Publisher Health

COVID-19 therapies made from antibodies often are given to patients who are at high risk of severe illness and hospitalization. However, there have been nagging questions about whether such antibody therapies retain their effectiveness as worrisome new virus variants arise.
New research at Washington University School of Medicine in St. Louis suggests that many, but not all, therapies made from combinations of two antibodies are effective against a wide range of variants of the virus. Further, combination therapies appear to prevent the emergence of drug resistance.
The study, in mice and hamsters, tested all single and combination antibody-based therapies authorized for emergency use by the Food and Drug Administration (FDA), or that are being evaluated in late-stage clinical trials, against a panel of emerging international and U.S. variants of SARS-CoV-2, the virus that causes COVID-19.
The findings, published June 21 in the journal Nature, suggest that COVID-19 drugs made of two antibodies often retain potency as a therapy against variants even when in vitro studies — experiments conducted in a dish — indicate that one of the two antibodies has lost some or all ability to neutralize the variant.
“We knew how these antibodies were behaving in vitro, but we don’t give people drugs based solely on cell culture data,” said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. “When we looked in animals, there were some surprises. Some of the combinations performed better than we thought they would, based on in vitro data. And there was no drug resistance to combinations whatsoever, across all of the different variants. We’re going to have to continue to monitor the effectiveness of antibody therapy as more variants arise, but combination therapy is likely needed for treating infections with this virus as more variants emerge.”
So-called monoclonal antibodies mimic those generated by the body to fight off the virus that causes COVID-19. Administration of antibody therapies bypasses the body’s slower and sometimes less effective process of making its own antibodies. At the time this study began, there were two dual-antibody combination therapies and a single antibody therapy authorized by the FDA for emergency use. The FDA withdrew authorization for the single antibody therapy, bamlanivimab, in April on the grounds that it was not effective against the variants circulating at that time. In May, the FDA authorized the single antibody sotrovimab as a treatment for COVID-19.

All coronaviruses produce four primary structural proteins and multiple nonstructural proteins. However, the majority of antibody-based SARS-CoV-2 research has focused on the spike and nucleocapsid proteins. A study published in PLOS Biology by Anna Heffron, Irene Ong and colleagues at the University of Wisconsin-Madison, USA, suggests that immune responses may develop against other proteins produced by the SARS-CoV-2 virus.
The efficacy of spike protein-based vaccines is variable and not everyone infected with SARS-CoV-2 produces detectable antibodies against the spike or nucleocapsid proteins. Therefore, expanded antibody-based options have the potential to play an important role in improving vaccines, diagnostics, and therapeutics, particularly given the emergence of new variants. To investigate whether SARS-CoV-2 infection induces robust antibody responses against all SARS-CoV-2 proteins, researchers mapped 79 “epitopes” — specific regions of the viral proteome that antibodies recognize and bind to. They also tested whether antibodies that develop in response to SARS-CoV-2 or existing antibodies from previous exposures to coronaviruses might bind to any of the proteins in the six other known human coronaviruses to identify potential cross-reactive epitopes.
In addition to spike and nucleocapsid proteins, the authors located previously unknown, highly reactive B cell epitopes throughout the full array of proteins in SARS-CoV-2 and other coronaviruses, expanding the potential for future vaccine and therapeutic development. Future research is needed, however, to determine how long these antibodies remain and whether responses of vaccinated individuals differ from those who contracted COVID-19 prior to vaccination. Dr. Ong and colleagues will continue to investigate these aspects in adults and children.
Although the authors did not directly profile variants of concern that have emerged since the beginning of the COVID-19 pandemic, a comparison of the original SARS-CoV-2 genome with a few of the variants of concern identified numerous variations in regions that are at or within 3 amino acids of identified antibody binding epitopes.
According to the authors, “Our extensive profiling of epitope-level resolution antibody reactivity in COVID-19 convalescent subjects, confirmed by independent assays, provides new epitopes that could serve as important targets in the development of improved diagnostics, vaccines, and therapeutics against SARS-CoV-2, variants of concern, and dangerous human coronaviruses that may emerge in the future.”
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Materials provided by PLOS. Note: Content may be edited for style and length.

In a new study published today in the American Journal of Human Genetics, researchers announced the development of a new method to increase the utility and equity of large genetic databases. The research was conducted by Audrey Hendricks, an associate professor of statistics at the University of Colorado Denver (CU Denver).
Summix, the new method developed by Hendricks and her team of CU Denver undergraduate and graduate students, estimates the genetic ancestry in databases and adjusts the information to match the ancestry of a person or sample of people. This method leads large genetic databases to become more useful for people of various ancestries such as African American or Latinx, as they are underrepresented in genetic databases and studies. Hendricks compares this method to translating a book from English to another language.
“Think of DNA as the words of our body,” says Hendricks. “All of the words of our body make the instruction book that makes each of us up. Right now, it’s like the DNA books are only written in English so the information in the library is not as useful for people who don’t speak English. We’re working to create books in the library that are more universal.”
According to Hendricks, individuals and samples from understudied populations, such as African American and Latnix, are the most likely to lack large public resources with precisely matched ancestry data. As a result, researchers working with those populations often resort to the closest, but still poorly matched ancestral group. This leads to biased results in the very populations where high-quality research is needed the most.
The team showed the effectiveness of Summix in over 5,000 simulation scenarios and in the widely used Genome Aggregation Database (gnomAD), a publicly available genetic resource. They found Summix’s estimates of ancestry proportions to be highly accurate (within 0.001%) and the ancestry-adjusted genetic information to be less biased. The Summix method is available in open access software increasing the utility of the method and its applications.
“Most people are a combination of multiple continental (e.g. African and European) or finer scale (e.g. Italian and German) ancestries,” said Hendricks. “As healthcare moves forward with precision medicine, matching the unique ancestral make-up of each person will become increasingly important. The ability of Summix to update a genetic resource to match the ancestry of an individual is an important step in this direction and helps to increase the utility and equity of genetic summary data.”
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Materials provided by University of Colorado Denver. Original written by Meghan Azralon. Note: Content may be edited for style and length.

Every day, our bodies face a bombardment of UV rays, ozone, cigarette smoke, industrial chemicals and other hazards.
This exposure can lead to free-radical production in our bodies, which damages our DNA and tissues. A new study from West Virginia University researcher Eric E. Kelley — in collaboration with the University of Minnesota — suggests that unrepaired DNA damage can increase the speed of aging.
The study appears in the journal Nature.
Kelley and his team created genetically-modified mice with a crucial DNA-repair protein missing from their hematopoietic stem cells, immature immune cells that develop into white blood cells. Without this repair protein, the mice were unable to fix damaged DNA accrued in their immune cells.
“By the time the genetically-modified mouse is 5 months old, it’s like a 2-year-old mouse,” said Kelley, associate professor and associate chair of research in the School of Medicine’s Department of Physiology and Pharmacology. “It has all the symptoms and physical characteristics. It has hearing loss, osteoporosis, renal dysfunction, visual impairment, hypertension, as well as other age-related issues. It’s prematurely aged just because it has lost its ability to repair its DNA.”
According to Kelley, a normal 2-year-old mouse is about equivalent in age to a human in their late 70s to early 80s.

A blood gene profile associated with a high risk of dying from a severe lung disease can also predict poor outcomes in patients with COVID-19, a multicenter retrospective study led by the University of South Florida Health (USF Health) demonstrated. The risk profile based on 50 genes could help customize how COVID-19 is treated, improve allocation of limited health care resources such as intensive care beds and ventilators, and potentially save lives.
Idiopathic pulmonary fibrosis (IPF), a disease of unknown cause, affects the lung interstitium or the space between the lung sacs and the bloodstream, leading to severe lung scarring. Severe COVID-19 can also damage the lung interstitium leading to severe lung scarring.
“Our study identified at the molecular level, a gene risk profile that predicts worse COVID-19 outcomes before the patient becomes severely ill,” said principal investigator Jose Herazo-Maya, MD, an associate professor and associate chief of pulmonary, critical care and sleep medicine at the USF Health Morsani College of Medicine. “That means every patient with COVID-19 could potentially get a blood test that could tell us if they are at high or low risk of dying… And if we know in advance who will likely end up in the ICU and who will likely do well recovering at home with appropriate monitoring, we can tailor our interventions to individual patients based on their level of risk.”
The USF Health study appeared online June 20 in EBioMedicine, a publication of THE LANCET. It builds upon previous genomic research by Dr. Herazo-Maya and colleagues at Yale School of Medicine. In 2017, they led an international team that studied and validated a gene expression signature in the blood that reliably forecasts the likelihood of IPF mortality. (Certain patients with lung scarring can live well for years, while others develop worsening disease and die quickly from IPF.)
As the COVID-19 pandemic unfolded, “the basic question we had was ‘Can we repurpose the gene signature known to predict mortality in a fibrotic lung disease to predict mortality in those infected with a new coronavirus that can cause lung fibrosis as well?” said the EBioMedicine paper lead author Brenda Juan-Guardela, MD, assistant professor of medicine at the USF Health Morsani College of Medicine and medical director of Respiratory Care Services at Tampa General Hospital (TGH). “To the best of our knowledge, this study is the first to compare overlapping immune gene profiles in COVID-19 and IPF, which were remarkably similar.”
The USF Health-led team analyzed gene expression patterns of 50 genes known to predict IPF mortality in three COVID-19 cohorts and two IPF cohorts. The researchers used a molecular scoring system to distinguish between high versus low-risk gene profiles in all five cohorts.

In the fight against viruses, antibodies have the potential to either block infection or enable infection and make the disease worse, leading to concern about their use as a therapy for COVID-19.
In a study published in the journal Cell, Duke investigators demonstrated in mice and monkeys that human antibodies lacked the ability to make SARS-CoV-2 infection worse and, instead, exerted their defensive powers against the infection. The findings help reinforce evidence that antibodies are safe when given as treatments or induced by COVID-19 vaccines.
The two types of antibodies — those that neutralize the virus or those that enhance virus replication — have been the subjects of much research, raising concerns that antibodies could potentially trigger severe infections in some recipients.
But the current research, led by scientists at the Duke Human Vaccine Institute, is the first to use animal models to examine what occurs when SARS-CoV-2 antibodies are tested with the virus.
“Our study, using mice and monkeys, demonstrates that antibodies that are potentially harmful in the test tube do not appear to be harmful in the setting of SARS-CoV-2 infection in mice or monkeys,” said co-senior author Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute (DHVI).
“We tested a number of disease-enhancing antibodies in mouse and monkey experiments — multiple trials with different antibodies — and determined that disease enhancement does not occur in the animals, and that’s good news for the development of effective treatments and vaccines.” Haynes said.
Senior author Kevin Saunders, Ph.D., director of research at DHVI, isolated more than 1,700 antibodies from people who had COVID and screened them for their effects on the virus.
“We quickly found a set that were capable of blocking infection, including a set of antibodies that are candidates for clinical trials to prevent people from getting COVID,” Saunders said. “We also found a set of antibodies that, instead of preventing infection in tissue culture, they enhanced infection in the test tube.”
But in tests administering the antibodies to mice and monkeys, there were no such effects in the body that could be attributed to antibody administration. The presence of the infection-enhancing antibodies also did not counter how well the protective antibodies functioned in the body.
“These results in animal models suggest that SARS-CoV-2 antibody treatments or the induction of SARS-CoV-2 antibodies by vaccination have a low likelihood of exacerbating COVID-19 disease in humans,” Saunders said. “Our findings are immediately applicable to COVID-19 vaccine candidates under development in use, and to antibodies and plasma being used to treat COVID-19.”
In addition to Saunders and Haynes, study authors include Dapeng Li, Robert J Edwards, Kartik Manne, David R. Martinez, Alexandra Schäfer, S. Munir Alam, Kevin Wiehe, Xiaozhi Lu, Robert Parks, Laura L. Sutherland, Thomas H. Oguin III, Charlene McDanal, Lautaro G. Perez, Katayoun Mansouri, Sophie M. C. Gobeil, Katarzyna Janowska, Victoria Stalls, Megan Kopp, Fangping Cai, Esther Lee, Andrew Foulger, Giovanna Hernandez, Aja Sanzone, Kedamawit Tilahun, Chuancang Jiang, Longping V. Tse, Ken Cronin, Victoria Gee-Lai, Margaret Deyton, Maggie Barr, Tarra Von Holle, M. Anthony Moody, Derek W. Cain, Aaron Schmidt, Tongqing Zhou, John Mascola, Barney Graham, Ian N. Moore, Robert Seder, Hanne Andersen, Mark G. Lewis, David C. Montefiori, Gregory Sempowski, Ralph S. Baric and Priyamvada Acharya.
The study received support in part from a cooperative agreement with the Department of Defense/DARPA (HR0011-17-2-0069), the National Institutes of Health (UC6-AI058607, R01-AI145687), and the State of North Carolina through the Coronavirus Aid, Relief, and Economic Security Act (CARES Act). A full disclosure of funding sources is provided in the study.

Biologists at the Universities of Bath and Vienna have discovered 71 new ‘imprinted’ genes in the mouse genome, a finding that takes them a step closer to unravelling some of the mysteries of epigenetics — an area of science that describes how genes are switched on (and off) in different cells, at different stages in development and adulthood.
To understand the importance of imprinted genes to inheritance, we need to step back and ask how inheritance works in general. Most of the thirty trillion cells in a person’s body contain genes that come from both their mother and father, with each parent contributing one version of each gene. The unique combination of genes goes part of the way to making an individual unique. Usually, each gene in a pair is equally active or inactive in a given cell. This is not the case for imprinted genes. These genes — which make up less than one percent of the total of 20,000+ genes — tend to be more active (sometimes much more active) in one parental version than the other.
Until now, researchers were aware of around 130 well-documented imprinted genes in the mouse genome — the new additions take this number to over 200.
Professor Tony Perry, who led the research from the Department of Biology & Biochemistry at Bath in the UK, said: “Imprinting affects an important family of genes, with different implications for health and disease, so the seventy-plus new ones add an important piece of the jigsaw.”
THE IMPORTANCE OF HISTONES
Close examination of the newly identified genes has allowed Professor Perry and his colleagues to make a second important discovery: the switching on and off of imprinted genes is not always related to DNA methylation, where methyl groups are added to genomic DNA- a process that is known to repress gene activity, switching them off). DNA methylation was the first known type of imprint, and was discovered around thirty years ago. From the results of the new work, it seems that a greater contribution to imprinting is made by histones — structures that are wrapped up with genomic DNA in chromosomes.
Although scientists have known for some time that histones act as ‘dimmer’ switches for genes, fading them off (or back on), until now it was thought that DNA methylation provided the major switch for imprinted gene activity. The findings from the new study cast doubt on this assumption: many of the newly identified genes were found to be associated with changes to the histone 3 lysine 27 (H3K27me3), and only a minority with DNA methylation.
WHY IMPRINTING MATTERS
Scientists have yet to work out how one parental version of a given gene can be switched (or faded) on or off and maintained that way while the other is in the opposite state. It is known that much of the on/off switching occurs during the formation of gametes (sperm and egg), but the precise mechanisms remain unclear. This new study points to the intriguing possibility that some imprinted genes may not be marked in gametes, but become active later in development, or even in adulthood.
Although it only involves a small proportion of genes, imprinting is important in later life. If it goes wrong, and the imprinted gene copy from one parent is switched on when it should be off (or vice versa), disease or death occur. Faulty imprinted genes are associated with many diseases, including neurological and metabolic disorders, and cancer.
“We may underestimate how important the relationship between imprinting and disease is, as well as the relationship of imprinting to the inheritance of parentally-acquired disease, such as obesity,” said Professor Perry. “Hopefully, this improved picture of imprinting will increase our understanding of disease.”
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Materials provided by University of Bath. Note: Content may be edited for style and length.

According to the American Burn Association, burn injuries affect approximately 250,000 children in the United States each year. The pain associated with burn injuries extends beyond the injury itself; there is also significant pain from dressing changes, which can be exacerbated by the anxiety of anticipating this additional pain.
Although opioids relieve burn injury-related pain, they have serious adverse side effects. Prior studies have investigated alternative approaches to pain reduction in burn injury patients that focus on distraction, such as music, hypnosis, toys, and virtual reality (VR).
In a study published today in JAMA Network Open, Henry Xiang, MD, MPH, PhD, MBA, and his research team reported the use of smartphone-based VR games during dressing changes in pediatric patients with burn injuries. “The smartphone-based VR game was very effective in reducing patient-reported pain,” says Dr. Xiang, a professor of pediatrics and epidemiology at Nationwide Children’s Hospital and director of the Center for Pediatric Trauma Research.
In the pilot study, designed as a randomized clinical trial, the research team divided 90 children, aged 6 to 17 years, into three treatment groups: active VR, passive VR, and standard care (e.g., toys, tablet). These patients, most with second-degree burns, received outpatient care for burn injuries between December 2016 and January 2019.
The VR game, called “Virtual River Cruise,” was designed specifically for the study by Nationwide Children’s Research Information Solutions and Innovation department. “Two factors were considered for the game’s design,” explains Dr. Xiang. “The first factor was a snow, cooling environment within the game. The second factor was cognitive processing to encourage active engagement.”
Patients played the game using a smartphone and a headset. During dressing changes, which lasted approximately 5 to 6 minutes, patients in the active VR group actively engaged with the game; to stay still while playing the game, the patients tilted their head to aim a target, notes Dr. Xiang. Patients in the passive VR group only watched the game.
Along with their caregivers, patients reported their perceived pain and subjective experience with the game in post-intervention surveys. Nurses evaluated the game’s clinical utility.
Among the three treatment groups, patients in the active VR group had the lowest overall pain scores. Most patients and their caregivers reported a positive experience with the game, calling it “fun, engaging, and realistic.”
Nurses considered the game to be clinically useful in the outpatient setting. Previously, computer-based games were used during dressing changes. However, the computers’ bulkiness was not clinically practical. “Smartphones are easy to use, and most families have them,” said Dr. Xiang.
Given the VR games’ ease of use and demonstrated effectiveness at reducing pain during burn dressing changes, Dr. Xiang believes the game can also be played at home to relieve this pain. “Pediatric burn patients still need dressing changes at home after hospital discharge, and these changes could be very painful,” said Dr. Xiang. Currently, Dr. Xiang is leading a research project, funded by the Division of Emergency Medical Service of Ohio Department of Public Safety, to evaluate the feasibility and efficacy of VR games in reducing pain during burn dressing changes at home.
The current opioid crisis underscores the need to continue to explore non-opioid approaches to controlling pain in burn patients. “The future research direction is to evaluate whether smartphone-based VR games have an opioid-sparing effect,” says Dr. Xiang.

Every year, about 400,000 people receive silicone breast implants in the United States. According to data from the U.S. Food and Drug Administration, a majority of those implants needs to be replaced within 10 years due to the buildup of scar tissue and other complications.
A team led by MIT researchers has now systematically analyzed how the varying surface architecture found in these implants influences the development of adverse effects, which in rare cases can include an unusual type of lymphoma.
“The surface topography of an implant can drastically affect how the immune response perceives it, and this has important ramifications for the [implants’] design,” says Omid Veiseh, a former MIT postdoc. “We hope this paper provides a foundation for plastic surgeons to evaluate and better understand how implant choice can affect the patient experience.”
The findings could also help scientists to design more biocompatible implants in the future, the researchers say.
“We are pleased that we were able to bring new materials science approaches to better understand issues of biocompatibility in the area of breast implants. We also hope the studies that we conducted will be broadly useful in understanding how to design safer and more effective implants of any type,” says Robert Langer, the David H. Koch Institute Professor at MIT and the senior author of the study.
Veiseh, who is now an assistant professor at Rice University, and Joshua Doloff, a former MIT postdoc who is now an assistant professor at Johns Hopkins University, are the lead authors of the paper, which appears today in Nature Biomedical Engineering. The research team also includes scientists from Rice University, Johns Hopkins, Establishment Labs, and MD Anderson Cancer Center, among other institutions.

In counties with already high COVID-19 infection rates, birthday bashes may have fueled infection spread during the peak months of the pandemic, according to a new analysis led by researchers at Harvard Medical School and the RAND Corporation.
The report, published June 21 in JAMA Internal Medicine, shows that in counties with high rates of COVID-19, households with recent birthdays were 30 percent more likely to have a COVID-19 diagnosis, compared with households with no birthdays. The analysis is based on data from health insurance claims.
The researchers point out that they did not count actual birthday parties in their analysis. Instead, they used birth dates of household members as a proxy for social gatherings and in-person festivities.
Nonetheless, the team said, the findings do signal that social gatherings, such as birthday parties, may have contributed to infections during the height of the pandemic.
“These gatherings are an important part of the social fabric that holds together families and society as a whole. However, as we show, in high-risk areas, they can also expose households to COVID-19 infections,” said study senior author Anupam Jena, the Ruth L. Newhouse Associate Professor of Health Care Policy at HMS.
With growing vaccination rates and infections dropping in many areas of the country, such hindsight analysis may seem outdated, but the findings hold important clues for public health officials and individuals should another surge occur, the scientists said.