An experimental “decoy” provided long-term protection from infection by the pandemic virus in mice, a new study finds.
Led by researchers at NYU Grossman School of Medicine, the work is based on how the virus that causes COVID-19, SARS-CoV-2, uses its spike protein to attach to a protein on the surface of the cells that line human lungs. Once attached to this cell surface protein, called angiotensin converting enzyme 2 (ACE2), the virus spike pulls the cell close, enabling the virus to enter the cell and hijack its machinery to make viral copies.
Earlier in the pandemic, pharmaceutical companies designed monoclonal antibodies to glom onto the spike and neutralize the virus. Treatment of patients soon after infection was successful in preventing hospitalization and death. However the virus rapidly evolved through random genetic changes (mutations) that altered the spike’s shape enough to evade even combinations of therapeutic monoclonal antibodies. Thus, such antibodies, which neutralized early variants, became about 300 times less effective against more recent delta and omicron variants.
Published online this week in the Proceedings of the National Academy of Sciences, the study describes an alternative approach from which the virus cannot escape. It employs a version of ACE2, the surface protein to which the virus attaches, which, unlike the natural, cell-bound version, is untethered from the cell surface. The free-floating “decoy” binds to the virus by its spikes so that it can no longer attach to ACE2 on cells in airways. Unlike the monoclonal antibodies, which are shaped to interfere with a certain spike shape, the decoy mimics the spike’s main target, and the virus cannot easily evolve away from binding to ACE2 and still invade cells.
Treatment with the decoy, either by injection or droplets in the nose, protected 100 percent of the study mice when they were infected in the lab with an otherwise lethal dose of SARS-CoV-2. The decoy lowered the virus load in the mice by 100,000-fold, while mice exposed to a non-active control treatment died. Decoy treatment of mice that were already infected with SARS-CoV-2 caused a rapid drop in viral levels and return to health. This suggests that the decoy could be effective as a therapy post-infection, similar to monoclonal antibodies, the researchers say.
What is remarkable about our study is that we delivered the decoy using a harmless, adeno-associated virus or AAV vector, a type of gene therapy that has been found in previous studies to be safe for use in humans. The viral vector instructs cells in the body to produce the decoy so that the mouse or person is protected long-term, without the need for continual treatment.”
Nathanial Landau, PhD, senior study author, professor, Department of Microbiology at NYU Langone Health
Administered with the vector, says Landau, the treatment caused cells, not only to make the decoy, but to continue making it for several months, and potentially for years.
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Importantly,vaccines traditionally include harmless parts of a virus they are meant to protect against, which trigger a protective immune response should a person later be exposed. Vaccines are less effective, however, if a person’s immune system has been compromised, by diseases like cancer or in transplant patients treated with drugs that suppress the immune response to vaccination. Decoy approaches could be very valuable for immunocompromised patients globally, adds Landau.
Future pandemics
For the new study, the research team made key changes to a free ACE2 receptor molecule, and then fused the spike-binding part of it to the tail end of an antibody with the goal of strengthening its antiviral effect. Attaching ACE2 to the antibody fragment to form what the team calls an “ACE2 microbody” increases the time that the molecule persists in tissues (its half-life). The combination also causes the molecules to form dimers, mirror-image molecular pairs that increase the strength with which the decoy attaches to the viral spike.
Whether administered via injection into muscle, or through droplets in the nasal cavity, the study’s AAV vectors provided mice with long-lasting protection COVID infection, including the current Omicron variants.
The approach promises to be effective even if another coronavirus, a type of virus common in birds and bats or apes, were to be transferred to humans in the future, an event termed “zoonosis.” As long as the future virus also uses ACE2 to target cells, the decoy would be ready for “off-the-shelf” soon after an outbreak. If the virus were to somehow switch its receptor a different protein on the surface of lung cells, the decoy could be modified to target the new virus, says Landau.
Along with Landau, the study authors were Takuya Tada and Julia Minnee in the Department of Microbiology at NYU Grossman School of Medicine. The study was supported by a grant from the National Institutes of Health.
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In a recent article published in the Lancet journal, researchers quantified the global bacterial antimicrobial resistance (AMR) burden to present deaths and disability-adjusted life-years (DALYs) attributable to and associated with 23 pathogens, 12 major infectious syndromes, 18 drug categories, and 88 pathogen–drug combinations.
They considered two counterfactual scenarios and used consistent methods to arrive at the study estimates as they had no clue of the extent to which susceptible or no infection would replace drug-resistant infections in a scenario when there was no drug resistance.
Bacterial AMR, an emerging public health threat, is making antibiotic use futile or less effective against many common bacterial diseases affecting animals and humans. A United Kingdom (UK) government-commissioned review of AMR stated that it could claim 10 million lives annually by 2050.
The World Health Organization (WHO) and numerous other researchers have also raised that AMR spread is a pressing issue that needs immediate attention; if left unaddressed, rising AMR will make several bacterial pathogens highly fatal in the near future. The challenge is to gather current data on pathogen–drug combinations contributing to actual bacterial AMR burden for all world regions, even those with minimal surveillance.
According to the authors, studies have only reported AMR-related data for specific regions and a limited number of pathogens and pathogen–drug combinations. For instance, the United States Centers for Disease Control and Prevention (US-CDC) published a report in 2019 on AMR-related deaths for 18 AMR-related threats using surveillance data.
Similarly, Cassini et al. estimated the burden of eight and 16 pathogens and pathogen–drug combinations, respectively, for the European region between 2007 and 2015. Despite the significant contributions made by these studies to the field of AMR, there is a lack of comprehensive global estimates covering all locations, all pathogens, and all pathogen–drug combinations contributing to the rising burden of bacterial AMR.
Key Takeaways
First comprehensive assessment of the global burden of antimicrobial resistance (AMR) for bacterial infections.
Estimated 4.95 million deaths associated with bacterial AMR in 2019, including 1.27 million deaths attributable to bacterial AMR.
Lower respiratory infections accounted for the most deaths associated with resistance in 2019.
Six leading pathogens for deaths associated with resistance.
One pathogen-drug combination, meticillin-resistant S aureus, caused more than 100,000 deaths attributable to AMR in 2019.
Burden of AMR is highest in low-resource settings, particularly in western sub-Saharan Africa.
Serious data gaps in many low-income settings
About the study
In the present study, researchers used predictive statistical modeling to generate global estimates of bacterial AMR burden for all world locations, covering 204 countries for which they used all available data from the Global Burden of Diseases (GBD), Injuries, and Risk Factors study. The GBD study collated age- and gender-specific estimates for 369 injuries and illnesses in 204 nations and territories between 1990 and 2019.
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They retrieved data from published scientific literature, multisite research collaborations, clinical trials, research institutes based in low-income and middle-income countries (LMICs), public and private hospital records, diagnostic testing data, surveillance systems of pharmaceutical companies, global, national, and enhanced surveillance systems, and other relevant sources, encompassing 471 million (MN) patient records or isolates and 7,585 study-location years, which they gathered using varied strategies and used for study estimations.
The researchers modeled deaths and DALYs for 204 countries and territories to present cumulative estimates of AMR burden globally and for 21 GBD regions, including seven GBD super-regions.
For the first counterfactual scenario, where susceptible infections substituted all drug-resistant infections, they estimated only deaths and DALYs directly due to AMR. For the second counterfactual scenario, where no infection substituted all drug-resistant infections, they estimated all deaths and DALYs related to resistant infections. Both estimates had different utilities; however, both could inform the development of intermediation strategies to regulate AMR spread.
The study approach comprised ten estimation steps within five all-encompassing modeling components, each with varied data requirements; consequently, input data for each modeling component also varied.
Study findings
Substituting drug-resistant infections by no infections (first counterfactual scenario) and susceptible infections (second counterfactual scenario) would have saved 4.95MN and 1.27MN deaths, respectively, in 2019, implying that in 2019, the global AMR burden related to drug-resistant infections for 88 pathogen–drug combinations was ~4.95MN deaths (95% UI), of which drug resistance alone caused 1.27MN deaths. Moreover, after ischaemic heart disease and stroke, AMR accounted for most deaths in 2019.
Additionally, the study analysis revealed that AMR-related all-age death rates were highest in some LMICs, as opposed to the common notion that the burden of bacterial AMR would be higher in high-resource settings with higher antibiotic consumption. Indeed, AMR is emerging as a more serious problem for some of the world’s poorest countries. The authors noted the highest AMR-related death rates in sub-Saharan Africa and South Asia as a function of the prevalence of resistance and critical lower respiratory, bloodstream, and intra-abdominal infections, in these regions.
The study also highlighted that in LMICs, there are other drivers of the higher AMR burden, like a scarcity of laboratory infrastructure for microbiological testing needed to narrow antibiotic use or make it more targeted. Among other factors, counterfeit antibiotics, poor sanitation and hygiene, poor regulations on antibiotics use, etc., also drive resistance.
Further, the researchers identified six pathogens, E. coli, K. pneumoniae, S. pneumoniae, A. baumannii, S. aureus, and P. aeruginosa, who contributed most to the burden of AMR in 2019; they accounted for 73.4% (95% uncertainty interval) of deaths attributable to bacterial AMR. WHO has recognized all six as priority pathogens; however, except S. pneumoniae, targeted primarily through pneumococcal vaccination, none is the focus of global health intervention programs.
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Seven pathogen–drug combinations caused more than 50000 deaths, highlighting the need for expanding infection prevention and control (IPC) policies targeting the deadliest combinations, bolstering vaccine and antibiotic development, and improving access to essential second-line antibiotics where needed. Furthermore, resistance to β-lactam antibiotics, e.g., penicillins and cephalosporins, and fluoroquinolones accounted for >70% of deaths attributable to AMR across pathogens. These antibiotics are the first line of empirical treatment for severe infections.
In 2017, the WHO published a priority list to inform research priorities related to new antibiotics for pathogens with multidrug resistance that caused deadly infections. However, this list covered only five of the seven pathogen–drug combinations estimated to have caused the most deaths in 2019; for instance, this list did not feature fluoroquinolone-resistant E. coli and meticillin-resistant S. aureus only as a “high” but not a “critical” priority.
Per study estimates, the magnitude of bacterial AMR as a global public health issue is as much as human immunodeficiency virus (HIV) and malaria, perhaps, much higher. Additionally, the AMR pattern varied with geographical location, pathogens, and pathogen–drug combinations. Thus, the regional estimates made in this study could help tailor local responses as the ‘One Size Fits All’ approach might not be appropriate.
Despite concerted data collection efforts, high-quality data on AMR was sparsely available for many LMICs. Nevertheless, an improved scientific understanding of this rapidly emerging health threat should be the highest priority for global health policymakers.
Conclusions
The present study used major methodological innovations, two varying AMR counterfactual scenarios, and comprehensive data to fetch novel insights into the global AMR burden. Most importantly, it incorporated models tested and iterated over years during GBD study analysis. So, when used collectively, these models provided a complete estimate of AMR burden with robust geographical coverage.
Further, the researchers compared findings with other causes of death, offering much-needed context on the scale of the burden of this rapidly growing public health problem. The study analysis confirmed that bacterial AMR posed the biggest threat to human health in sub-Saharan Africa and South Asia, involved a diverse set of pathogens, and is exceptionally high for multiple essential antibiotic classes, including β-lactams and fluoroquinolones.
Furthermore, efforts to build and enhance laboratory infrastructure and bolster national & global AMR plans of action are essential to addressing the universal AMR burden. Future studies should also evaluate the indirect effects of AMR, such as its effect on the prophylaxis of infections in organ transplant recipients.
In the future, the study estimates could inform treatment guidelines against many predominant bacterial pathogens for a given infectious syndrome, which, along with estimates of pathogen–drug burden, could inform their treatment guidelines customized for a specific location.
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The National Institute of Allergy and Infectious Diseases awarded an up to $16 million contract to Tulane University to bring to phase one clinical trial a nasal spray vaccine university researchers invented to thwart antibiotic-resistant Klebsiella pneumoniae, a leading cause of pneumonia.
Antibiotic-resistant bacteria are on the rise and are a significant cause of infections requiring hospitalization among children and the elderly. As doctors try to find new types of antibiotics to fight these so-called superbugs, Tulane University School of Medicine researchers Elizabeth Norton, PhD, and Jay Kolls, MD, inventors of the vaccine, are working to protect people before they are exposed to the pathogens in the first place.
“Multidrug-resistant bacteria are causing more severe infections and are a growing public health threat. Vaccines targeting these pathogens represent the most cost-effective option, particularly if you can use this vaccine to prevent or treat the infection in high-risk individuals,” said Norton, principal investigator and associate professor of microbiology and immunology. “Right now, there is no vaccine on the market that targets this type of pneumonia.”
Klebsiella pneumoniae is the third leading cause of hospital-acquired pneumonia and the second leading cause of bloodstream infections with the highest incidence of serious infections. It is also a major cause of childhood pneumonia in parts of Asia. The Tulane vaccine would target high-risk populations such as immunocompromised individuals, diabetics or organ transplant recipients.
Norton said that while the vaccine targets the Klebsiella bacteria, its unique design gives it the potential to be cross-reactive to other members of the Enterobacteriaceae family, the antibiotic-resistant bacterial species behind many hospital-acquired infections, including E. coli.
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The vaccine, called CladeVax, is designed to efficiently target mucosa in the nose, throat and lungs to protect the area most at risk for infection.
The nasal spray vaccine uses an adjuvant -; a compound that stimulates the immune system -; named LTA1 that Norton developed at Tulane. That adjuvant, which is made using a protein derived from the E. coli bacteria, will be combined with a series of proprietary antigens identified by the Kolls lab that include outer membrane proteins from the target bacteria.
This is an entirely novel vaccine platform, from the use of the adjuvant to the needle-less route of administration. This represents an entirely new class of vaccines for bacteria that elicits protection in two ways -; both antibody and T-cell immunity. All current pneumonia vaccines only elicit antibodies against surface carbohydrates. Our platform has the potential advantage of providing a much broader protection against pneumonia.”
Jay Kolls, co-principal investigator, and the John W. Deming Endowed Chair in Internal Medicine
Tulane researchers will first test vaccine formulations in animal models and nonhuman primates for dosing and safety before advancing to clinical trials. The project will include collaborators at Tulane National Primate Research Center, the School of Public Health and Tropical Medicine, Tulane Clinical Translational Unit, and the University of North Carolina as well as contractors for GMP manufacturing.
“If this succeeds, we will have another arsenal for the growing number of antibiotic resistant sources of pneumonia or bloodstream infections,” Norton said. “And we can hopefully expand this nasal spray delivery platform to other infections, working on a single, combination vaccine that is needle-less and targets several organisms at once.”
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 LeadersDr. Tomislav MeštrovićAffiliate Associate ProfessorUniversity of WashingtonAs part of World Antimicrobial Resistance Week 2022, News-Medical speaks to Dr. Tomislav Meštrović about his new research discussing the burden of bacterial antimicrobial resistance in the WHO European region, as well as about how we can prevent antimicrobial resistance together.
Please can you introduce yourself and tell us about your background and interest in antimicrobial resistance (AMR)?
Before participating in the research on the global burden of antimicrobial resistance (AMR), as a medical doctor, clinical microbiologist, and biomedical scientist, I was a part of relevant research endeavors on antibiotic resistance in my home country Croatia – such as a nationwide study on extended-spectrum beta-lactamases and plasmid diversity in urinary Escherichia coli isolates, as well as describing the emergence of multidrug-resistant Proteus mirabilis in long-term care facilities.
Since my Ph.D. thesis was on addressing AMR in the most common sexually transmitted bacterial agent, Chlamydia trachomatis, I was also a part of the team that aimed to standardize the method for laboratory susceptibility testing of chlamydiae by using both special cell culture and direct molecular-based monitoring, which was published in one methodological textbook.
Therefore, I would say AMR in different microorganisms was always my passion – from the diagnostic standpoint and the therapeutic one. More specifically, I was also involved in certain aspects of drug research, such as proposing a novel dual antagonist to prevent and treat urinary Escherichia coli infections and the usage of liposomal encapsulation to increase the efficacy of azithromycin against Chlamydia trachomatis. The latter technology gained a lot of prominence when liposome-based mRNA COVID-19 vaccines entered the market, so it is no wonder that we tried to capitalize on the positive aspects of such an approach.
Regarding my other professional positions, I am also a Secretary General of the Croatian Society for Clinical Microbiology, Executive Committee Member of the ESCMID study group for Mycoplasma and Chlamydia Infections, and External Affairs Committee Member of the Society for Healthcare Epidemiology of America (SHEA). I have several leadership roles in the American Society for Microbiology (ASM), where I organized conference sessions on antibiotic resistance, such as the Track Hub Session for ASM Microbe, “The global scenario of antimicrobial resistance: do developing and developed countries share the same threats?”. Finally, I am very invested in science communication. As one of the writers for News-Medical, I have written several pieces on the topic of antimicrobial resistance and many other topics.
AMR is a threat to not only humans but also animals, plants, and the environment. Can you tell us more about what exactly AMR is?
Antimicrobial resistance (AMR) is regarded as one of the predominant and most salient public health issues of the 21st century, as it threatens the effective treatment and prevention of an ever-growing range of infections caused by bacteria, viruses, fungi, and parasites. In other words, these groups of microorganisms are no longer susceptible to the common medical agents used to treat them, and the issue is particularly serious and urgent in bacteria. This is an evolving issue that took place over several decades, resulting in frequent pathogenic bacteria harboring some type of resistance to each new antibiotic coming to the market. This means there is an urgent call for action to avoid a global crisis in health care when we can lose the ability to perform surgeries and other types of quotidian medical procedures.
In an attempt to define AMR, we can say that this is a natural phenomenon arising when microorganisms are exposed to antimicrobials or antibiotics. Under such selective pressure, susceptible bacteria are inhibited or killed, whereas those that are naturally (or intrinsically) resistant or those with antibiotic-resistant traits have a much greater chance of surviving and multiplying. The issue arises not only as a result of the overuse of antimicrobial agents but also when they are used inappropriately (such as inadequate drug choices, faulty dosing regimens, and/or low compliance to relevant treatment guidelines). All of this can have a compounding effect and contribute to the rise of antibiotic resistance.
During the last few years, the importance of animal reservoirs and the environment in spreading AMR has been widely recognized. In the past several decades, we have witnessed an increased awareness of the potential problems that resistance among food-producing animals could have on human health. In addition, the soil is regarded as a reservoir of AMR genes since most antibiotics are derived from soil microorganisms that are intrinsically resistant to the antibiotics produced. Finally, water potentially contaminated with organic fertilizers and fecal microorganisms may disseminate resistant bacteria in the soil and is considered a principal way of bacterial propagation between various environmental compartments.
Given the dangers of AMR and the slogan of World Antimicrobial Awareness Week – ‘Antimicrobials: Handle with Care,’ why is it crucial to handle antimicrobials with care?
Judicious and careful use of antimicrobial agents is one of the pillars of successfully diminishing the threat of AMR. In the clinical milieu, there is an important concept of antimicrobial stewardship that refers to a set of coordinated strategies for improving patient care and outcomes by instituting optimal therapy, minimizing collateral damage by reducing antimicrobial usage (which translates to lower resistance rates), and lowering the price of antimicrobials. This concept is also amenable to global implementation to help control AMR by increasing awareness of the public and educating healthcare professionals on the prudent use of antimicrobials.
In the hospital setting, antimicrobial stewardship programs and infection control measures are of utmost importance to prevent the emergence and transmission of antibiotic-resistance microorganisms and preserve the effectiveness of currently available antimicrobial drugs. Hence, multidisciplinary teams of experts (such as infectious disease specialists, medical microbiologists, and clinical pharmacists) participate in such endeavors. Moreover, as the ongoing COVID-19 pandemic can lead to the increased indiscriminate usage of antimicrobials (which was particularly the case in the early days of SARS-CoV-2 spread), handling antibiotics with care can result in lower bacterial resistance and, subsequently, a lower death toll.
Nevertheless, the antimicrobial stewardship concept has to be extended to family doctors in the community, where there is often a very high consumption of antibiotics. Relevant public health actions that are needed to reduce inappropriate antimicrobial prescriptions and antibiotic misuse should consider adequate information campaigns for the consumers, training of healthcare professionals, enhanced diagnostics to improve treatment decisions, the development of treatment guidelines, as well as regular prescription audits. In a nutshell, different healthcare organizations should strive to make coordinated efforts to institute new policies and put more emphasis on antimicrobial stewardship in professional curricula.
Image Credit: dturphoto/Shutterstock
You recently published research concerning the burden of bacterial antimicrobial resistance in the WHO European region. Can you tell us more about this study and the results you identified?
To our knowledge, this new study brings the most comprehensive analysis of the AMR burden in the WHO European region, and our estimates span across 53 countries, 23 bacterial pathogens, and 88 pathogen–drug combinations in 2019. There are several advances in comparison to previous work on this topic, primarily in scope (as not only the European Union is included, but all countries of the WHO European region), as well as in the number of included pathogen-drug combinations.
Furthermore, we used major methodological innovations that were first identified in the 2019 global burden of bacterial AMR study. The magnitude of the problem was described with the use of two scenarios, which means we provided estimates for both deaths directly caused by AMR (attributable mortality) and deaths that occurred from a drug-resistant infection, but for which AMR may or may not have been the cause (associated mortality).
Finally, our study allows comparisons with other causes of death since it builds on estimates of disease incidence, prevalence, and mortality from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019.
And results were striking. By identifying more than half a million deaths associated with AMR and more than 130 thousand deaths attributable to AMR, we have shown that antibiotic resistance is a considerable and potentially neglected problem in the WHO European region as a whole, with evident differences between subregions and specific countries. The largest fatal burden of AMR in the region came from bloodstream infections, followed by intra-abdominal infections and respiratory infections. The leading pathogens that we identified were (in descending order of death) Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterococcus faecium.
Such estimates of the impact of AMR on morbidity and mortality are crucial for informing public health investment decisions for each country in this region. Furthermore, highlighting specific pathogens and pathogen–drug combinations with the highest estimated burden – which we showed were methicillin-resistant Staphylococcus aureus (MRSA) and aminopenicillin-resistant Escherichia coli – might specifically inform policy targets and policy design. Our results emphasize that the most effective way to address AMR in this region will necessitate targeted efforts and investments, together with continuous outcome-based research endeavors.
Study: fizkes/Shutterstock
What do you believe are some of the challenges with approximating the magnitude of the AMR crisis and its downstream effect on human health?
There are indeed many challenges with this type of complex estimation process, and the biggest one is definitely data scarcity, as the availability of data on AMR can differ from one country to the next. This is not the only problem with our study but is universal for all research projects that aim to assess the burden of AMR. We also acknowledge that the effect of resistance on mortality may differ across locations, which can be pertinent when we pursue a global estimation of the AMR crisis.
More specifically, certain locations might not be well-suited to treat susceptible infections, which means that the effect of resistance is minimized; conversely, other locations might not have access to second-line antimicrobials; thus, the effect of resistance is magnified. It is also possible that the relative risk of death attributable to resistance can be different across anatomical sites of infection due to variable antibiotic penetrance.
Moreover, countries with low socio-demographic index (which is a summary measure that combines information on the education, economy, and fertility rate) might have much less stringent surveillance systems, as well as insufficient laboratory support – potentially resulting in an underestimation of attributable and associated AMR mortality globally and the countries of the WHO European Region. Nonetheless, our estimates are informed by data from all countries included in the study. When data for a specific country were lacking, estimates and model building relied on regional patterns, co-variates, and out-of-sample predictive validity.
Despite these limitations, our analysis reflects the widest and presently best available range of data, as well as the use of models that have been developed and implemented specifically for incorporating disparate data sources for the Global Burden of Disease analysis. We are in agreement with other studies that highlight and underscore critical data gaps on resistant organisms in certain parts of the world; therefore, solving this problem which will be extremely important in the future to fine-tune our estimates additionally.
WHO: What is antimicrobial resistance (AMR)?
The specific theme of World Antimicrobial Awareness Week (WAAW) 2022 is ‘Preventing antimicrobial resistance together.’ What does this theme mean to you personally, and how do you believe we can take steps toward this goal?
It is without any doubt that manifold joint efforts from healthcare workers (acting as prescribers) and patients to policymakers and international regulators are necessary to stand a chance against the global spread of antibiotic resistance. In other words, different stakeholders have to join forces in order to tackle this issue from many angles, as no single action will provide an acceptable solution in isolation.
Also, this issue is a truly global problem. Together with rational and prudent usage of currently available antimicrobial drugs and the introduction of antibiotics where there is a lack of them, the development of new and effective compounds, as well as the introduction of new diagnostic approaches, are all recognized as urgent priorities.
Governments should introduce several essential processes to inspire change by all stakeholders related to AMR, as appropriately described within the WHO policy package for combating drug resistance. More specifically, this policy package refers to a national plan that strives to be comprehensive, engages civil societies, and insists on the accountability of everyone involved. Also, strengthened surveillance systems, improved laboratory capacity, wide access to essential medicines of sufficient quality, regulated use of antibiotics, the emphasis on infection prevention and control, as well as promotion of innovations will be crucial in the near future. There has to be a commitment to a rather high level of human health protection.
How do you believe that different sectors, for example, healthcare, animal care, farming, and agriculture, can work collaboratively to help curb AMR?
Our quest against AMR should be addressed through the lens of a One Health approach. This means more stringent infection prevention/control in healthcare facilities, food industry premises, and farms, as well as insisting on best practices in agriculture, clean water, sanitation and waste management. A set of diverse but coordinated strategies against antibiotic resistance should be implemented, taking into account the type of pathogen (either human or zoonotic), the setting (healthcare or the community) and possibly other specific factors contributing to the emergence of resistance.
In veterinary medicine, the required interventions consist in enforcing regulations for improved surveillance and monitoring, governing the use of antimicrobials in food-producing animals, and decreasing the need for antibiotics through improved animal husbandry. Naturally, more research is needed to elucidate the exact pathways of transmission of resistant microbial agents between animals and humans (but also their subsequent impact). There is a need to adequately implement legislation if we are to achieve long-lasting effects.
In addition, innovative approaches are needed for the development of new antibiotics and other products to limit AMR. There is a shortage of new antibiotics in the pipeline and few incentives for the industry to invest in research and development in this field. Research into digital technologies and eHealth solutions has to be strengthened to improve prescription practices, care solutions, and overall awareness of this issue. All of this necessitates a well-designed roadmap to orchestrate further collaboration efforts between governments, industry, and non-governmental organizations.
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What are the next steps for you and your research? Do you have any exciting projects coming up?
The Global Research on AntiMicrobial resistance (GRAM) Project will definitely continue to be one of the most important global projects in years to come. Assessing the burden of bacterial antimicrobial resistance in the WHO European region in 2019 was our first regional endeavor, which will be followed by research publications covering other regions of the world. We believe it is of utmost importance to obtain a full picture of this pressing issue not only on a global but also on a regional and country level. In the future, one of the goals is to pursue a time-series analysis of the AMR burden through the years, which will be helpful in forecasting, preparedness planning, and key policy decisions.
Furthermore, we have already mentioned how the animal and environmental sectors present a plethora of opportunities for resistance to evolve and be introduced into human populations. Therefore, we believe it will be important to assess data gaps and links between animal and human resistance in one of our future projects. Our goal is also to assess significant indirect effects of AMR, such as the effect of AMR on antibiotic prophylaxis in transplant recipients or for the prevention of surgical site infections. One of the salient goals is to assess AMR in the context of health equity, particularly considering the results from the paper on the global burden of AMR.
Finally, there is a need to prioritize the improved collection of high-quality AMR data in both the human and animal sectors, as well as the environment, in order to improve all our future estimation processes. One of our goals is to facilitate data and resource sharing between countries to improve policy-making and capacity building. Finally, continuously broadening both the quantity and quality of data acquisition worldwide will allow us to monitor levels of resistance much more effectively and course-correct action where needed. We are confident that our data-driven approach will result in even more stringent estimates and help in tackling this enormous challenge.
Dr. Tomislav Meštrović is an Associate Professor at the University North in Croatia and an Affiliate Associate Professor at the Institute for Health Metrics and Evaluation (IHME) and the Department of Health Metrics Sciences of the University of Washington. He finished his medical and doctoral training at the University of Zagreb School of Medicine (Croatia), his MPH at the London School of Hygiene and Tropical medicine of the University of London (United Kingdom), and his MBA in International Healthcare Management at the Frankfurt School of Finance & Management (Germany). He is a board-certified clinical microbiology and sexual medicine specialist, with an additional one-year training in clinical research from Harvard Medical School.
His primary research interest with IHME is the public health significance and impact of antimicrobial resistance (AMR) within the Global Burden of Antimicrobial Resistance (GRAM) project, working in the AMR research team led by Professor Mohsen Naghavi. He joined this group as a Fulbright Visiting Scholar during the academic year 2021/2022, and was a lead author on the comprehensive assessment of AMR burden in the WHO European Region. Alongside his ongoing work in antibiotic resistance, he participates in other IHME-led and GBD-related projects, providing expertise for many pivotal global and public health research questions (particularly those in relation to infectious diseases). He is also a member of the WHO/HIFA Working Group Member on Learning for Quality Health Services, which is a part of the WHO Global Learning Laboratory (GLL) for Quality Universal Health Coverage (UHC).
IHME was established at the University of Washington in Seattle in 2007. Its mission is to deliver to the world timely, relevant, and scientifically valid evidence to improve health policy and practice.
Rutgers scientists have developed a new approach to stopping viral infections: a so-called live-attenuated, replication-defective DNA virus vaccine that uses a compound known as centanamycin to generate an altered virus for vaccine development.
The method was tested to produce a weakened or “attenuated” version of a mouse cytomegalovirus, a common virus, that has been altered so it can’t reproduce or replicate inside the cell. A replication-defective DNA virus is incapable of replicating its genome, its essential genetic matter. As a result, it is unable to produce an infectious progeny virus in infected cells, and thus restricted primarily to the site of inoculation.
When the weakened viral particles are injected into animals, the researchers said, they stimulate a specific host’s immune system to recognize the invading live virus particles as foreign, causing the virus to be eliminated whenever it is detected.
The new approach, published in Cell Reports Methods, has been shown to effectively shut down viral infections in lab animals.
We have found that this method is safe; the attenuated virus infects certain cells without proliferating beyond that, and alerts the host to produce specific neutralizing antibodies against it. We see this as a novel method that we hope will accelerate vaccine development for many untreated viral infections in humans and animals.”
Dabbu Jaijyan, Researcher, Department of Microbiology, Rutgers New Jersey Medical School and Study Author
The method is called a live-attenuated DNA virus vaccine because it specifically targets DNA viruses – viruses such as cytomegalovirus, chicken pox and herpes simplex that reproduce by making copies of their DNA molecules – and uses an altered DNA virus to fight against them. Developing a method that can quickly and easily generate replication-defective live-attenuated viruses, the researchers said, will accelerate vaccine development for diseases caused by DNA viruses.
The researchers have shown that the method is effective in mice against several DNA viruses, including human cytomegalovirus, mouse cytomegalovirus and herpes simplex virus 1 and 2.
“One of the major advantages of our technology is the safety offered by the robust inhibition of virus replication and that no progeny viruses are produced,” Jaijyan said. “Our technology can be easily applied to any DNA virus to generate live-attenuated replication defective viruses for vaccine development.”
Not all viruses replicate this way. The COVID-19 virus, SARS-CoV-2, for example, is known as an RNA virus because it produces new copies of itself through its RNA. Vaccines against COVID take advantage of that. RNA, which is short for ribonucleic acid, is used to build proteins in SARS-CoV-2.
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The DNA virus vaccine method works specifically with DNA viruses because the researchers treat the cytomegalovirus particles destined for use in the vaccine with centanamycin. The compound is known as a DNA-binder because it latches onto organisms’ DNA, including that of DNA viruses, blocking reproduction.
The team is looking to eventually test the method in humans, with the goal to treat cytomegalovirus and other DNA-virus infections.
Cytomegalovirus is a common virus for people of all ages, according to the U.S. Centers for Disease Control and Prevention (CDC). A healthy person’s immune system usually keeps the virus from causing illness. However, infection with cytomegalovirus can have severe consequences in immunocompromised and organ transplant patients. Congenital infection also is the leading cause of birth defects in newborns.
The virus is spread through body fluids, including blood, saliva, urine, semen and breast milk. According to the CDC and World Health Organization, approximately 50 percent of adults around the world have been infected with cytomegalovirus. One in three children is infected with the virus in the U.S. by the age of five.
For the experiment, the researchers grew samples of cytomegalovirus in their lab, purified them, then bathed them in centanamycin. Once injected into lab mice, the weakened virus infects cells but didn’t spread. Over time, the mouse immune system produced sufficient antibodies to shut down the virus and eliminate the infection.
An analysis confirmed that the treated viral cells were not toxic to other cells in the mouse body.
The researchers are continuing to test the method in other medically important viruses, including guinea pig cytomegalovirus as a model to test vaccine efficacy in guinea pigs, with the intention of moving to clinical trials to test the method’s effectiveness in humans.
Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number U01HL150852. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Hua Zhu, an associate professor in the Department of Microbiology at New Jersey Medical School was also on the study. Other scientists on the study included Moses Lee, a professor in the Department of Chemistry at Georgia State University in Atlanta, and Kavitha Govindasamy, a teaching assistant professor at the New Jersey Center for Science, Technology and Mathematics at Kean University in Union, N.J.
Jaijyan, D.K., et al. (2022) A chemical method for generating live-attenuated, replication-defective DNA viruses for vaccine development. Cell Reports Methods.doi.org/10.1016/j.crmeth.2022.100287.
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.”
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.
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Metrics Sciences of the University of Washington. He finished his medical and doctoral training at the University of Zagreb School of Medicine (Croatia), his MPH at the London School of Hygiene and Tropical medicine of the University of London (United Kingdom), and his MBA in International Healthcare Management at the Frankfurt School of Finance & Management (Germany). He is a board-certified clinical microbiology and sexual medicine specialist, with an additional one-year training in clinical research from Harvard Medical School.
