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Researchers in Boston Find COVID-19 Spike Protein Lingers in Long COVID-19 Patients

Viral reservoir could be behind persistence, says study, which also suggests a blood biomarker could be found for clinical laboratory testing

Microbiologists and virologists working closely with physicians treating long COVID-19 patients will gain new insights in a study that found coronavirus spike protein in COVID-19 patients’ blood up to 12 months after diagnosis. The researchers believe their findings could be used to develop a clinical laboratory biomarker for long COVID-19.

Researchers at Brigham and Women’s Hospital and Massachusetts General Hospital said medical experts are not sure why some people have unwelcome symptoms weeks and months after a positive COVID-19 diagnosis, while others clear the infection without lingering effects.

The scientists believe if this work is validated, clinical laboratories might gain an assay to use in the diagnosis of long COVID-19.

“The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. … Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir,” the researchers wrote in their published study, which can be found on the preprint server medRxiv, titled, “Persistent Circulating SARS-CoV-2 Spike Is Associated with Post-Acute COVID-19 Sequelae.”

David Walt, PhD

“The half-life of spike protein in the body is pretty short, so its presence indicates that there must be some kind of active viral reservoir,” said David Walt, PhD (above), Professor of Pathology, Brigham and Women’s Hospital, and lead author of the study that found coronavirus spike protein in long COVID patients. The study findings indicate a potential clinical laboratory biomarker for long COVID-19. (Photo copyright: Brigham and Women’s Hospital.)

Viral Reservoir Possibly Behind Long COVID-19

The study suggests that SARS-CoV-2 finds a home in the body, particularly the gastrointestinal tract, “through viral reservoirs, where it continues to release spike protein and trigger inflammation,” Medical News Today reported.

Lead author of the study David Walt, PhD, Professor of Pathology, Brigham and Women’s Hospital and the Hansjörg Wyss Professor Biologically Inspired Engineering at Harvard Medical School, told The Guardian he “was motivated to carry out the study after earlier research by his colleagues detected genetic material from the COVID virus (viral RNA) in stool samples from children with multisystem inflammatory syndrome (a rare but serious condition that often strikes around four weeks after catching COVID) as well as spike protein and a marker of gut leakiness in their blood.”

Long COVID—also known as long-haul COVID, post-COVID-19, or its technical name, post-acute sequelae of COVID-19 or PASC—can involve health problems continuing weeks, months, or even years after a positive diagnosis, according to the federal Centers for Disease Control and Prevention (CDC).

Symptoms of long COVID, according to the researchers, include:

  • fatigue,
  • loss of smell,
  • memory loss,
  • gastrointestinal distress, and
  • shortness of breath. 

“If someone could somehow get to that viral load and eliminate it, it might lead to resolution of symptoms,” Walt told the Boston Globe, which noted that the researchers may explore a clinical trial involving antiviral drugs for treatment of long COVID-19.

Clues from Earlier Studies on Long COVID-19

Medical conditions that persisted following a COVID-19 infection have been studied for some time. In fact, in an earlier study, Walt and others found children who developed a multisystem inflammation syndrome weeks after being infected by SARS-CoV-2, according to their 2021 paper published in The Journal of Clinical Investigation, titled, “Multisystem Inflammatory Syndrome in Children Is Driven by Zonulin-Dependent Loss of Gut Mucosal Barrier.”

Although these earlier studies provided clues, the cause of PASC remains unclear, the researchers noted. They planned to take a more precise look at PASC biology by using appropriate sampling and patient recruitment.

“Disentangling the complex biology of PASC will rely on the identification of biomarkers that enable classification of patient phenotypes. Here, we analyze plasma samples collected from PASC and COVID-19 patients to determine the levels of SARS-CoV-2 antigens and cytokines and identify a blood biomarker that appears in the majority of PASC patients,” the researchers wrote.

Finding a Marker of a Persistent Infection

The researchers used plasma samples from 63 people with a previous SARS-CoV-2 diagnosis (37 also had PASC), Medical News Today reported. Over a 12-month period, the researchers’ findings included:

  • Detection in 65% of PASC samples of full-length spike, S1 spike, and nucleocapsid throughout the year of testing.
  • Spike detected in 60% of PASC patient samples, and not found in the COVID-19 samples.

In an interview with Scientific American, bioengineer Zoe Swank PhD, post-doctoral researcher, Brigham and Women’s Hospital, and co-author of the study, said, “Our main hypothesis is that the spike protein is not causing the symptoms, but it’s just a marker that is released because you still have infection of some cells with SARS-CoV-2.” 

In that article, Swank shared the scientists’ intent to do more research involving hundreds of samples over the course of the COVID-19 pandemic from many hospitals and people.

COVID-19 Not the Only Virus That Hangs On

Having a long-haul COVID-19 marker is a “game-changer,” according to an infectious disease expert who was not involved in the study.

“There has not so far been a clear, objective marker that is measurable in the blood of people experiencing long COVID-19,” Michael Peluso, MD, Assistant Professor, Medicine, University of California San Francisco, told Scientific American. “I hope their findings will hold up. It really would make a difference for a lot of people if a marker like this could be validated,” he added.

However, COVID-19 is not the only virus that could persist. Ebola also may linger in areas that skirt the immune system, such as the eye interior and central nervous system, according to a World Health Organization fact sheet.

Thus, medical laboratory leaders may want to follow the Brigham and Women’s Hospital research to see if the scientists validate their finding, discover a biomarker for long-haul COVID-19, and pursue a clinical trial for antiviral drugs. Such discoveries could have implications for how diagnostic professionals work with physicians to care for long COVID patients.   

Donna Marie Pocius

Related Information:

Persistent Circulating SARS-CoV-2 Spike Is Associated with Post-Acute COVID-19 Sequelae

Long COVID: “Viral Reservoir” of Spike Protein May Explain Long-Term Symptoms

Are Pockets of COVID in the Gut Causing Long-Term Symptoms?

CDC: COVID-19: Long-Term Effects

Boston Researchers May Have Found Biomarker for Long COVID

Multisystem Inflammatory Syndrome in Children Is Driven by Zonulin-Dependent Loss of Gut Mucosal Barrier

People with Long COVID May Still Have Spike Proteins in Their Blood

WHO: Ebola Virus Disease

Human Antibodies in Medical Laboratory May Be Key to Immunity and Preventing Diseases Such as Influenza A

Scientists with Francis Crick Institute and Ragon Institute have successfully created human antibodies in vitro that can be made to recognize specific antigens in the human body; Could lead to new treatments for cancer and other infectious diseases

It’s been long-recognized that the ability to design human antibodies customized to recognize specific antigens could be a game-changer in the diagnosis and treatment of many diseases. It would enable the creation of useful new clinical laboratory tests, vaccines, and similar therapeutic modalities.

Now an international research team has published the findings of its novel technique that was developed to generate human antibodies in vitro. The research was conducted at the Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), Harvard, and the Francis Crick Institute in London.

Antibodies and antigens are used in a large number of clinical laboratory and anatomic pathology tests and assays. In many cases, animal antibodies/antigens are used in test kits because they attract and bind to specific human antibodies/antigens that are biomarkers for diagnoses. Thus, as this technology is validated and further developed, it could be the source of useful biomarkers for lab tests as well as for vaccines.

Antibodies—also referred to as immunoglobulins—are made by the body’s B-lymphocytes (B cells) in response to antigens, such as bacteria, viruses, or other harmful substances. Each antibody has a special bearing on a particular antigen. For example, the human immunodeficiency virus (HIV) antibody and HIV antigen (p24) test screens and diagnoses people for HIV infection, explained LabTestsOnline.

Many medical laboratory tests use animal antibodies and antigens. But what if human antibodies could be generated and stimulated to recognize specific human antigens? That’s what the researchers believe they have done, according to a press release.

The Ragon Institute at MGH, MIT, and Harvard (above) was established in 2009 to find an HIV vaccine and to be a worldwide leader in the study of immunology. The Francis Crick Institute, formed in 2015, is a biomedical research institute using biology to understand health and disease. (Photo copyright: The Ragon Institute.)

The researchers know the novel technique they developed for generating human antibodies in vitro needs further development and validation. If this happens, the technique could one day be the source of useful biomarkers for medical lab tests, and may be a way to prevent infectious diseases.

“Specifically, it should allow the production of these antibodies within a shorter time frame in vitro and without the need for vaccination or blood/serum donation from recently infected or vaccinated individuals,” said Facundo D. Batista, PhD, in the press release. Batista is Principle Investigator with the Ragon Institute and led the research teams. “In addition, our method offers the potential to accelerate the development of new vaccines by allowing the efficient evaluation of candidate target antigens.”

Researchers Aim to Make Human Antibodies in Medical Laboratory

This international team of researchers sought to replicate in the lab—using patient blood samples—a natural human process for creation of antibodies from B cells. This is the process they wished to replicate:

·       Antibodies are made by the body’s B cells;

·       An antigen molecule is recognized by a B cell;

·       Plasma cells (able to secrete antibodies) develop;

·       An antibody binds to a particular antigen to fight an infection.

“B lymphocytes (B cells) play a critical role in adaptive immunity, providing protection from pathogens through the production of specific antibodies. B cells recognize and respond to pathogen-derived antigens through surface B cell receptors,” the researchers wrote in The Journal of Experimental Medicine (JEM).

Nanoparticles Key to the Approach

But finding an exact antigen is only one part of the B cell’s job. In the lab, B cells also need a trigger that enables them to grow and develop into plasma cells, which are key to fighting disease, the researchers noted.

“The in vitro activation of B cells in an antigen-dependent manner is difficult to achieve,” the authors stated in the JEM. “To overcome limitations, we developed a novel in vitro strategy to stimulate human B cells with streptavidin nanoparticles conjugated to both CpG and antigen. B cells producing antigen-specific antibodies were identified, quantified, and characterized to determine the antibody repertoire.”

According to the press release, “CpG oligonucleotides internalize into B cells that recognize the specific antigen.”

The statement, which garnered worldwide attention, noted the following steps taken by the researchers:

·       B cells from patient blood samples were isolated;

·       Then, they were treated with tiny nanoparticles coated with both CpG oligonucleotides and the right antigen;

·       These DNA molecules are unique, because they can activate toll-like receptor 9 (TLR9);

·       TLR9 develops into antibody-secreting plasma cells.

Results: Antibodies for Tetanus, Influenza, HIV

This method, according to the scientists, could be used in further research to develop antibodies to treat infectious diseases and cancer.

According to The Times of India,

·       “The team successfully demonstrated their approach using various bacterial and viral antigens, including the tetanus toxoid and proteins from several strains of influenza A;

·       “In each case, the researchers were able to produce specific, high-affinity antibodies in just a few days. Some of the anti-influenza antibodies generated by the technique recognized multiple strains of the virus and were able to neutralize its ability to infect cells;

·       “The procedure does not depend on the donors having been previously exposed to any of these antigens through vaccination or infection; and,

·       “Researchers were able to generate anti-HIV antibodies from B cells isolated from HIV-free patients.”

Research Suggests More Possibilities

While this highly scientific study may not be on the radar of most anatomic pathologists and medical laboratory leaders at the moment, it holds enormous promise to produce cures for infectious disease and more effective cancer treatments. This research project also demonstrates how new techniques using antibodies have the potential to create an entirely new generation of clinical laboratory assays that improve diagnostic accuracy and better inform physicians when they consider the most appropriate therapies for their patients.

—Donna Marie Pocius

Related Information:

Researchers Develop New Method to Generate Human Antibodies

Novel In Vitro Booster Vaccination to Rapidly Generate Antigen-Specific Human Monoclonal Antibodies

Human Antibodies Produced in Lab for First Time