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Monday, July 13, 2020

Key element of strong antibody response to COVID-19 discovered

A team led by scientists at Scripps Research has discovered a common molecular feature found in many of the human antibodies that neutralize SARS-CoV-2, the coronavirus that causes COVID-19.
The scientists, whose study appears July 13 in Science, reviewed data on nearly 300 anti-SARS-CoV-2 that their labs and others have found in convalescent COVID-19 patients over the past few months. They noted that a subset of these antibodies is particularly powerful at neutralizing the virus—and these are all encoded, in part, by the same antibody gene, IGHV3-53.
The scientists used a powerful tool known as X-ray crystallography to image two of these antibodies attached to their target site on SARS-CoV-2. The resulting atomic-structure details of this interaction should be useful to designers, as well as to scientists hoping to develop antiviral drugs targeting the same site on SARS-CoV-2.
Prior research suggests that antibodies encoded by IGHV3-53 are generally present, at least in small numbers, in healthy people’s blood. The results therefore offer hope that using a vaccine to boost levels of these ever-present antibodies will protect adequately against the virus.
“This type of antibody has been isolated frequently in studies of COVID-19 patients, and we can now understand the structural basis for its interaction with SARS-CoV-2,” says the study’s senior author Ian Wilson, DPhil, Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology at Scripps Research.
“This study provides important inspiration for effective COVID-19 vaccine design,” says co-author Dennis Burton, Ph.D., professor and co-chair of the Department of Immunology and Microbiology at Scripps Research.
The research was a collaboration chiefly involving the Wilson and Burton labs, and the Scripps Research-based Neutralizing Antibody Center of IAVI, a prominent non-profit vaccine research organization.
SARS-CoV-2 so far has infected more than 12 million people around the world and killed more than 500,000, in addition to causing widespread socioeconomic disruption and damage. Developing an effective vaccine to stop the pandemic is currently the world’s top public health priority.
Although several potential vaccines are already in clinical trials, scientists don’t yet have a full understanding of the molecular features that would define a protective antibody response. In the new study, the scientists took a big step toward that goal.
The team started by analyzing 294 different SARS-CoV-2-neutralizing antibodies isolated from COVID-19 patients’ blood over the past few months. Antibodies are Y-shaped proteins made in called B-cells. Each B-cell makes a specific antibody type, or clone, which is encoded by a unique combination of antibody genes in the cell. The scientists found that an antibody gene called IGHV3-53 was the most common of the genes for the 294 antibodies, encoding about 10 percent of them.
The scientists also noted that the IGHV3-53-encoded antibodies in their study contain an unusually short variant of the CDR H3 loop, normally a key target-binding element. These antibodies are nevertheless very potent against SARS-CoV-2 when compared to other antibodies not encoded by IGHV3-53.
A powerful response right off the bat
The IGHV3-53 antibodies had yet another property suggesting that boosting their numbers would be a good and achievable aim for a SARS-CoV-2 vaccine: They appeared to have mutated only minimally from the original versions that would be circulating, initially in small numbers, in the blood of healthy people.
Normally, when activated by an encounter with a virus to which they fit, B-cells will start proliferating and also mutating parts of their antibody genes, in order to generate new B-cells whose antibodies fit the viral target even better. The more mutations needed for this “affinity maturation” process to generate virus-neutralizing antibodies, the harder it can be to induce this same process with a vaccine.
Fortunately, the IGHV3-53 antibodies found in the study seemed to have undergone little or no affinity maturation and yet were already very potent at neutralizing the virus—which hints that a vaccine may be able to induce a protective response from these potent neutralizers relatively easily.
“Coronaviruses have been around for hundreds to thousands of years, and one can imagine that our immune system has evolved in such a way that we carry antibodies like these that can make a powerful response right off the bat, so to speak” Wilson says.
Map for vaccine-makers, gauge for clinical trials
Wilson’s team used high-resolution X-ray crystallography to image two different IGHV3-53 antibodies bound to their target on SARS-CoV-2. This target, known as the receptor binding site, is a crucial structure on the viral “spike” protein that normally connects to a receptor on human cells to begin the process of cell infection. Many of the antibodies that neutralize SARS-CoV-2 appear to do so by blocking this virus-receptor connection.
“We were able to reveal unique structural features of these IGHV3-53-encoded antibodies—features that facilitate their high binding affinity and their specificity for the SARS-CoV-2 receptor binding site,” says co-first author Meng Yuan, Ph.D., a postdoctoral research associate in the Wilson lab.
The detailed atomic-scale structural data should be of interest to vaccine designers and drug developers. Moreover, the researchers say, the identification of IGHV3-53-encoded antibodies as key elements of the immune response to COVID-19 suggests that levels of these antibodies might be useful as an indirect marker of success in ongoing and future vaccine trials.
Explore further
More information: Meng Yuan et al. Structural basis of a shared antibody response to SARS-CoV-2. Science  13 Jul 2020. DOI: 10.1126/science.abd2321

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Better vaccines are in our blood

Red blood cells do more than shuttle oxygen from our lungs to our organs: they also help the body fight off infections by capturing pathogens on their surfaces, neutralizing them, and presenting them to immune cells in the spleen and liver. Now, a team of researchers from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS) has harnessed this innate ability to build a platform technology that uses red blood cells to deliver antigens to antigen-presenting cells (APCs) in the spleen, generating an immune response. This approach successfully slowed the growth of cancerous tumors in mice, and could also be used as a biocompatible adjuvant for a variety of vaccines. The technology, called Erythrocyte-Driven Immune Targeting (EDIT), is reported this week in PNAS.
“The spleen is one of the best organs in the body to target when generating an immune response, because it is one of the few organs where red and naturally interact,” said senior author Samir Mitragotri, Ph.D., a Wyss Core Faculty member who is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS. “Red ‘ innate ability to transfer attached pathogens to has only recently been discovered, and this study unlocks the door to an exciting array of future developments in the field of using for disease treatment and prevention.”
Don’t eat me, just check me out
Using red blood cells as delivery vehicles for drugs is not a new idea, but the vast majority of existing technologies target the lungs, because their dense network of capillaries causes cargoes to shear off of red blood cells as they squeeze through the tiny vessels. Mitragotri’s research team first needed to figure out how to get antigens to stick to red blood cells strongly enough to resist shearing off and reach the spleen.
They coated polystyrene with ovalbumin, an antigenic protein known to cause a mild immune response, then incubated them with mouse red blood cells. The ratio of 300 nanoparticles per blood cell resulted in the greatest number of nanoparticles bound to the cells, retention of about 80% of the nanoparticles when the cells were exposed to the found in lung capillaries, and moderate expression of a lipid molecule called phosphatidyl serine (PS) on the cells’ membranes.
“A high level of PS on red blood cells is essentially an ‘eat me’ signal that causes them to be digested by the spleen when they are stressed or damaged, which we wanted to avoid. We hoped that a lower amount of PS would instead temporarily signal ‘check me out’ to the spleen’s APCs, which would then take up the red blood cells’ antigen-coated nanoparticles without the cells themselves getting destroyed,” said Anvay Ukidve, a graduate student in the Mitragotri lab and co-first author of the paper.
To test that hypothesis, the team injected red blood cells coated with their nanoparticles into mice, then tracked where they accumulated in their bodies. 20 minutes after injection, more than 99% of the nanoparticles had been cleared from the animals’ blood, and more nanoparticles were present in their spleens than their lungs. The higher nanoparticle accumulation in the spleen persisted for up to 24 hours and the number of EDIT red blood cells in the circulation remained unchanged, showing that the had successfully delivered their cargoes to the spleen without being destroyed.
Effective, adjuvant-free vaccines
Having confirmed that their nanoparticles were successfully delivered to the spleen in vivo, the researchers next evaluated whether the antigens on the nanoparticles’ surfaces induced an immune response. Mice were injected with EDIT once a week for three weeks, and then their spleen cells were analyzed. Treated mice displayed 8-fold and 2.2-fold more T cells displaying the delivered ovalbumin antigen than mice that were given “free” nanoparticles or were untreated, respectively. Mice treated with EDIT also produced more antibodies against ovalbumin in their blood than either of the other groups of mice.
To see if these EDIT-induced immune responses could potentially prevent or treat disease, the team repeated their three-week prophylactic injection of EDIT into mice, then inoculated them with lymphoma cells that expressed ovalbumin on their surfaces. The mice that received EDIT had about three-fold slower tumor growth compared with the control group and the group that received free nanoparticles, and had lower numbers of viable cancerous cells. This outcome significantly increased the window of time during which the tumor could be treated before the mice succumbed to the disease.
“EDIT essentially is an adjuvant-free vaccine platform. Part of the reason why vaccine development today takes so long is that foreign adjuvants delivered along with an antigen have to go through a full clinical safety trial for each new vaccine,” said Zongmin Zhao, Ph.D., a Postdoctoral Fellow in the Mitragotri lab and co-first author of the paper. “Red blood cells have been safely transfused into patients for centuries, and their ability to enhance immune responses could make them a safe alternative to foreign adjuvants, increasing the efficacy of vaccines and speed of vaccine creation.”
The team is continuing to work on understanding exactly how an that is specific to the antigen presented by EDIT is generated by the spleen’s APCs, and plans to test it with other antigens beyond ovalbumin. They hope to use this additional insight to drive their pursuit of the optimal clinical setting(s) for the technology.
“The human body is a treasure trove of elegant solutions to healthcare problems, and while medicine has come a long way in understanding those mechanisms, we are still in the early stages of being able to harness them to improve the length and quality of human life. This research is an exciting step forward toward that goal, and could dramatically change how immune responses are modulated in patients,” said the Wyss Institute’s Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and Professor of Bioengineering at SEAS.
Additional authors of the paper include Vinu Krishnan, Daniel C. Pan, Yongsheng Gao, and Abhirup Mandal from the Wyss Institute and SEAS; Alexandra Fehnel from SEAS, and Vladimir Muzykantov from the Perelman School of Medicine at the University of Pennsylvania. This research was supported by the Wyss Institute at Harvard University and the National Institutes of Health under grant # 1R01HL143806-01.
More information: Anvay Ukidve el al., “Erythrocyte-driven immunization via biomimicry of their natural antigen-presenting function,” PNAS (2020). www.pnas.org/cgi/doi/10.1073/pnas.2002880117

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Older Adults Often Underestimate Ability to Prevent Falls

An intervention designed to prevent serious fall injuries among older adults was less effective than researchers expected but did identify important ways for clinicians to help, including screening all older patients for fall risk and deprescribing certain medications when possible.
The study was conducted by Shalender Bhasin, MD, MBBS, from Brigham and Women’s Hospital, Harvard Medical School, in Boston, Massachusetts, and colleagues on behalf of the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial investigators and was published online July 8 in The New England Journal of Medicine.
Patients are often unaware of their increased risk until they have fallen for the first time, and they often underestimate how many of their risk factors can be improved, Bhasin told Medscape Medical News.
“Fall injuries are a very important cause of injury-related deaths among older adults, and these are preventable. Yet they are so difficult; for 30 years the rates of fall injuries have not declined,” he said.
Using a pragmatic, cluster-randomized trial, the researchers studied the clinical effectiveness of a “patient-centered intervention that combined elements of practice redesign (reconfiguration of workflow to improve quality of care) and an evidence-based, multifactorial, individually tailored intervention implemented by specially trained nurses in primary care settings,” the authors explain.
Participants in the intervention group worked with trained nurses (fall care managers) to identify their risk factors and determine which risks they wanted to modify. Participants in the control group received their typical care and a pamphlet with information on falls and were encouraged to talk with their primary care physicians (who received the results on risk factor screening) about fall prevention. Those in the intervention group also received the pamphlet.
Fall care managers evaluated patients’ home environments and in some cases visited the patient’s home, Bhasin said.
The researchers enrolled community-dwelling adults aged 70 years or older who were at higher risk for fall injuries from 86 primary care practices across 10 US healthcare systems. Half of the practices were randomly assigned to provide the intervention to their patients; the other half of the practices provided enhanced usual care.
The researchers defined patients with increased risk for fall injuries as those who had suffered a fall-related injury at least twice during the previous year or those whose difficulties with balance or walking made them fearful of falling. Serious fall injuries were defined as falls that cause a fracture (other than a thoracic or lumbar vertebral fracture), joint dislocation, a cut needing closure, or falls that resulted in hospital admission for a “head injury, sprain or strain, bruising or swelling, or other serious injury,” they explain.
Demographic and baseline characteristics were similar for both groups of patients (mean age, 80 years; 62.0% women); 38.9% had experienced a fall-related injury during the previous year, and 35.1% had suffered at least two falls during the previous year.
The researchers hypothesized that serious fall injuries would be 20% lower in the intervention group compared with the control group, but that was not the case.
The findings showed no significant difference between the intervention group (4.9 events per 100 person-years of follow-up) and the control group (5.3 events per 100 person-years of follow-up) for the rate of first adjudicated serious fall injury (hazard ratio [HR], 0.92; P = .25).
Results were similar in a practice-level analysis and a sensitivity analysis adjusted for participant-level covariates.
However, there was a difference in rates of first participant-reported fall injury, which was a secondary endpoint, at 25.6 events per 100 person-years of follow-up among participants in the intervention group vs 28.6 events among those in the control group (HR, 0.90; P = .004).
There were no significant differences between the groups for rates of all adjudicated serious fall injuries and all patient-reported fall injuries. Bone fractures and injuries resulting in hospitalization were the most frequent types of adjudicated serious fall injuries.
Rates of serious adverse events resulting in hospitalization were similar for the intervention group and the control group (32.8 vs 33.3 hospitalizations per 100 person-years of follow-up, respectively), as well as rates of death (3.3 deaths per 100 person-years of follow-up in both groups).

Simple Steps Can Help

“The most important thing clinicians can do is a quick screen for fall injury risk,” Bhasin told Medscape Medical News. The screening tool he uses consists of three questions and can be completed in less than a minute. Clinicians should share that information with patients, he continued.
“Just recognizing that they are at risk for falls, patients are much more motivated to take action,” Bhasin added.
The top three risk factors identified among trial participants were trouble with strength, gait, or balance; osteoporosis or vitamin D deficiency; and impaired vision. “The use of certain medications, postural hypotension, problems with feet or footwear, and home safety hazards were less commonly identified, and the use of certain medications was the least commonly prioritized,” the authors write.
It is vital that clinicians help patients implement changes, Bhasin said. He noted that many patients encounter barriers that prevent them from taking action, including transportation or insurance problems and lack of access to exercise programs in the community.
Deprescribing medications such as sleep medications and benzodiazepines is also a key piece of the puzzle, he added. “They’re pretty huge risks and yet it is so hard to get people off these medications.”
Future research will focus on how to improve the intervention’s effectiveness and also will test the strategy among those with cognitive impairments who have even higher risk for fall injuries, Bhasin said.

Falls Remain Common

A report published online July 9 in Morbidity and Mortality Weekly Report underscores the prevalence of fall-related injuries: In 2018, more than one quarter (27.5%) of adults aged 65 years or older said they had fallen at least once during the previous year (35.6 million falls), and 10.2% said they had experienced a fall-related injury (8.4 million fall-related injuries). The percentage of adults who reported a fall increased from 2012 to 2016, then decreased from 2016 to 2018.
Briana Moreland, MPH, from Synergy America, Inc, and the Division of Injury Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention (CDC), both in Atlanta, Georgia, and colleagues write that older adults and healthcare providers can work together to reduce fall risk.
“CDC created the Stopping Elderly Accidents, Deaths and Injuries (STEADI) initiative, which offers tools and resources for health care providers to screen their older patients for fall risk, assess modifiable fall risk factors, and to intervene with evidence-based fall prevention interventions (https://www.cdc.gov/steadi). These include medication management, vision screening, home modifications, referral to physical therapists who can address problems with gait, strength, and balance, and referral to effective community-based fall prevention programs,” Moreland and colleagues explain.
Bhasin has received grants from the National Institute on Aging (NIA) and Patient-Centered Outcomes Research Institute (PCORI) during the conduct of the study. He has received grants, personal fees, and nonfinancial support from AbbVie, grants from Transition Therapeutics, grants from Alivegen, grants from Metro International Biotechnology, and personal fees from OPKO, outside the submitted work. Latham has received grants from the NIA and PCORI during the conduct of the study and is co-owner of Lynx Health LLC. Peduzzi received grants and other compensation from NIA-PCORI during the conduct of the study. Reuben and Gill have disclosed no relevant financial relationships. The remaining authors report a variety of relevant financial relationships; a complete list is available on the journal’s website. The authors of the article in Morbidity and Mortality Weekly Report have disclosed no relevant financial relationships.
N Engl J Med. Published online July 8, 2020. Abstract
Morb Mortal Wkly Rep. Published online July 9, 2020. Full text

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