ELISA tests at Icahn School of Medicine contradict earlier studies which found that antibodies developed to combat the SARS-CoV-2 coronavirus are short-lived
Medical laboratories at the forefront of the COVID-19 pandemic will be intrigued to learn that antibodies produced by the body to combat the coronavirus infection may actually provide long-term immunity, contrary to previous studies that found otherwise.
A recent study from the Icahn School of Medicine at Mount Sinai found that the protection may be more robust than previously believed. This may surprise many clinical laboratory scientists and clinical pathologists. Since the outbreak of the pandemic, multiple studies have been published with conflicting findings about the strength of the immune response to SARS-CoV-2 and the length of immunity provided after an infection.
In a Mount Sinai news release, however, Florian Krammer, PhD, microbiologist and Professor of Vaccinology in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai, and a senior author of the paper, said, “While some reports have come out saying antibodies to this virus go away quickly, we have found just the opposite—that more than 90% of people who were mildly or moderately ill produce an antibody response strong enough to neutralize the virus, and the response is maintained for many months.”
The researchers published the findings of their study—which was based on an internally-developed antibody test—in Science.
The study concludes, “Although this cannot provide conclusive evidence that these antibody responses protect from reinfection, we believe it is very likely that they will decrease the odds ratio of reinfection and may attenuate disease in the case of breakthrough infection. We believe it is imperative to swiftly perform studies to investigate and establish a correlate of protection from infection with SARS-CoV-2.”
Florian Krammer, PhD (above), runs the Krammer Laboratory in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai in New York. He noted that the longevity and neutralizing effects of antibody response are “critically important to enabling us to effectively monitor seroprevalence in communities, and to determining the duration and levels of antibody that protect us from reinfection.” Antibody response, he added, is also “essential for effective vaccine development.” (Photo copyright: Icahn School of Medicine at Mount Sinai.)
Details of the Icahn School of Medicine Study
The study arose from an effort by Mount Sinai to identify potential donors for a convalescent plasma therapy program. Beginning in late March, the health system used an enzyme-linked immunosorbent assay (ELISA) to screen thousands of individuals for presence of antibodies to the spike protein in the SARS-CoV-2 virus. The virus uses the spike protein to bind to a receptor in host cells, the researchers noted, making it “the main, and potentially only target for neutralizing antibodies.”
Screened patients either had confirmed cases of COVID-19, as determined by a polymerase chain reaction (PCR) test, or suspected cases, “defined as being told by a physician that symptoms may be related to SARS-CoV-2 or exposure to someone with confirmed SARS-CoV-2 infection,” the researchers wrote. The Mount Sinai health system also offered the test to employees.
Samples from each person were diluted in five discrete titers (concentrations) ranging from 1:80 to 1:2880, and each was tested for detectable presence of the antibodies. This allowed the researchers to categorize the samples as low, moderate, or high:
Low titers: 1:80 or 1:160
Moderate titers: 1:320
High titers: 1:960 or >1:2880
Between the start of the program and early October, the health system screened 72,401 people, of whom 30,082 tested positive for at least the lowest levels of antibodies. Among those who tested positive, a large majority fell into the moderate or high categories:
1:80: 690 (2.29%)
1:160: 1453 (4.83%)
1:320: 6765 (22.49%)
1:960: 9564 (31.79%)
1:2880: 11610 (38.60%)
The researchers also wanted to see whether the antibodies offered actual protection against the virus. So, they selected 120 samples and ran a quantitative microneutralization assay. In the lowest of the three categories, 50% of the samples showed neutralizing activity. That rose to 90% in the moderate category and 100% in the high category.
Finally, to determine how long protection might last, the researchers recalled 121 plasma donors for additional tests at two different points during the study. The researchers reported a slight drop in antibody levels about three months after onset of symptoms, and then a larger drop after five months. But antibodies were still present in most samples.
“It is still unclear if infection with SARS-CoV-2 in humans protects from reinfection and for how long,” the researchers wrote. “We know from work with common human coronaviruses that neutralizing antibodies are induced, and these antibodies can last for years and provide protection from reinfection or attenuate disease, even if individuals get reinfected.”
Previous ‘Conflicting’ Research
As previously noted, other studies raised doubts about the longevity of the antibodies produced by the body’s immune system. For example, the Mount Sinai researchers cited a study from China published in Nature Medicine that looked at the immune responses of 37 symptomatic patients and an equal number of asymptomatic individuals with laboratory-confirmed cases of the COVID-19 disease. In the latter group, 40% had no detectable levels of IgG antibodies after eight weeks.
The study also found a decrease in neutralizing antibodies in 30 of the asymptomatic individuals (81.1%) and 23 of the symptomatic individuals (62.2%) over the same period.
However, the Mount Sinai researchers pointed out that the antibody test in the Chinese study targeted a different protein. “The same paper also reported relatively stable (slightly declining) neutralizing antibody titers, which shows much higher concordance with our present findings,” they wrote. “Thus, the stability of the antibody response over time may also depend on the target antigen.”
A different study from England saw a 26% decline in antibodies over three months, CNN reported. That study, conducted by Imperial College London and Ipsos MORI, a market research firm, was based on responses from more than 365,000 randomly selected people who had self-administered a lateral flow antibody test.
But the seemingly conflicting studies from New York and the UK may not be contradictory, CNN reported. “People’s bodies produce an army of immune compounds in response to an infection and some are overwhelming at first, dying off quickly, while others build up more slowly. Measurements that show a waning antibody response in the first months after infection might be measuring this first wave—but there’s a second team building its forces in the background.”
In the same CNN report, Ania Wajnberg, MD, Director of Clinical Antibody Testing at Mount Sinai Hospital and co-author of the Icahn Mount Sinai study, said, “The serum antibody titer we measured in individuals initially were likely produced by plasmablasts—cells that act as first responders to an invading virus and come together to produce initial bouts of antibodies whose strength soon wanes.”
She added, “The sustained antibody levels that we subsequently observed are likely produced by long-lived plasma cells in the bone marrow. This is similar to what we see in other viruses and likely means they are here to stay. We will continue to follow this group over time to see if these levels remain stable as we suspect and hope they will.”
Does this mean that most people who get infected with the COVID-19 coronavirus will retain an immunity to the disease? Maybe. In the Icahn Mount Sanai study, Florian Kramer wrote, “More than 90% of people who were mildly or moderately ill produce an antibody response strong enough to neutralize the virus, and the response is maintained for many months.”
Thus, clinical laboratories engaged in serological testing may be asked to perform follow-up antibody tests to see if we do indeed create long-term immunity to COVID-19. Further, pathologists and medical laboratory scientists will want to follow future studies published in peer-reviewed journals to see if the findings of the Mount Sinai study are replicated at other sites.
It’s the latest example of how the ongoing SARS-CoV-2 pandemic is making it possible for new competitors to enter the clinical laboratory marketplace
In response to increasing demand for COVID-19 testing, warehouse retailer Costco (NASDAQ:COST) is seizing the opportunity to sell at-home saliva self-collection test kits to its customers. It makes Costco the latest company to enter the market for SARS-CoV-2 testing and compete against clinical laboratories.
And these non-invasive tests—which are as simple as spitting saliva into a container and mailing it to a medical laboratory—may be more effective at detecting the SARS-CoV-2 coronavirus than uncomfortable nasal swabs.
Costco is selling its COVID-19 Saliva PCR Test Kit for $129.99 ($139.99 with video observation). Included in the price is a self-collection device, a biohazard bag, a sticker for personal data, and a box for shipping the saliva to a medical laboratory.
The test is actually P23 Labs’ TaqPath SARS-CoV-2 assay and will be administered by Azova, a digital health services provider. P23 says their test has a 98% sensitivity and 99% specificity, according to Business Insider.
The Costco P23 test kit above, “uses parts from Thermo Fisher Scientific and works with collection kits made by testing companies Everlywell and OraSure Technologies, according to the FDA and a P23 spokesperson,” Business Insider reported. “Samples are tested in [P23’s] lab in Little Rock, Arkansas.” (Photo copyright: Costco.)
Saliva-Collection Kits Gain Popularity and FDA Emergency Use Authorizations
P23 Labs’ assay is one of 12 COVID-19 home tests that have received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA). Three of which use saliva specimens.
The FDA’s EUA authorization summary for the P23 assay states it is “for use with saliva specimens that are self-collected at home or in a healthcare setting with or without the supervision and/or assistance of [a healthcare provider (HCP)], by individuals using the P23 At-Home COVID-19 Test Collection Kit, when determined to be appropriate by an HCP based on the results of a COVID-19 medical questionnaire. This test is also for use with nasal swab specimens that are self-collected at home or in a healthcare setting with or without the supervision and/or assistance of an HCP by individuals.”
In a news release announcing the first diagnostic test using saliva specimens, oncologist and FDA Commissioner Stephen Hahn, MD, said that “Authorizing additional diagnostic tests with the option of at-home sample collection will continue to increase patient access to testing for COVID-19. This (saliva sample collection) provides an additional option for the easy, safe, and convenient collection of samples required for testing without traveling to a doctor’s office, hospital, or testing site.” That test was manufactured by Clinical Genomics laboratory of Rutgers New Jersey Medical School.
Below is a list from Business Insider for at-home self-collection SARS-CoV-2 coronavirus tests that have received an FDA EUA. Most can be ordered online, and prices range from $109 to $149, which may be covered by insurance depending on the health plan.
Binx Health Home Nasal Swab COVID-19 sample collection kit
Yale Study Indicates Saliva Tests Have Greater Detection Sensitivity over Swab
Should consumers choose COVID-19 saliva tests over nasal cavity swab tests? Maybe.
A study led by the Yale School of Public Health found and “conducted at Yale New Haven Hospital with 44 inpatients and 98 health care workers—found that saliva samples taken from just inside the mouth provided greater detection sensitivity and consistency throughout the course of an infection than the broadly recommended nasopharyngeal (NP) approach. The study also concluded that there was less variability in results with the self-sample collection of saliva,” states a Yale University news release.
Anne Wyllie, PhD, Associate Research Scientist at Yale School of Public Health, told Time magazine, “Saliva itself is a newer diagnostic method, and a lot of people don’t know how to work with it, are scared to work with it, or not sure how to work with it. Just because a protocol is working with swabs doesn’t mean the same protocol will work with saliva.” Nevertheless, public demand for less invasive COVID-19 testing means clinical laboratories may soon be receiving more requests for processing saliva over nasal swabs. (Photo copyright: Yale University.)
Yale received FDA EUA for SalivaDirect, a real-time quantitative polymerase chain reaction (RT-qPCR) for detection of SARS-CoV-2. However, SalivaDirect is not an “at-home” test. It requires saliva samples to be self-collected into a sterile container in the presence of a healthcare professional, and is being provided by Yale to clinical laboratories as an “open source” protocol, the FDA said in a news release.
“We are trying to work with smaller local labs that want to get up and running to support schools, community groups, universities, and colleges,” Wyllie told Time.
In “Saliva or Nasopharyngeal Swab Specimens for Detection of SARS-CoV-2,” published in the New England Journal of Medicine (NEJM), Wyllie and others suggest saliva can be just as effective in detecting the coronavirus that causes COVID-19. In their study, COVID-19 patients who were tested by healthcare workers using nasopharyngeal swabs were then asked to collect their own saliva samples.
The researchers found that “Collection of saliva samples by patients themselves negates the need for direct interaction between healthcare workers and patients. This interaction is a source of major testing bottlenecks and presents a risk of nosocomial infection. Collection of saliva samples by patients themselves also alleviates demands for supplies of swabs and personal protective equipment. Given the growing need for testing, our findings provide support for the potential of saliva specimens in the diagnosis of SARS-CoV-2 infection.”
The Yale scientists used primer sequences identified by the Centers for Disease Control and Prevention to detect the coronavirus. They found more SARS-CoV-2 RNA in saliva specimens than in the nasopharyngeal swab specimens. Also, 81% of saliva samples were positive one to five days after diagnosis, as compared to 71% of the nasopharyngeal swab specimens.
“The findings suggest saliva specimens and nasopharyngeal swab specimens have at least similar sensitivity in the detection of SARS-CoV-2 during the course of hospitalization,” the researchers wrote in their NEJM paper.
The increasing popularity of at-home COVID-19 testing—along with studies showing that results improve when specimens are self-collected—suggest that medical laboratory managers should closely monitor the rise of COVID-19 home tests, as well as progress being made in saliva for diagnosing the SARS-CoV-2 coronavirus.
Further, it might be a smart strategy for clinical laboratories with the capability to perform this testing to approach retailers in their region and establish relationships where retailers sell the collection kits, and the lab performs the test and reports the results.
Since patients pay cash for the SARS-CoV-2 tests at the time they purchase the kits, clinical labs are guaranteed payment for the tests without the need to submit claims to consumers’ insurance companies. That’s another benefit to these types of arrangements.
United Airlines creates pilot program for on-site rapid PCR tests, as other airlines facilitate at-home specimen collection for rapid coronavirus testing
Four US airlines attempting to recover lost business due to the COVID-19 pandemic are partnering with developers of rapid RT-PCR (reverse transcription polymerase chain reaction) tests to facilitate testing of passengers either at airports before they board their flights, at drive-through testing sites, or at-home in advance of scheduled travel.
This would be a great opportunity for clinical laboratories to gain business, but few details are known about how these airlines are selecting providers for the COVID-19 tests that will be part of their programs.
The deals come amid calls from the International Air Transport Association (IATA) “for the development and deployment of rapid, accurate, affordable, easy-to-operate, scalable and systematic COVID-19 testing for all passengers before departure as an alternative to quarantine measures” in many countries, states an IATA press release.
“The key to restoring the freedom of mobility across borders is systematic COVID-19 testing of all travelers before departure,” said Alexandre de Juniac, IATA Director General and CEO, in the IATA press release. “This will give governments the confidence to open their borders without complicated risk models that see constant changes in the rules imposed on travel.”
From a clinical laboratory testing perspective, the requirement for passengers to be tested prior to travel may contribute to two changes in the lab testing marketplace:
Consumers may become accustomed to buying home collection kits for COVID-19 and sending specimens to clinical laboratories. This could have the added benefit of helping consumers become comfortable doing this for other diagnostic tests as well.
Pursuit of profit from manufacturing COVID-19 tests that utilize consumer-collected specimens may increase competition in this market and would likely increase the number of at-home specimen collection products that are easier and more convenient to use.
US carriers offering the COVID-19 tests include United Airlines, American Airlines, Hawaiian Airlines, and JetBlue.
United Airlines
United is providing on-site testing through pilot programs at San Francisco International Airport (SFO) and Newark Liberty International Airport (EWR). At SFO, passengers are tested before taking flights to Hawaii. At EWR, they are tested prior to boarding a thrice-weekly flight to London Heathrow.
“We believe the ability to provide fast, same-day COVID-19 testing will play a vital role in safely reopening travel around the world and navigating quarantines and travel restrictions, particularly to key international destinations like London,” said Toby Enqvist, United’s Chief Customer Officer, in a press release.
United began offering testing at SFO on Oct. 15. According to “COVID-19 Testing for United Travelers,” the San Francisco to Hawaii passengers have two options:
A $105 drive-through test administered two or three days prior to flights by Color, a San Francisco Bay area health technology company.
The airline says a negative test ensures that travelers can bypass Hawaii’s mandatory quarantine requirements in Lihue, Maui, and Honolulu. For the Newark-to-London flights, United plans to run a pilot rapid testing program from Nov. 16 to Dec. 11. for passengers boarding Flight 14, departing at 7:15 p.m. Mondays, Wednesdays, and Fridays. Premise Health will administer the testing, which will be free to passengers. Those who choose not to be tested will be placed on other flights.
A United Airlines flight attendant (above) receives an RT-PCR test for COVID-19 prior to boarding. If the flying public embraces preflight coronavirus testing, including at-home specimen collection kits, clinical laboratories may see a spike in requests for test processing. (Photo copyright: The Washington Post.)
American Airlines
American is offering COVID-19 testing for passengers scheduled on flights to Hawaii, Latin America, and the Caribbean, according to a press release. For the most part, these are at-home specimen collection RT-PCR tests provided by healthcare testing services company PrivaPath Diagnostics, Inc. (d.b.a., LetsGetChecked). Customers receive their results within 24 to 72 hours after the lab receives the samples.
As with the United flights to Hawaii, the testing program allows passengers to bypass quarantine requirements at their destinations. Customers pay $119 for the LetsGetChecked at-home specimen-collection kit and subsequent RT-PCR testing.
“Our initial preflight testing has performed remarkably well, including terrific customer feedback about the ease and availability of testing options,” American Airlines President Robert Isom said in the press release.
Hawaiian Airlines and JetBlue
In separate press releases, Hawaiian Airlines and JetBlue announced partnerships with Vault Health to offer at-home saliva tests to passengers. After receiving the at-home specimen collection kit, customers can connect through Zoom video conferencing with a Vault Health supervisor who ensures the sample is collected properly.
Hawaiian Airlines also offers drive-through testing at SFO and Los Angeles International Airport through a partnership with Worksite Labs. Passengers pay $90 to receive test results within 36 hours or $150 for express service on the day of travel. Worksite uses a Droplet Digital PCR shallow nasal swab test. The airline says it plans to expand this to other airports.
The Vault Health and Worksite Labs tests meet the state’s guidelines for exemption from the 14-day quarantine requirement, the airlines say.
Impact on Medical Laboratories
Airlines offering COVID-19 testing to their passengers may trigger both an opportunity and a change in the clinical laboratory testing marketplace. First, there is a business opportunity for labs to provide rapid molecular SARS-COV-2 tests to airlines.
Second, if consumers begin using at-home specimen collection kits in greater numbers as part of their air travel requirements, might this make them more comfortable doing self-collection for other types of clinical laboratory tests? A shift in consumer willingness to collect their own medical laboratory specimens—accompanied by ongoing innovations in diagnostic technologies, may eventually reduce the need for medical labs to operate extensive networks of patient service centers.
Of course, such a scenario is years away. But airline COVID-19 testing programs are just one of the progressive steps that can help make that possibility into a reality.
Clinical laboratory managers and pathology practice administrators should consider how these trends may affect their business and patients when planning for the future.
The McKinsey graphic above illustrates the “six trends that are likely to shape post-COVID-19 healthcare.” Clinical laboratories that support health networks struggling with any of these challenges should take steps to prepare for anticipated changes to healthcare delivery. (Graphic copyright: McKinsey and Company.)
1: Healthcare Reform
McKinsey identified three areas where the coronavirus pandemic may impact healthcare reform:
“COVID-19-era waivers that could become permanent.
“Actions that may be taken to strengthen the healthcare system to deal with pandemics.
“Reforms to address the COVID-19-induced crisis.”
McKinsey reports that “the Centers for Medicare and Medicaid Services has introduced more than 190 waivers since the beginning of March 2020.” These waivers can affect all aspects of healthcare, from clinical practice to reimbursement. Some of them, according to McKinsey, are “only relevant during the crisis (for example, the waiver of intensive care unit death reporting). A retrospective assessment of others (for example, expansion of telehealth access) could reveal beneficial innovation worth preserving.”
Several areas that McKinsey says are clearly ripe for reform include improving the resiliency of the healthcare system and the way the system is funded.
Public sector budgets are generally kept strictly separate, each with its own rules and policies that dictate operations. But in his article, “After COVID-19—Thinking Differently About Running the Health Care System,” published in JAMA Health Network, Stuart M. Butler, PhD, Senior Fellow in Economic Studies at the Brookings Institution, wrote, “The intensity of the COVID-19 pandemic … is forcing jurisdictions all across the country to find ways to be nimble so that multiple agencies can work together.”
Thus, McKinsey recommends, “Given the substantial shifts in relative market positioning among industry players that prior reforms have created, leaders would do well to plan ahead now.”
2: Better Access to Healthcare Services
Some people who develop COVID-19 are at far greater risk of hospitalization and death than others, including those who have:
Chronic health conditions, including obesity.
Mental and behavioral health challenges, such as substance abuse.
Unmet social needs, such as food or housing insecurity.
Poor access to healthcare.
McKinsey wrote that these “intersecting health and social conditions,” combined with certain races that have higher risk for severe complications, including Black, Indian, and Hispanic/Latino Americans, “correlated with poorer health outcomes.”
Value-based healthcare, telehealth, and greater attention to the social determinants of health may help address some of these issues, McKinsey notes, but the pandemic has shined a spotlight on how lack of care increases risk for certain populations during a public health crisis.
3: Era of Exponential Improvement Unleashed
Some of the trends that appear to be accelerating as a result of the pandemic are good news. McKinsey cites several benefits, including:
Improved understanding of patients.
Delivery of more convenient and individualized care.
$350-$410 billion in annual revenue by 2025.
Through telehealth and other types of virtual care enabled by digital technology, “intuitive healthcare ecosystems” may arise and offer a more integrated experience for patients and their caregivers, McKinsey notes.
“While the pace of change in healthcare has lagged other industries in the past, potential for rapid improvement may accelerate due to COVID-19. An example is the exponential uptake of digitally enabled, virtual care,” McKinsey wrote. “Our analysis … showed that health systems, primary care, and behavioral health practices are reporting increases of more than 50–175 times in telehealth visits, and the potential market size for virtual care could reach around $250 billion.”
The graphic above is taken from the McKinsey and Co. report, which noted, “Proliferation of digitally enabled, virtual care could further contribute to the rise of personalized and intuitive healthcare ecosystems [that] have the potential to deliver an integrated experience to consumers, enhance productivity of providers, engage both formal and informal caregivers, and improve outcomes while lowering cost.” (Graphic copyright: McKinsey and Company.)
4: The Big Squeeze
The pandemic has caused an enormous outflow of cash from the healthcare system, and some experts don’t expect an injection of funding until 2022. “This outflow is expected to be primarily driven by coverage shifts out of employer-sponsored insurance and possible coverage reductions by employers as well as Medicaid rate pressures from states,” McKinsey states.
“We estimate that COVID-19 could depress healthcare industry earnings by between $35 billion and $75 billion compared with baseline expectations,” McKinsey predicted, adding, “Select high-growth segments will remain attractive (for example, virtual care, home health, software and platforms, specialty pharmacy) and will disproportionally drive growth. These high-growth areas are expected to increase more than 10% over the next five years, while other segments may stagnate or decline altogether.”
5: Fragmented, Integrated, Consolidated Care Delivery
McKinsey says, “The shift of care out of hospitals is not new but has been accelerated by COVID-19.” Rather than the hospital being the center of care delivery, patients are increasingly choosing to receive care at a range of sites across many healthcare ecosystems that are connected digitally and through analytics.
Early in the course of the pandemic, visits to ambulatory care facilities dropped nearly 60% by early April. But by mid-May, those visits were beginning to rebound.
In, “The Impact of the COVID-19 Pandemic on Outpatient Visits: A Rebound Emerges,” the Commonwealth Fund reported that “the relative decline in visits remains largest among surgical and procedural specialties and pediatrics” but is “smaller in other specialties, such as adult primary care and behavioral health.”
The McKinsey graphic above shows how “virtual care and outpatient options show more potential revenue growth through 2022.” Clinical laboratories that support those healthcare settings, especially ambulatory surgery, behavioral health, and retail clinics, should experience similar growth. (Graphic copyright: McKinsey and Company.)
6: Adoption of Next-Generation Managed Care Is Accelerating
How will COVID-19 affect the managed care industry? McKinsey says the “next generation” of managed care might use Medicare Advantage as a model.
“Payers pursuing the next generation of managed care model (through deep integration with care delivery) demonstrate better financial performance, capturing an additional 50 basis points of earnings before interest, taxes, depreciation, and amortization above expectation,” McKinsey noted, adding, “Employers and payers could consider fundamentally rethinking how employer-sponsored health coverage is structured. Learning from Medicare Advantage could provide inspiration for such a reimagination.”
What Should Clinical Laboratory Managers Do?
The McKinsey article concludes by stating, “While the challenges are numerous, leaders who seize the mindset that “disruptive change provides an opportunity to separate yourself from the pack” will build organizations meaningfully stronger than the ones they ran going into the crisis.”
The McKinsey article authors recommend that healthcare organizations take several proactive steps, including:
Launch a plan-ahead team.
Question your role and your future business model.
Prepare to transform your business.
Reimagine your organization to make faster decisions.
Take action to drive health equity.
Though the McKinsey and Company article covered healthcare in general, many of the authors’ observations and recommendations can apply to clinical laboratories and pathology groups as well and may be valuable in future planning.
Breakthrough assay a ‘tenfold improvement over any prior assay for TERT mutations in the blood for brain tumors,’ MGH says in an affirmation of a diagnostic technology clinical labs might soon use
In recent years, investors have poured tens of millions of dollars into companies that promised to create non-invasive cancer tests which use liquid biopsy technology. Medical laboratory scientists even watched some of these companies hype their particular liquid biopsy tests before clinical studies generated data demonstrating that these tests produced accurate, reliable, and reproducible results.
For diagnosing cancer, a liquid biopsy test typically uses a blood sample with the goal of finding and identifying circulating tumor cells. Harvard Medical School researchers at Massachusetts General Hospital (MGH) believe they have developed just such a blood test. Their assay utilizes an enhanced form of liquid biopsy to detect and monitor one of the more prevalent types of brain tumor in adults—a glioma—and, according to a Harvard news release, can detect the presence of glioma at a significantly higher “overall sensitivity” than other similar liquid-biopsy tests.
Gliomas start in glia cells contained in the brain or spine. They account for about 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors.
During their study, MGH researchers compared blood samples and tumor biopsy tissues from patients diagnosed with a glioma. They discovered that an assay they developed—a droplet digital polymerase chain reaction (ddPCR) blood test—could detect and monitor two types of telomerase reverse transcriptase (TERT) promoter gene mutations—C228T and C250T. These two gene mutations promote cancer growth and are present in more than 60% of all gliomas. The mutations are also present in 80% of all high-grade gliomas, which are the most aggressive and life-threatening types of the cancer.
In the press release, instructor in Neurosurgery at MGH and one of the study’s authors, Leonora Balaj, PhD, said, “By ‘supercharging’ our ddPCR assay with novel technical improvements, we showed for the first time that the most prevalent mutation in malignant gliomas can be detected in blood, opening a new landscape for detection and monitoring of the tumors.”
Bob Carter, MD, PhD (above), is neurosurgical oncologist and Chief of Neurosurgery at MGH, a Professor of Neurosurgery at Harvard Medical School, and one of the study’s authors. In the MGH press release he said, “We envision the future integration of tests like this one into the clinical care of our patients with brain tumors. For example, if a patient has a suspected mass on MRI scanning, we can take a blood sample before the surgery and assess the presence of the tumor signature in the blood and then use this signature as a baseline to monitor as the patient later receives treatment, both to gauge response to the treatment and gain early insight into any potential recurrence.” What Carter describes is precision medicine and could open new diagnostic opportunities for anatomic pathology groups and clinical laboratories. (Photo copyright: Massachusetts General Hospital.)
MGH’s Ten-Fold Improvement over Previous ddPCR Assays
A liquid biopsy is the sampling and analysis of non-solid tissue in the body—primarily blood. MGH’s liquid-biopsy method detects cancer by examining fragments of tumor DNA circulating in the bloodstream. Since the technique is mostly non-invasive, tests can be performed more frequently to track tumors and mutations and monitor treatment progression. Prior to this new method, brain tumors had been difficult to detect using liquid biopsies.
“Liquid biopsy is particularly challenging in brain tumors because mutant DNA is shed into the bloodstream at a much lower level than any other types of tumors,” Balaj said in the press release.
However, MGH’s new ddPCR assay has an overall sensitivity rate of 62.5% and a specificity of 90%, which represents a tenfold improvement over prior assays for TERT mutations in the blood.
And when testing the performance of the ddPCR assay in tumor tissue, the MGH researchers discovered their results were the same as results from a previous independently-performed clinical laboratory assessment of TERT mutations within collected tumor specimens. They also found that their assay could detect TERT mutations when looking at blood plasma samples collected at other facilities.
The researchers believe that their test could be performed in most clinical laboratories and can be utilized to follow the course of disease in cancer patients. The MGH researcher’s goal is to expand and adapt the blood test to diagnose, differentiate, and monitor other types of brain tumors in addition to gliomas.
Of course, more research will be needed before MGH’s new assay can become a vital tool in the fight against disease. However, this type of genetic analysis may soon provide pathologists with new techniques to more accurately diagnose and monitor cancers, and to provide healthcare providers with valuable data regarding which therapies would be the most beneficial for individual patients, a key element of precision medicine.
About 50% of South Asians and 16% of Europeans carry gene cluster associated with respiratory failure after SARS-CoV-2 infection and hospitalization
Clinical pathology laboratories and medical laboratory scientists may be intrigued to learn that scientists from two research institutes in Germany and Sweden have determined that a strand of DNA associated with a higher risk of severe COVID-19 in humans is similar to the corresponding DNA sequences of a roughly 50,000-year-old Neanderthal from Croatia.
The researchers concluded that this gene cluster—passed down from Neanderthals to homo sapiens—triples the risk of developing severe COVID-19 respiratory symptoms for some modern day humans.
In a press release, Pääbo said, “It is striking that the genetic heritage from the Neanderthals has such tragic consequences during the current pandemic. Why this is must now be investigated as quickly as possible.”
Might Useful Biomarkers for Clinical Laboratory Tests Be Identified?
Though it is not immediately clear how these findings may alter current approaches to developing treatments and a vaccine for the SARS-CoV-2 coronavirus, it is another example of how increased knowledge of human DNA leads to new understandings about genetic sequences that can spur development of useful biomarkers for clinical laboratory diagnostics tests.
Swedish geneticist Svante Pääbo, PhD (above right), Director of the Max Planck Institute for Evolutionary Anthropology in Germany, is co-author of a recent study that traced a gene cluster linked to a higher risk of severe COVID-19 to 50,000-year-old Neanderthals from Croatia. “It is striking that the genetic heritage from the Neanderthals has such tragic consequences during the current pandemic,” he said. Nevertheless, such discoveries sometimes lead to new biomarkers for clinical laboratory tests and diagnostics. (Photo copyright: Max Planck Institute for Evolutionary Anthropology.)
This latest research reveals that people who inherit a specific six-gene combination on chromosome 3—called a haplotype—are three times more likely to need artificial ventilation if they are infected by the SARS-CoV-2 coronavirus. Yet, the researchers can only speculate as to why the gene cluster confers a higher risk.
“The genes in this region may well have protected the Neanderthals against some other infectious diseases that are not around today. And now, when we are faced with the [SARS-CoV-2] coronavirus, these Neanderthal genes have these tragic consequences,” Pääbo told the Guardian.
According to the study, the gene risk variant is most common in South Asia where about half of the population carries the Neanderthal risk variant. In comparison, one in six Europeans have inherited the gene sequence and the trait is almost nonexistent in Africa and East Asia.
“About 63% of people in Bangladesh have at least one copy of the disease-associated haplotype, and 13% have two copies (one from their mother and one from their father). For them, the Neandertal DNA might be partially responsible for increased mortality from a coronavirus infection. People of Bangladeshi origin living in the United Kingdom, for instance, are twice as likely to die of COVID-19 as the general population,” Science News reported.
Other Research Connecting Genes to Severe COVID-19 Symptoms
The haplotype on chromosome 3 first made headlines in June when the New England Journal of Medicine (NEJM) published the “Genomewide Association Study of Severe COVID-19 with Respiratory Failure,” which analyzed COVID-19 patients in seven hospitals in Italy and Spain. The researchers found an association between the gene cluster on chromosome 3 and severe symptoms of SARS-CoV-2 after infection and hospitalization. The study also pointed to the potential involvement of chromosome 9, which contains the ABO blood-group system gene, indicating that humans with type A blood may have a 45% higher risk of developing severe COVID-19 infections.
However, Mark Maslin, PhD, Professor of Climatology at University College London, cautions against drawing strong conclusions from the initial research tying disease risk to the genetic legacy of Neanderthals, the Guardian reported. He suggested that, while the Neanderthal-derived variant may contribute to COVID-19 risk in certain populations, genes are more likely to be just one of multiple risk factors for COVID-19 that include age, gender, and pre-existing conditions.
“COVID-19 is a complex disease, the severity of which has been linked to age, gender, ethnicity, obesity, health, virus load among other things,” Maslin told the Guardian. “This paper links genes inherited from Neanderthals with a higher risk of COVID-19 hospitalization and severe complications. But as COVID-19 spreads around the world it is clear that lots of different populations are being severely affected, many of which do not have any Neanderthal genes.
“We must avoid simplifying the causes and impact of COVID-19, as ultimately a person’s response to the disease is about contact and then the body’s immunity response, which is influenced by many environmental, health and genetic factors.”
Andre Franke, PhD, Director of the Institute of Clinical Molecular Biology, Kiel University in Germany, agrees with Maslin, the Associated Press reported. In a statement “ahead of the study’s final publication,” he said these latest findings have no immediate impact on the treatment of COVID-19, and he questioned “why that haplotype—unlike most Neanderthal genes—survived until today,” AP reported.
All of this deepens the mystery of the SARS-CoV-2 coronavirus. Genomics research continues to add new insights into what is known about COVID-19 and may ultimately provide answers on why some people contract the disease and remain asymptomatic—or have mild symptoms—while others become seriously ill or die. Understanding why and how certain genes increase the risk of severe COVID-19 could give rise to targeted clinical laboratory tests and therapies to fight the disease.
