The antibodies target portions of the SARS-CoV-2 spike protein that resist mutation, potentially leading to better treatments and vaccines
One challenge in the battle against COVID-19 is the emergence of SARS-CoV-2 variants, especially the Delta variant, which may be more resistant to neutralizing antibodies compared with the original coronavirus. But now, scientists led by researchers at the Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle say they have identified antibodies that could be broadly protective against multiple sarbecoviruses, the subgenus that contains SARS-CoV-2 as well as SARS-CoV-1, the virus responsible for the 2002-2004 severe acute respiratory syndrome (SARS) outbreak.
In “SARS-CoV-2 RBD Antibodies That Maximize Breadth and Resistance to Escape,” the researchers described how they compared 12 antibodies obtained from patients infected with either SARS-CoV-2 or SARS-CoV-1. They pointed to one antibody in particular—S2H97—that could lead to development of new vaccines and therapies against current and future variants. It might even protect against sarbecoviruses that have not yet been identified, they wrote.
Unsaid in the news release about these research findings is the fact that these particular antibodies could eventually become useful biomarkers for clinical laboratory tests designed to help physicians determine which patients have these antibodies—and the protection from infection they represent—and which do not.
So far, however, S2H97 has only been tested in hamsters. But results are promising.
“This antibody, which binds to a previously unknown site on the coronavirus spike protein, appears to neutralize all known sarbecoviruses—the genus of coronaviruses that cause respiratory infections in mammals,” said Jay Nix, PhD, an affiliate in Berkeley Lab’s Biosciences Area and Beamline Director of the Molecular Biology Consortium at Berkeley Lab’s Advanced Light Source (ALS), in a Berkeley Lab news release. “And, due to the unique binding site on mutation-resistant part of the virus, it may well be more difficult for a new strain to escape,” he added.
Scientists have long known that the SARS-CoV-2 virus uses the spike protein to attach to human cells. The federal Centers for Disease Control and Prevention (CDC) notes that the variants have mutations in their spike proteins that make some of them more transmissible.
The Delta variant, the CDC notes, was the predominant variant in the US as of August 28, 2021. It “has been shown to have increased transmissibility, potential reduction in neutralization by some monoclonal antibody treatments, and reduction in neutralization by post-vaccination sera,” the agency states.
The key to S2H97, the researchers wrote, is that it targets a portion of the spike protein that is common among sarbecoviruses, and that is likely to be resistant to mutations.
The researchers used a variety of techniques to analyze how the 12 antibodies bind to the virus. They “compiled a list of thousands of mutations in the binding domains of multiple SARS-CoV-2 variants,” Nature reported. “They also catalogued mutations in the binding domain on dozens of SARS-CoV-2-like coronaviruses that belong to a group called the sarbecoviruses. Finally, they assessed how all these mutations affect the 12 antibodies’ ability to stick to the binding domain.”
William Schaffner, MD (above), Professor of Preventive Medicine in the Department of Health Policy as well as Professor of Medicine in the Division of Infectious Diseases at the Vanderbilt University School of Medicine in Nashville, believes that “people who test positive for SARS-CoV-2 and who are at risk of progressing to severe disease—including those who are over the age of 65 years and those who have weakened immune systems—should talk with a doctor about receiving monoclonal antibody treatment,” Medical News Today reported. “[The monoclonal antibody treatment is] designed to prevent the evolution of the infection from a mild infection into a serious one,” he noted. “In other words, you’ve just [contracted the virus], but we can now give you a medication that will help prevent [you] being hospitalized and getting seriously ill.” (Photo copyright: Vanderbilt University.)
Earlier Antibody Treatment Receives an EUA from the FDA
In issuing the EUA for sotrovimab, the FDA cited “an interim analysis from a phase 1/2/3 randomized, double-blind, placebo-controlled clinical trial in 583 non-hospitalized adults with mild-to-moderate COVID-19 symptoms and a positive SARS-CoV-2 test result. Of these patients, 291 received sotrovimab and 292 received a placebo within five days of onset of COVID-19 symptoms.”
Among these patients, 21 in the placebo group were hospitalized or died compared with three who received the therapy, an 85% reduction.
“While preventive measures, including vaccines, can reduce the total number of cases, sotrovimab is an important treatment option for those who become ill with COVID-19 and are at high risk—allowing them to avoid hospitalization or worse,” stated Adrienne E. Shapiro, MD, PhD, of the Fred Hutchinson Cancer Research Center in a GSK news release. Shapiro was an investigator in the clinical trial.
The EUA allows use of sotrovimab in patients who have tested positive for SARS-CoV-2, have mild-to-moderate symptoms, and “who are at high risk for progression to severe COVID-19, including hospitalization or death. This includes, for example, individuals who are 65 years of age and older or individuals who have certain medical conditions.” It is not authorized for patients who are hospitalized or for those who require oxygen therapy.
The therapy was originally known as VIR-7831. The companies say they have developed a similar treatment, VIR-7832, with modifications designed to enhance T cell function against the disease.
The antibody, they wrote, targets a region of the SARS-CoV-1 spike protein that is “highly conserved” among sarbecoviruses. Clinical laboratory testing, they wrote, also indicated that the therapy was likely to be effective against known SARS-CoV-2 variants.
“Our distinctive scientific approach has led to a single monoclonal antibody that, based on an interim analysis, resulted in an 85% reduction in all-cause hospitalizations or death, and has demonstrated, in vitro, that it retains activity against all known variants of concern, including the emerging variant from India,” stated Vir Biotechnology CEO George Scangos, PhD, in the GSK news release. “I believe that sotrovimab is a critical new treatment option in the fight against the current pandemic and potentially for future coronavirus outbreaks, as well.”
Pathologists and clinical laboratory managers working with rapid molecular tests and antibody tests for COVID-19 will want to monitor the development of monoclonal antibody treatments, as well as further research studies that focus on these specific antibodies.
Researchers found that early in life intestinal microorganisms “educate” the thymus to develop T cells; findings could lead to improved immune system therapeutics and associated clinical laboratory tests
The researchers published their findings in Nature. They used engineered mice as the test subjects and say the study could lead to a greater understanding of human conditions such as Type 1 and Type 2 diabetes and inflammatory bowel disease (IBD). In turn, this new knowledge could lead to new diagnostic tests for clinical laboratories.
“From the time we are born, our immune system is set up so that it can learn as much as it can to distinguish the good from the bad,” Matthew Bettini, PhD, Associate Professor of Pathology said in a University of Utah news release.
Does Gut Bacteria ‘Educate’ the Immune System?
The researchers were attempting to learn how the body develops T cells specific to intestinal microorganisms. T cells, they noted, are “educated” in the thymus, an organ in the upper chest that is key to the adaptive immune system.
“Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection,” they wrote in their study. “Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen, while limiting inflammatory anti-commensal responses.”
Matthew Bettini, PhD (left), Associate Professor of Pathology at the University of Utah, co-authored the study along with Gretchen Diehl, PhD (right), an immunologist at Sloan Kettering Institute. The team also included researchers from the Baylor College of Medicine in Houston and the Washington University School of Medicine in St. Louis. “Our studies make clear that there is a window in which gut microbiota have access to the immune education process. This opens up possibilities for designing therapeutics that can influence the trajectory of the immune system during this early time point,” Bettini said in the University of Utah news release. (Photo copyright: University of Utah/Sloan Kettering Institute.)
Findings Challenge Earlier Assumptions about Microbiota’s Influence on Immunity
The researchers began by seeding the intestines of mice with segmented filamentous bacteria (SFB), which they described as “one of the few commensal microorganisms for which a microorganism-specific T-cell receptor has been identified.” In addition, SFB-specific T cells can be tracked using a magnetic enrichment technique, they wrote in Nature.
They discovered that in young mice, microbial antigens from the intestines migrated to the thymus, resulting in an expansion of T cells specific to SFB. But they did not see an expansion of T cells in adult mice, suggesting that the process of adapting to microbiota happens early.
“Our study challenges previous assumptions that potential pathogens have no influence on immune cells that are developing in the thymus,” Bettini said in the news release. “Instead, we see that there is a window of opportunity for the thymus to learn from these bacteria. Even though these events that shape which T cells are present happen early in life, they can have a greater impact later in life.”
For example, T cells specific to microbiota can also protect against closely related harmful bacteria, the researchers found. “Mice populated with E. coli at a young age were more than six times as likely to survive a lethal dose of Salmonella later in life,” the news release noted. “The results suggest that building immunity to microbiota also builds protection against harmful bacteria the body has yet to encounter.”
According to the researchers, in addition to protecting against pathogens, “microbiota-specific T cells have pathogenic potential.” For example, “defects in these mechanisms could help explain why the immune system sometimes attacks good bacteria in the wrong place, causing the chronic inflammation that’s responsible for inflammatory bowel disease,” they suggested.
Other Clinical Laboratory Research into the Human Microbiome
All of this suggests the potential in the future “for clinical laboratories and microbiologists to do microbiome testing in support of clinical care,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report. Of course, more research is needed in these areas.
“We believe that our findings may be extended to areas of research where certain bacteria have been found to be either protective or pathogenic for other conditions, such as Type 1 and Type 2 diabetes,” Bettini said in the University of Utah news release. “Now we’re wondering, will this window of bacterial exposure and T cell development also be important in initiating these diseases?”
Studies presented at the Alzheimer’s Association International Conference point to the p-tau217 protein as an especially useful biomarker
Researchers disclosed a potentially useful biomarker for Alzheimer’s Disease at a major conference this summer. The good news for clinical laboratories is that the biomarker is found in blood. If further research confirms these early findings, medical laboratories could one day have a diagnostic test for this condition.
That possibility emerged from the Alzheimer’s Association International Conference (AAIC), which was held online July 27-31. Researchers presented findings from multiple studies that suggested blood/plasma levels of a protein known as phospho-tau217 (p-tau217) can indicate brain anomalies associated with Alzheimer’s.“Changes in brain proteins amyloid and tau, and their formation into clumps known as plaques and tangles, respectively, are defining physical features of Alzheimer’s disease in the brain,” states an AAIC press release. “Buildup of tau tangles is thought to correlate closely with cognitive decline. In these newly reported results, blood/plasma levels of p-tau217, one of the forms of tau found in tangles, also seem to correlate closely with buildup of amyloid.”
At present, “there is no single diagnostic test that can determine if a person has Alzheimer’s disease,” the association states on its website. Clinicians will typically review a patient’s medical history and conduct tests to evaluate memory and other everyday thinking skills. That may help determine that an individual has dementia, but not necessarily that Alzheimer’s is the cause.
“Currently, the brain changes that occur before Alzheimer’s dementia symptoms appear can only be reliably assessed by positron-emission tomography (PET) scans, and from measuring amyloid and tau proteins in [cerebrospinal] fluid (CSF),” the association states. “These methods are expensive and invasive. And, too often, they are unavailable because they are not covered by insurance or difficult to access, or both.”
In the AAIC press release, Alzheimer’s Association Chief Science Officer Maria C. Carrillo, PhD, said that a clinical laboratory blood test “would fill an urgent need for simple, inexpensive, non-invasive and easily available diagnostic tools for Alzheimer’s.
“New testing technologies could also support drug development in many ways,” she added. “For example, by helping identify the right people for clinical trials, and by tracking the impact of therapies being tested. The possibility of early detection and being able to intervene with a treatment before significant damage to the brain from Alzheimer’s disease would be game changing for individuals, families, and our healthcare system.”
However, she cautioned, “these are early results, and we do not yet know how long it will be until these tests are available for clinical use. They need to be tested in long-term, large-scale studies, such as Alzheimer’s clinical trials.”
The study, led by Oskar Hansson, MD, of Lund University in Sweden, included 1,402 participants. About half of these were enrolled in BioFINDER-2, an ongoing dementia study in Sweden. In this group, researchers were most interested in the test’s ability to distinguish Alzheimer’s from other neurodegenerative disorders that cause dementia.
Diagnostic accuracy was between 89% and 98%, the researchers reported, which was similar to the performance of PET imaging and CSF tests. P-tau217 was more accurate than magnetic resonance imaging (MRI) as well as other biomarkers, such as p-tau181.
“Today the majority of individuals with Alzheimer’s disease around the world do not get a timely diagnosis, which results in suboptimal symptomatic treatment and care,” Oskar Hansson, MD, said in an Eli Lilly news release. “With rising prevalence of Alzheimer’s disease, more patients will be evaluated in primary care and other clinics where CSF and PET biomarkers are not available. Blood-based biomarkers, like plasma p-tau217, together with digital tools for checking memory performance, such as smartphone-based apps, can considerably improve the diagnostic work-up of Alzheimer’s disease patients in such clinics.” (Photo copyright: Alzheimer’s Fund.)
Another cohort consisted of 81 participants in the Brain and Body Donation Program at Banner Sun Health Research Institute in Sun City, Ariz. In this program, elderly volunteers submit to periodic clinical assessments and agree to donate their organs and tissue for study after they die.
Here, the researchers’ primary goal was to determine the test’s ability to distinguish between individuals with and without Alzheimer’s. Researchers ran the p-tau217 test on plasma samples collected within 2.9 years of death and compared the results to postmortem examinations of the brain tissue. Accuracy was 89% in individuals with amyloid plaques and tangles, and 98% in individuals with plaques and more extensive tangles.
The third cohort consisted of 622 members of a large extended family in Colombia whose members share a genetic mutation that makes them susceptible to early-onset Alzheimer’s, The New York Times reported. Among the members, 365 were carriers of the mutation. In this group, levels of plasma p-tau217 increased by age, and “a significant difference from noncarriers was seen at age 24.9 years,” the researchers wrote in Jama Network. That’s about 20 years before the median age when mild cognitive impairment typically begins to appear in carriers.
Other Alzheimer Biomarker Studies Presented at AAIC
Suzanne Schindler, MD, PhD, a neurologist and instructor in the Department of Neurology at the Washington University School of Medicine (WUSM) in St. Louis, presented results of an Alzheimer’s Disease (AD) study that used mass spectrometry to analyze amyloid and p-tau variants in blood samples collected from participants. The researchers compared these with CSF and PET results and found that some of the of p-tau isoforms, especially p-tau217, had a strong concordance.
“These findings indicate that blood plasma Aβ and p-tau measures are highly precise biomarkers of brain amyloidosis, tauopathy, and can identify stages of clinical and preclinical AD,” stated an AAIC press release on the studies.
The WUSM researches launched the effort to develop and validate Alzheimer’s blood biomarkers called the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) in April 2019. It runs through August 2023 and will seek to enroll more than 1,100 participants in the St. Louis area.
Another study presented at the conference compared the performance of p-tau217 and p-tau181 in distinguishing between Alzheimer’s and Frontotemporal Lobar Degeneration (FTLD), another condition that causes dementia. Study author Elisabeth Thijssen, MSc, of the UC San Francisco Memory and Aging Center reported that both biomarkers could be useful in differential diagnosis, but that p-tau217 was “potentially superior” for predicting a tau positive PET scan result.
For decades, physicians have wanted a diagnostic test for Alzheimer’s Disease that could identify this condition early in its development. This would allow the patient and the family to make important decisions before the onset of severe symptoms. Such a clinical laboratory test would be ordered frequently and thus would be a new source of revenue for medical laboratories.
Called ‘ViroCap,’ this new diagnostic technology is able to discover more viruses in patient samples, as compared to PCR genome sequencing tests
It could be the ultimate multi-analysis medical laboratory test ever. Researchers at Washington University School of Medicine in St. Louis have developed a diagnostic test that they claim tests for any virus infecting people and animals.
The HHMI research resulted in VirScan, an alternative to medical laboratory tests that test for specific viruses one at a time, and which can detect all diseases a patient has had over his or her lifetime, according to an HHMI news statement about the new technology. (more…)
