produce on their surfaces a matrix made of large amounts of elastic proteins. These elastic proteins have the ability to bind to each other and form hydrogels, a type of material that can retain large amounts of water.
When two genetically modified bacterial cells come in close proximity, these proteins come together and keep the cells attached to each other. By surrounding each cell with this sticky, elastic material, bacterial cells will cluster together to form a living slime.
Furthermore, we can modify the elastic proteins to change the properties of the final material. For example, we could turn bacteria into hard construction materials that have the ability to self-repair in the event of damage. Alternatively, we could turn bacteria into soft materials that could be used as fillers in products.
Usually, creating multifunctional materials is extremely difficult, due in part to very expensive processing costs. Like a tree growing from a seed, living materials, on the other hand, grow from cells that have minimal nutrient and energy requirements. Their biodegradability and minimal production requirements allow for sustainable and economical production.
The technology to make living materials is unsophisticated and cheap. It only takes a shaking incubator, proteins and sugars to grow a multifunctional, high-performing material from bacteria. The incubator is just a metal or plastic box that keeps the temperature at about 98.6 degrees Fahrenheit (37 Celsius), which is much lower than a conventional home oven, and shakes the cells at speeds slower than a blender.
Transforming bacteria into living materials is also a quick process. My team and I were able to grow our bacterial living materials in about 24 hours. This is pretty fast compared to the manufacturing process of other materials, including living materials like wood that can take years to produce.
Moreover, our living bacterial slime is easy to transport and store. It can survive in a jar at room temperature for up to three weeks and placed back into a fresh medium to regrow. This could lower the cost of future technology based on these materials.
Lastly, engineered living materials are an environmentally friendly technology. Because they are made of living cells, they are biocompatible, or nontoxic, and biodegradable, or naturally decomposable.
There are still some aspects of our bacterial living material that need to be clarified. For example, we don’t know exactly how the proteins on the bacterial cell surface interact with each other, or how strongly they bind to each other. We also don’t know exactly how many protein molecules are required to keep cells together.
Answering these questions will enable us to further customize living materials with desired qualities for different functions.
Next, I’m planning to explore growing different types of bacteria as living materials to expand the applications they can be used for. Some types of bacteria are better than others for different purposes. For example, some bacteria survive best in specific environments, such as the human body, soil or fresh water. Some, on the other hand, can adapt to different external conditions, like varying temperature, acidity and salinity.
By having many types of bacteria to choose from, researchers can further customize the materials they can create.
Japan opens borders to tourists as last pandemic travel restrictions eased
Independent Task Force report outlines a One Health approach to address risk factors for future pandemics
The Independent Task Force on COVID-19 and other Pandemics (www.independentcovidtaskforce.org) announced that their report “Pandemic Origins and a One Health Approach to Preparedness and Prevention: Solutions Based on SARS-CoV-2 and Other RNA Viruses” has been published in the Proceedings of the National Academy of Sciences (https://doi.org/10.1073/pnas.2202871119).
Independent Task Force chair, Dr. Gerald T. Keusch of the National Emerging Infectious Diseases Laboratory and Center for Emerging Infectious Diseases Policy and Research at Boston University said that “The world has largely failed to meet the challenge to be better prepared to prevent or respond adequately enough to the next pandemic, whatever the etiology. Our Task Force believes that the best way to address risk factors for future pandemics is a One Health approach that balances and optimizes the health of people, animals, and ecosystems.”
The Independent Task Force focused on scientific findings before and during the pandemic, and a historical review of multiple previous RNA virus outbreaks to identify critical intervention points to interrupt zoonotic transmission and translates this knowledge into recommendations based on a One Health approach to prevent or mitigate an outbreak, and if necessary, to respond rapidly to prevent epidemic or pandemic spread.
Background of the Task Force
The emergence of animal-origin (zoonotic) RNA viruses like SARS-CoV-2, whether from wildlife, livestock, or domestic animals, is an urgent and growing threat to public health. Understanding how SARS-CoV-2 and other RNA virus outbreaks originate can guide how we can more effectively prevent, mitigate, or respond to future emerging infectious diseases (EIDs). Increasing outbreaks in recent decades have been driven by many factors, including human and livestock population growth coupled with expanding human-animal-environment interfaces, changing patterns of land use, climate change, globalized travel, and trade. These outbreaks have common characteristics, including zoonotic spillover from an animal reservoir host to humans, with or without involvement of another animal transmission host. These events highlight the importance of a One Health approach to design relevant, feasible, and implementable solutions to prevent, mitigate, and respond rapidly to future outbreaks.
The Independent Task Force is a group of internationally renowned scientists with diverse disciplinary expertise in human, animal, and public health, virology, epidemiology, wildlife biology, ecology, and EIDs. Twelve members were convened in June 2020 as a Task Force within the Lancet COVID-19 Commission. In November 2021 with the addition of 2 new expert members, they formed the Independent Task Force to assess available evidence on what drove the origins and early spread of COVID-19 and provide evidence-based recommendations to reduce the impact of and improve responses to outbreaks. A critical review of the literature, interviews with other scientists, and extensive discussions culminated in the present PNAS report.
Key findings
The Independent Task Force Report shows that:
- Animal RNA viruses, including coronaviruses, have a long history of crossing species barriers to humans. The report provides a historic timeline of estimated origin dates for major coronavirus outbreaks affecting people or livestock and highlights coronaviruses that represent a growing risk to both human and animal health.
- The risk of pandemics emerging increases when people and animals interact closely in new settings driven by land use and climate change, environmental degradation, the wildlife trade, population growth, and economic pressure. Evidence indicates that most new zoonotic outbreaks have wildlife or livestock origins. The report provides recommendations that target high-risk animal-human interfaces to prevent or mitigate the risk of future spillovers. An important strategy is ‘Smart Surveillance’ and sampling programs which have proven helpful for disease outbreak forecasting and to guide strategies to reduce risks at the source.
- Substantial newly published scientific evidence reviewed in the PNAS Perspective report strongly indicates that COVID-19 originated via a pathway similar to SARS-CoV, involving spillover from bats to intermediate animal hosts, then to people within the wildlife trade, leading to the first known cluster of COVID-19 in the Huanan Seafood Market in Wuhan, China, in December 2019. The Task Force finds no verifiable or credible evidence to support the possibility that SARS-CoV-2 was created in or released from a laboratory (See Table S.6. in Supporting Information: http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2202871119/-/DCSupplemental)
- Efforts to control and respond to the COVID-19 pandemic were hindered in many countries by politics, misinformation and disinformation, and a growing anti-science/anti-vaccine movement.
- The importance of critically evaluating the potential of a zoonotic link to wildlife is that it leads to implementable One Health-oriented changes in policy and practice that can reduce the likelihood of similar occurrences in the future. Importantly, this presents no conflict with continuous efforts to improve laboratory and field biosafety and biosecurity.
Recommendations
The Independent Task Force Report makes the following recommendations:
(1) “Smart Surveillance” to identify high-threat potential pathogens. Targeting surveillance to people, wildlife, and domestic animals within emerging disease hot spots; improving methodologies for safe surveillance; and innovating a risk assessment framework to provide early warning of pathogens most likely to emerge. The benefits of Smart Surveillance conducted by trained personnel using rigorous protocols to maximize safety and security far outweigh risks and provide critical data for research and development of vaccines, therapeutics, diagnostics and better early warning systems, and inform One Health strategies for prevention and response..
(2) Preparedness and translational research. Investing in R&D for innovative and broad spectrum diagnostics, antiviral and vaccine strategies for priority pathogens based on data from ‘Smart Surveillance’; streamlining approaches to build capacity for clinical trials, licensure, and manufacture of medical countermeasures; and understanding the pathogenesis of potential high-threat pathogens to guide new therapeutic strategies.
(3) Reduce the drivers for spillover risk and spread. Working with communities and countries on the frontline of disease emergence to understand epidemiological, value chain, and behavioral drivers of EID emergence; implementing risk reduction strategies; developing incentives to minimize human-wildlife contact at interfaces in rural areas and commercial markets; and strengthening awareness of the emerging disease-linked health impacts and costs of land use and climate change to provide incentives for sustainable development.
(4) Counter misinformation and disinformation about the prevention and control of emerging diseases. Interdisciplinary research on what drives the emergence, spread and public acceptance of misinformation and disinformation in order to develop robust counter-mechanisms; develop strategies to counter distrust of science and expert advice, including creating organizations to support scientists under threat arising from disinformation and politically-motivated attacks; designing and promoting programs to improve public understanding of the scientific method and where to find trusted evidence-based scientific information.
(5) Strengthen One Health governance and science. Creating an inclusive, multi-stakeholder One Health-based governance framework at local, regional, national and international levels for pandemic preparedness and response; increasing funding for cross-disciplinary, collaborative One Health research; learning from indigenous knowledge; participation of civil society and engagement of public and private sector expertise; and efforts to educate new generations concerning the scientific method and reliable sources of information.
Comments from other members of the Independent Task Force:
“Applying data from predictive programs must be coupled with government engagement and widespread education campaigns. By building a united front against misinformation and disinformation, we can equip people around the world with the tools needed effectively to protect themselves and others.”
- Dr. Malik Peiris, School of Public Health, University of Hong Kong, Hong Kong
“Humans share the planet with animals and viruses, which evolve in an ever-shifting evolutionary landscape of risks. To stay ahead of the challenges posed by emerging infectious diseases like COVID-19 and to protect the human family from the next global pandemic, we need to find new frameworks for international scientific collaboration that transcend the tensions of geopolitics. Cooperation on smart surveillance is our best bet to stay one step ahead of the next virus.”
- Dr. Peter Daszak, EcoHealth Alliance, New York, USA
“As climate change, land use patterns, and the growing wildlife trade in certain regions continue to create opportunities for zoonotic spillover of EIDs, the solutions in this report have crucial implications for the global community for years to come. We must learn from past pandemics to prepare for success in anticipating, mitigating, and responding effectively to future pandemics. “
- Dr. Marion Koopmans, Erasmus Medical Center, Rotterdam, The Netherlands
“The COVID-19 pandemic introduced or highlighted scientific disciplines, such as virology and epidemiology, to the broader community. Although the ‘lessons learned’ are certainly not new to scientists, it is our responsibility to ensure that these lessons and our recommendations are better understood and are more readily embraced and acted upon to protect communities, animals and ecosystems now and in the future”
- Dr Danielle Anderson, Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
“COVID-19 has decisively challenged our perception and our capacity to handle threats that on top of causing the loss of human lives, represent a risk to other animal species, global economies, food security and systems, or the trust of people in science, just to name a few. We need stronger international regulatory and financial systems that, embodying a one health approach, can truly help transform the way we live and use our planet’s resources, so that we can prevent and be better prepared for threats such as SARS-CoV-2.”
– Dr Carlos G. das Neves, Norwegian Veterinary Institute, Ås, Norway
“Despite advancements in biomedical science and technology over the past century, we have largely turned a blind eye to the inextricable interconnections among humans, other animals, and the shared environment. COVID-19 has taught us that failing to recognize the relevance, complexity and dynamism of the socioecological systems of planet earth not only puts the world at risk of pandemics, but limits our ability to effectively counter them. One Health approaches are therefore urgently needed in all sectors at all levels!”
– Dr. John Amuasi, Kwame Nkrumah University of Science and Technology, Ghana
“This pandemic has pointed out, once again, that spread of viruses from animals in formerly isolated locales to human populations is increasingly likely as humans impinge on these environments. This report provides a One Health framework for thinking about, and responding to, these cross-over events, recognizing that people at all levels, ranging from local to international, must be involved to prevent future pandemics.”
– Dr. Stanley Perlman, University of Iowa, Iowa City, USA
“SARS-CoV-2 taught us that viruses do not respect borders, walls, demographics or politics; nor do they respect species barriers. Emerging/re-emerging RNA viruses (including coronaviruses) are a major cause of zoonoses leading to epidemics/pandemics that impact human, animal and ecosystem health. They spillover from animals to humans and spill back into animals to establish new host reservoirs of viral persistence and evolution. Our Perspective highlights One Health (animal-human-environment interconnections) strategies based on integrated cross-disciplinary, interagency, regional, national and global collaborations to survey, detect, research, respond to and stem zoonotic disease outbreaks, leading to measures to predict, prevent, mitigate and control future pandemics.”
- Dr. Linda J Saif, The Ohio State University, Wooster, USA
“SARS-CoV-2 is not the first virus that found its way from animals to humans, and will not be the last. A lot could have been learnt from SARS-CoV-1 already decades ago, a vírus that even belongs to the same species as SARS-CoV-2, or from MERS-CoV, yet, the world was not prepared for a coronavirus pandemic. The devastating impact on human health and on our societies due the COVID-19 pandemic should be the ultimate lesson that we need to invest more in preparedness, but also prevention of novel viral spillovers.”
– Dr. Isabella Eckerle, Geneva Centre for Emerging Viral Diseases, Switzerland
“Acceptance of the underlying epidemiological drivers of disease emergence, ‘smart’ surveillance, universal diagnostic and vaccine platforms, and a genuine One Health/One World approach are fundamental to mitigating and managing future global pandemics.”
- Dr. Hume Field, University of Queensland, Australia
List of Independent Task Force members (www.independentcovidtaskforce.org)
Dr. Gerald Keusch MD (Chair November 2021 – present) is Associate Director of the National Emerging Infectious Diseases Laboratories and a core faculty member of the Center for Emerging Infectious Disease Policy and Research at Boston University, Boston Massachusetts, U.S. His research has focused on pathogenesis and control of emerging bacterial, protozoal and viral diseases through collaborative basic laboratory, field and clinical research. He is the former Director of the Fogarty International Center of the U.S. National Institutes of Health and is a member of the U.S. National Academy of Medicine. Contact: Rachel Lapal [email protected]
Dr. John Amuasi MBChB Ph.D. is the head of Global Health at the School of Public Health, Kwame Nkrumah University of Science and Technology, and is Group Leader of the Global Health and Infectious Diseases Research Group at the Kumasi Centre for Collaborative Research in Tropical Medicine, Accra Ghana and the Bernhard Nocht Institute of Tropical Medicine, Hamburg, Germany. He has extensive experience in One Health approaches to emerging zoonotic diseases.
Dr. Danielle Anderson Ph.D. is a Research Scientist at the Victorian Infectious Diseases Reference Laboratory at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. She is a virologist investigating pathogenesis of high consequence emerging viruses. Contact: Aline Riche. Phone: +61 3 8344 1911; email: [email protected]
Dr. Peter Daszak Ph.D. (Chair July 2020 – November 2021) is the President of EcoHealth Alliance, New York, N.Y., in the U.S. He is a member of the U.S. National Academy of Medicine, and chairs its Forum on Microbial Threats. He is an expert in ecology, surveillance, and field research of emerging zoonotic viruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2. Contact: [email protected]
Dr. Isabella Eckerle MD is Associate professor, physician-scientist at the Centre for Emerging Viral Diseases at the University Hospitals of Geneva. She has led extensive clinical, epidemiological, and pathogenesis research on endemic coronaviruses, MERS-CoV, and SARS-CoV-2. Contact: [email protected] & [email protected]
Dr. Hume Field DVM Ph.D is Adjunct Professor in the School of Veterinary Science at the University of Queensland, Australia and a science and policy advisor to Ecohealth Alliance. He has made expertise in field studies and surveillancey of bat-origin emerging viruses such as Hendra, Nipah, SARS-CoV and SARS-CoV-2. Contact: [email protected]
Dr. Marion Koopmans DVM Ph.D. is Head of the Dept. of Viroscience, Erasmus Medical Center and Pandemic and Disaster Preparedness Center, Rotterdam, Netherlands. Her research focus is to understand the modes of transmission of viruses among animals and between animals and humans, explore the potential of next generation sequencing techniques and other types of data on drivers for emergence for outbreak prediction, detection and tracking. She is a member of the WHO-WOAH-FAO-UNEP One Health High Level Expert Panel, and a member of the Royal Dutch Academy of Sciences. Contact: [email protected]
Dr. Dato’ Sai Kit (Ken) Lam Ph.D. is Professor Emeritus at the University of Malaya, and Senior Fellow of the Malaysian Academy of Sciences. He is an expert in vector borne viral diseases such as dengue and a co-discoverer of Nipah virus in Malaysia, for which he has received the 2001 Prince Mahidol Award for Public Health in 2001 and the Merdeka Award for Outstanding Scholastic Achievement in 2013.
Dr. Carlos das Neves DVM Ph.D. Dipl.ECZM is the Director for Research and Internationalization at the Norwegian Veterinary Institute, Past President of the International Wildlife Disease Association, member of the IUCN SSC–Wildlife Health Specialist Group and Chair of the Wildlife Population Health Specialty at the European College of Zoological Medicine. He is an expert in zoonotic wildlife viral infections and One Health approaches to contain and control spillovers. We works also on the science to policy interface both in Norway and internationally. Contact: [email protected]
Dr. Malik Peiris Ph.D. FRS is the Professor of Virology at the School of Public Health, at the University of Hong Kong. His research focuses on the pathogenesis, innate immune responses, transmission, ecology and epidemiology of human and animal (poultry, swine, wild birds) influenza viruses, and emerging coronaviruses. Dr. Peiris was the first person to isolate SARS-CoV and is conducting active research on COVID-19.
Dr. Stanley Perlman MD Ph.D. is Professor of Microbiology and Immunology, Professor of Pediatrics, and University of Iowa Distinguished Chair, Iowa City Iowa in the U.S. He is a physician-scientist involved in studies of the pathogenesis of respiratory coronaviruses including SARS-CoV, MERS-CoV, and SARS-CoV-2.
Dr. Supaporn Wacharapluesadee Ph.D. is the Senior Research Scientist at the Emerging Infectious Diseases Clinical Center, King Chulalongkorn Memorial Hospital, Thai Red Cross Society and Chula School of Global Health, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Dr. Wachaeapluesadee’s team was the team leader for detecting the first MERS-CoV case in Thailand in 2015 and the first to positively identify a human COVID-19 infection outside of China.
Su Yadana, MPH. is a Research Scientist and Project Coordinator at EcoHealth Alliance in New York NY in the U.S., and a team member of the EcoHealth Alliance collaborative research network in Southeast Asia to study the spillover of viral pathogens from wildlife to humans. Her research interests focus on identifying risk factors for spillover of animal viruses to humans and development of evidence-based strategies to reduce these risks and improve population health. Contact: [email protected]
Dr. Linda J. Saif Ph.D. is Distinguished University Professor, Center for Food Animal Health, Departments of Animal Sciences (CFAES, OARDC) and Veterinary Preventive Medicine (CVM), Wooster Ohio, and Co-Director of the Viruses and Emerging Pathogens Program of the Infectious Diseases Institute, The Ohio State University, Columbus, Ohio, U.S.A. Her expertise is in virology, pathogenesis, immunology and epidemiology of animal coronaviruses resulting in consequential animal diseases and spillovers and spillbacks between animals and humans. She is a member of the U.S. National Academy of Sciences. Contact: Emily Caldwell, [email protected]
Sources:
Journal reference:
Keusch, G.T., et al. (2022) Pandemic origins and a One Health approach to preparedness and prevention: Solutions based on SARS-CoV-2 and other RNA viruses. PNAS. doi.org/10.1073/pnas.2202871119.
