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.
Clinical laboratories may see increase in flu and COVID-19 specimen processing as people return to pre-pandemic social behaviors, experts predict
While SARS-CoV-2 infections continue to ravage many parts of the world, influenza (flu) cases in North America have hit a historic low. As winter approached last year, infectious disease experts warned of a “twindemic” in which the COVID-19 outbreak would combine with seasonal influenza to overwhelm the healthcare system. But this did not happen, and many doctors and medical laboratory scientists are now investigating this unexpected, but welcomed, side-effect of the pandemic.
From the start of the current flu season in September 2020, clinical laboratories in the US reported that 1,766 specimens tested positive for flu out of 931,726—just 0.2%—according to the CDC’s Weekly US Influenza Surveillance Report. That compares with about 250,000 positive specimens out of 1.5 million tested in the 2019-2020 flu season, the CDC reported. Public health laboratories reported 243 positive specimens out of 438,098 tested.
The graphic above taken from the CDC’s Weekly Influenza Surveillance Report for the week ending April 17, 2021, illustrates how “Nationwide during week 15, 1.1% of patient visits reported through ILINet were due to ILI [Influenza-like Illness].” This percentage, according to the CDC, is below the national baseline of 2.6%. “Seasonal influenza activity in the United States remains lower than usual for this time of year.” (Graphic copyright: Federal Centers for Disease Control and Prevention.)
Fear of COVID-19 Linked to Fewer Flu Deaths in Children
WebMD reported that just one child in the US has died from the flu this year, compared with 195 in 2020. Why the low numbers?
Precautions people take to avoid COVID-19 transmission, including masking, social distancing, and handwashing.
Reduced human mobility, including less international travel.
Higher-than-usual flu vaccination rates. As of February 26, the CDC reported that nearly 194 million doses of flu vaccine had been distributed in the US.
WebMD noted this could be a record, but that the CDC data doesn’t indicate how many doses were actually administered.
However, Schaffner told WebMD that efforts to keep kids home from school and away from social gatherings were likely a bigger factor. “Children are the great distributors of the influenza virus in our society,” he said. But due to fears about COVID-19 transmission, kids “weren’t even playing together, because mothers were keeping them off the playground and not having play dates.”
Repercussions for Fighting Flu Next Year
Public health experts welcomed the low flu levels, however, Politico reported that limited data about flu circulation this year could hamper efforts to develop an effective vaccine for next season’s flu strains.
Each February, Politico explained, experts convened by the World Health Organization (WHO) look at data from the current and previous flu seasons to predict which strains are likely to predominate in the Northern Hemisphere next winter. That includes data about which strains are currently circulating in the Southern Hemisphere. The WHO uses these predictions to recommend the composition of flu vaccines. In the US, the final decision is made by an FDA advisory committee.
A similar WHO meeting in September guides vaccine development in the Southern Hemisphere.
The WHO issued this year’s Northern Hemisphere recommendations on Feb. 26. The advisory includes recommendations for egg-based and cell- or recombinant-based vaccines, and for quadrivalent (four-strain) or trivalent (three-strain) vaccines.
In a document accompanying the recommendations, the WHO acknowledged concerns about this year’s limited pool of data.
“The volume of data available from recently circulating influenza viruses, and the geographic representation, have been significantly lower for this northern hemisphere vaccine recommendation meeting than is typical,” the document stated. “The reduced number of viruses available for characterization raises uncertainties regarding the full extent of the genetic and antigenic diversity of circulating influenza viruses and those likely to pose a threat in forthcoming seasons.”
The report notes that experts identified changes in circulating Influenza A(H3N2) viruses this year, and that the changes are reflected in the new vaccine recommendation.
But Paul A. Offit, MD, who serves on the FDA’s vaccine advisory panel, downplayed worries about the vaccine. “The belief is that there was enough circulating virus to be able to pick what is likely to be the strains that are associated with next year’s flu outbreak,” he told Politico. Offit is a Professor of Vaccinology and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania and Director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.
Pediatrician and internationally recognized expert in the fields of virology and immunology, Paul A. Offit, MD (above), told Politico that the low level of flu circulation this year, along with the resulting uncertainty, “is unprecedented.” Clinical laboratories might not have noticed the severe decrease in influenza specimens sent for processing due to being hyper-focused on COVID-19 testing. But as the pandemic subsides, loss of flu testing revenues will likely become more apparent. (Photo copyright: University of Pennsylvania.)
Offit suggests that efforts to mitigate the COVID-19 outbreak could be useful to combat other infectious disease outbreaks. However, both Offit and Gostin expressed doubt about that prospect.
“I mean, could we reasonably in a winter month, wear masks just at least when we’re outside in large crowds? … Or are we comfortable having hundreds of 1000s of cases of hospitalizations for flu and 10s of 1000s [of] deaths? I suspect the answer is B. We’re comfortable with that, we’re willing to have that even though we just learned, there’s a way to prevent it,” Offit told Politico.
“Remember after the 1918 flu pandemic, most people don’t realize what happened when that was over. But what happened was the roaring ‘20s,” Gostin told Politico. “People started congregating, mingling, hugging, kissing. All the things they missed. They crowded into theaters and stadiums and went back to church. That’s what’s likely to happen this fall and that makes the influenza virus very happy.”
So, what should clinical laboratories expect in future flu and COVID-19 vaccines? That is not yet clear. One thing is certain, though. New lab test panels that test for influenza and the SARS-CoV-2 coronavirus will be arriving in the marketplace.
Clinical laboratories and microbiologists will want to be on the alert for this deadly infectious agent that has killed patients through blood infections
Healthcare continues to struggle with the issue of how much to disclose to the public when new and deadly infectious agents are identified in a limited number of patients. Timely disclosure of new pathogens is a matter of great concern to clinical laboratory scientists, microbiologists, and clinical pathologists because their laboratories get specimens from infected patients and they must correctly identify rare or emerging pathogens to help minimize the spread of disease.
This is why many medical laboratory professionals were surprised to see national news headlines recently about a particularly deadly new form of a pathogen. The Centers for Disease Control and Prevention (CDC) has been dealing with one particularly nasty example of Candida auris, or C. auris. This “superbug” fungus has been appearing in hospitals and healthcare clinics across the globe and it has killed people.
The news coverage of C. auris focused on two
elements:
First, how the pathogen was recognized by such
healthcare agencies as the CDC.
Second, why CDC and others did not issue a
public alert to hospitals, physicians, and other caregivers once it was known
that C. auris was responsible for the death of several patients.
Once C. auris takes hold, it can enter a patient’s bloodstream or wounds and cause life- threatening complications like sepsis. When hospitals rooms are not properly decontaminated, life-threatening hospital-acquired infections (HAIs), also known as nosocomial infections, can occur.
Incidences of HAIs have been on the rise in the past few
years. Dark Dailyhas reported
on this disturbing trend many times.
The New York Times (NYT) reported on one such HAI that had tragic consequences. A patient admitted to Mount Sinai Hospital in New York for abdominal surgery was later discovered to have contracted C. auris. He was immediately isolated and spent 90 days in the hospital before passing away. Tests showed that Candida auris was everywhere in his room.
“Everything was positive—the walls, the bed, the doors, the curtains, the phones, the sink, the whiteboard, the poles, the pump,” Scott Lorin, MD, President and Chief Operating Officer at Mount Sinai Brooklyn Hospital, told the NYT. “The mattress, the bed rails, the canister holes, the window shades, the ceiling, everything in the room was positive,” he said.
The hospital had to use special cleaning equipment to
sterilize the room and even found it necessary to tear out some ceiling and
floor tiles to annihilate the fungus, the NYT reported.
Media News Coverage of ‘Culture of Secrecy’
When this deadly fungus first emerged in America, it was not
disclosed to the public for a lengthy period of time. Then, when details of
deaths in hospitals due to the superbug went public, the national news media
reacted but then went silent. Why?
In that article, the NYT states that “under its
agreement with states, the CDC is barred from publicly identifying hospitals
that are battling to contain the spread of dangerous pathogens.” So, the CDC is
prevented from revealing to the public the names and locations of facilities
that are dealing with C. auris. And state governments typically do not
share that information either.
The NYT article also states, “The CDC declined to
comment, but in the past officials have said their approach to confidentiality
is necessary to encourage the cooperation of hospitals and nursing homes, which
might otherwise seek to conceal infectious outbreaks.”
And that, “Those pushing for increased transparency say they
are up against powerful medical institutions eager to protect their
reputations, as well as state health officials who also shield hospitals from
public scrutiny.”
“Who’s speaking up for the baby that got the flu from the hospital worker or for the patient who got MRSA from a bedrail? The idea isn’t to embarrass or humiliate anyone, but if we don’t draw more attention to infectious disease outbreaks, nothing is going to change,” Arthur Caplan, PhD (above), told the NYT. Caplan is Drs. William F and Virginia Connolly Mitty Professor and founding head of the Division of Medical Ethics at NYU School of Medicine in New York City. (Photo copyright: NYU Langone Health.)
Common Yeast Infection or Killer Superbug? Both!
C. auris grows as a common yeast infection. However,
it can be life threatening if it enters the bloodstream.
“The average person calls Candida infections yeast infections,” William Schaffner, MD, Professor and Chair, Department of Preventative Medicine at Vanderbilt University Medical Center, told Prevention. “However, Candida auris infections are much more serious than your standard yeast infection. They’re a variety of so-called superbugs [that] can complicate the therapy of very sick people.”
The CDC reports that, as of May 31, 2019, there have been a total of 685 cases of C. auris reported in the US. The majority of those cases occurred in Illinois (180), New Jersey (124), and New York (336). Twenty more cases were reported in Florida, and eight other states—California, Connecticut, Indiana, Maryland, Massachusetts, Oklahoma, Texas, and Virginia—each had less than 10 confirmed cases of C. auris.
The CDC states the infection seems to be most prominent among populations that have had extended stays in hospitals or nursing facilities. Patients who have had lines or tubes such as breathing tubes, feeding tubes, or central venous catheters entering their body, and those who have recently been given antibiotics or antifungal medications, seem to be the most vulnerable to contracting C. auris.
The fungus typically attacks people who are already sick or have weakened immune systems, which can make it challenging to diagnose, the CDC notes. C. auris infections are typically diagnosed with special clinical laboratory testing of blood specimens or other body fluids. Infections have been found in patients of all ages, from infants to the elderly.
Data from the CDC indicates that C. auris can cause
bloodstream infections, wound infections, and ear infections. Common symptoms
that indicate a person has Candida auris include fever, chills,
weakness, low blood pressure, and general malaise that do not improve with
antibiotics.
“A patient’s temperature may go up, their blood pressure can
go down, and they have complications of a pre-existing illness because of Candida
auris,” Schaffner told Prevention.
The CDC reports that more than one in three patients with
invasive C. auris dies. Even though the mortality rates for Candida
auris are high, it is unclear whether patients are dying from the infection
or from their underlying illnesses. “Whatever the cause, having Candida
auris doesn’t help a patient in any way,” Schaffner noted.
The CDC states that it and its public health partners are
working hard to discover more about this fungus, and to devise ways to protect
people from contracting it. Average healthy people probably don’t need to worry
about becoming infected with Candida auris. However, individuals who are
at high risk, and healthcare professionals, microbiologists, and pathologists,
should be on the alert for this new superbug strain of fungus.
SHERLOCK makes accurate, fast diagnoses for about 61-cents per test with no refrigeration needed; could give medical laboratories a new diagnostic tool
The tool is called SHERLOCK, which stands for (Specific High-sensitivity Enzymatic Reporter unLOCKing). And it is causing excitement in the scientific community for several reasons:
It can detect pathogens in extremely small amounts of genetic matter;
Tests can be performed using urine and/or saliva rather than blood;
The tests are extremely sensitive; and they
Cost far less than the diagnostic tests currently in use.
How SHERLOCK and CRISPR Differ and Why That’s Important
Scientists have long suspected that CRISPR could be used to detect viruses. However, far more attention has been given to the its genome editing capabilities. And, there are significant differences between how CRISPR and SHERLOCK work. According to the Science article, when CRISPR is used to edit genes, a small strip of RNA directs an enzyme capable of cutting DNA to a precise location within a genome. The enzyme that CRISPR uses is called Cas9 (CRISPR associated protein 9). It works like scissors, snipping the strand of DNA, so that it is either damaged or replaced by a healthy, new sequence.
SHERLOCK, however, uses a different enzyme—Cas13a (originally dubbed C2c2 by the researchers who discovered it). Cas13a goes to RNA, rather than DNA, and once it starts cutting, it doesn’t stop. It chops through any RNA it encounters. The researchers who developed SHERLOCK describe these cuts as “collateral cleavage.” According to an article published by STAT, “All that chopping generates a fluorescent signal that can be detected with a $200 device or, sometimes, with the naked eye.”
The screenshot above is from a video in which Feng Zhang, PhD (center), a Core Member of the Broad Institute at MIT and one of the lead researchers working on SHERLOCK, and his research team, explain the difference and value SHERLOCK will make in the detection of diseases like Zika. Click on the image above to watch the video. (Video copyright: Broad Institute/MIT.)
Early Stage Detection in Clinical Laboratories
A research paper published in Science states that SHERLOCK can provide “rapid DNA or RNA detection with attomolar sensitivity and single-base mismatch specificity.” Attomolar equates to about one part per quintillion—a billion-billion. According to the article on the topic also published in Science, “The detection sensitivity of the new CRISPR-Cas13a system for specific genetic material is one million times better than the most commonly used diagnostic technique.” Such sensitivity suggests that clinical laboratories could detect pathogens at earlier stages using SHERLOCK.
The Stat article notes that, along with sensitivity, SHERLOCK has specificity. It can detect a difference of a single nucleotide, such as the difference between the African and Asian strains of Zika (for example, the African strain has been shown to cause microcephaly, whereas the Asian strain does not). Thus, the combination of sensitivity and specificity could mean that SHERLOCK would be more accurate and faster than other diagnostic tests.
Clinicians in Remote Locations Could Diagnose and Treat Illness More Quickly
Perhaps one of the most important aspects of SHERLOCK is the portability and durability of the test. It can be performed on glass fiber paper and works even after the components have been freeze dried. “We showed that this system is very stable, so you can really put it on a piece of paper and it will survive. You don’t have to refrigerate it all the times,” stated Feng Zhang, PhD, in an interview with the Washington Post. Zhang is a Core Member of the Broad Institute at MIT and was one of the scientists who developed CRISPR.
The researchers note that SHERLOCK could cost as little as 61-cents per test to perform. For clinicians working in remote locations with little or no power, such a test could improve their ability to diagnose and treatment illness in the field and possibly save lives.
“If you had something that could be used as a screening test, very inexpensively and rapidly, that would be a huge advance, particularly if it could detect an array of agents,” stated William Schaffner, MD, Professor and Chair of the Department of Preventive Medicine at Vanderbilt University Medical Center, in the Post article. Schaffner describes the Broad Institute’s research as being “very, very provocative.”
The test could radically change the delivery of care in more modern settings, as well. “It looks like one significant step on the pathway [that] is the Holy Grail, which is developing point-of-care, or bedside detection, [that] doesn’t require expensive equipment or even reliable power,” noted Scott Weaver, PhD, in an article on Big Think. Weaver is a Professor and Director at the Institute for Human Infections and Immunity University of Texas Medical Branch in Galveston, Texas.
Just the Beginning
Anatomic pathologists and clinical laboratories will want to follow SHERLOCK’s development. It could be on the path to fundamentally transforming the way disease gets diagnosed in their laboratories and in the field.
According to the Post article, “The scientists have filed several US patent applications on SHERLOCK, including for uses in detecting viruses, bacteria, and cancer-causing mutations.” In addition to taking steps to secure patents on the technology, the researchers are exploring ways to commercialize their work, as well as discussing the possibility of launching a startup. However, before this technology can be used in medical laboratory testing, SHERLOCK will have to undergo the regulatory processes with various agencies, including applying for FDA approval.
