How long is antibody duration in Covid 19 ? / Antibodies

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Army researchers team up to test alternative ways to measure COVID-19 antibody levels

10/14/20


https://www.news-medical.net/news/20201 ... evels.aspx


Researchers with the U.S. Army Futures Command are part of a team that tested alternative ways to measure COVID-19 antibody levels, resulting in a process that is faster, easier and less expensive to use on a large scale. Their method holds promise for accurately identifying potential donors who have the best chance of helping infected patients through convalescent plasma therapy.

Dr. Jimmy Gollihar, biochemist and biotechnologist for the U.S. Army Combat Capabilities Development Command's Army Research Laboratory at CCDC ARL South in Austin, Texas, and chief technology officer of the Bioindustrial Manufacturing Innovation Institute, in collaboration with Dr. John Dye at the U.S. Army Medical Research Institute of Infectious Diseases, or USAMRIID, and collaborators at Houston Methodist, Pennsylvania State University and the University of Texas at Austin, sought to find alternatives to measuring virus neutralization, or VN, titers.

These titers are the gold standard of COVID-19 antibody testing, as VN antibodies in the blood have been shown to correlate with levels of protective immunity.

According to the researchers, this kind of antibody testing is not widely available as it is technically complex and requires days to set up, run and interpret. Thus, the team looked to another type of test, called enzyme-linked immunosorbent assays, or ELISAs.

According to Gollihar, ELISAs are standard quantitative tests used to measure the amount of antibody to a particular antigen in a given sample.


" ELISAs are standard assays that can be performed in almost any academic or medical laboratory. This is important in emergency care centers treating critically ill patients. The assays can also be used for serological monitoring of the disease."

- Dr. Jimmy Gollihar, Biochemist and Biotechnologist

Specifically, scientists looked at the relationship of anti-spike ectodomain, or ECD, and anti-receptor binding domain, or RBD, antibody titers in the bloodstream. The spike ECD and RBD proteins are components of the much-talked-about spike protein made by SARS-CoV-2 and are critical to how the virus enters the body, spreads and causes COVID-19 disease.

Gollihar's specific roles included coordinating the plasma sample delivery from Houston Methodist, scaling production and purification of the antigens, and setting up the collaboration with USAMRIID for live virus neutralization testing under biocontainment conditions. He also helped transition the ELISA assay to Houston Methodist's automation team.Dye and his team performed neutralization assays on all the specimens in a Biosafety Level 3 laboratory at USAMRIID. Their work determined that the relative amount of antibody in the bloodstream of COVID-19 patients is linked to their ability to control viral infection; essentially, the more severe the disease, the higher the levels of neutralizing antibody present. This information provides potential benchmarks for a clinical product for convalescent plasma treatment studies; it could also be used to assess how well a vaccine recipient may respond to a subsequent infection.

The researchers found that the ELISA tests had an 80 percent or greater probability of predicting VN titers at or above the Food and Drug Administration-recommended levels for COVID-19 convalescent plasma.

"In all, we discovered that high titer ELISAs correlate well to virus neutralization and can be used as a surrogate for screening convalescent plasma," Gollihar said.

In addition, the researchers found that convalescent donors maintain high levels of immunity over the course of many weeks, and that frequent plasma donations did not cause a significant decrease in antibody or virus neutralization levels.

Perhaps most surprising, the researchers said, is that they identified 27 individuals from the surveillance cohort with high enough antibody titers to indicate that some asymptomatic individuals may have plasma suitable for therapeutic use and may have a degree of relative immunity against SARS-CoV-2.

"This collaboration between the Army, Houston Methodist and our partners in academia shows the incredible diversity of complementary capabilities we can deploy in responding to a worldwide pandemic," Dye said.

The team's findings are described in a paper titled, "Convalescent plasma anti-SARS-CoV-2 spike protein ectodomain and receptor binding domain IgG correlate with virus neutralization," featured in the Journal of Clinical Investigation.

Source:

U.S. Army Research Laboratory
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Re: How long is antibody duration in Covid 19 ? / Antibodies

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Study: 90% of patients have detectable antibodies up to 7 months post contracting COVID-19

10/23/20


https://www.news-medical.net/news/20201 ... ID-19.aspx


A new study led by Marc Veldhoen, principal investigator at Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal) with an interdisciplinary team of clinicians and researchers from Faculdade de Medicina da Universidade de Lisboa (FMUL) and Centro Hospitalar Lisboa Norte (CHLN) and collaborators at Instituto Português do Sangue e Transplantação (IPST), shows that 90% of subjects have detectable antibodies 40 days up to 7 months post contracting COVID-19. These results, now published in the scientific journal European Journal of Immunology, also show that age is not a confounding factor in levels of antibodies produced, but disease severity is.

This comprehensive and cross-sectional study was thought off in the early days of the pandemic, back in March 2020. The researchers Patrícia Figueiredo-Campos and Birte Blankenhaus, first authors of this study, setup an in-house sensitive specific and versatile COVID-19 serology test. The optimization and validation of the assay was performed as part of Serology4COVID, a consortium of 5 research institutes of Lisbon and Oeiras. Collaborating with physicians in the campus of the Santa Maria Hospital, the research team started to monitor the antibody levels of over 300 COVID-19 hospital patients and healthcare workers, and over 200 post-COVID-19 volunteers.

"Our immune system recognizes the virus SARS-CoV-2 as harmful and produces antibodies in response to it, which helps to fight the virus." "The results of this 6 months cross-sectional study show a classic pattern with a rapid increase of antibody levels within the first three weeks after COVID-19 symptoms and, as expected, a reduction to intermediate levels thereafter", explains Marc Veldhoen, adding that "in this early response phase, on average men produce more antibodies than women, but levels equilibrate during the resolution phase and are similar between the sexes in the months after SARS-CoV-2 infection".

In the acute phase of the immune response, the team observed higher antibody levels in subjects with more severe disease. Also, the results show that age is not a confounding factor for the production of antibodies, as no significant differences were observed between age groups. Globally, 90% of subjects have detectable antibodies up to 7 months post contracting COVID-19.

Next, the research team, evaluated the function of these antibodies, i.e. their neutralizing activity against the virus SARS-CoV-2. In collaboration with Instituto Português do Sangue e Transplantação (IPST), the research team analyzed the neutralizing capacity of the antibodies produced by the patients and volunteers.


" Although we observed a reduction in the levels of antibodies over time, the results of our neutralizing assays have shown a robust neutralization activity for up to the seventh month post-infection in a large proportion of previously virus-positive screened subjects."

- Marc Veldhoen, principal investigator at Instituto de Medicina Molecular João Lobo Antunes

On the importance of this study, Marc Veldhoen states: "Our work provides detailed information for the assays used, facilitating further and longitudinal analysis of protective immunity to SARS-CoV-2. Importantly, it highlights a continued level of circulating neutralizing antibodies in most people with confirmed SARS-CoV-2. The next months will be critical to evaluate the robustness of the immune response to SARS-CoV-2 infection, and to find clues for some open questions, such as the duration of circulating antibodies and the impact of reinfection."

This study was conducted at iMM in collaboration with the Biobank-IMM, Lisbon Academic Medical Centre, Faculdade de Medicina da Universidade de Lisboa (FMUL), Centro Hospitalar Lisboa Norte (CHLN) and Instituto Português do Sangue e Transplantação (IPST). The SARS-CoV-2 protein used in the serology testing was produced at Instituto de Biologia Experimental e Tecnológica (iBET) as part of the Serology4COVID consortium. This work was funded by the European Union H2020 ERA project EXCELLtoINNOV (No 667824), the Fundação para a Ciência a Tecnologia and Sociedade Francisco Manuel dos Santos.

Source:

Instituto de Medicina Molecular

Journal reference:


Figueiredo‐Campos, P., et al. (2020) Seroprevalence of anti‐SARS‐CoV‐2 antibodies in COVID‐19 patients and healthy volunteers up to six months post disease onset. European Journal of Immunology. doi.org/10.1002/eji.202048970.
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Re: How long is antibody duration in Covid 19 ? / Antibodies

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Researchers demonstrate potent antibody that fights against coronavirus

10/28/20


https://www.news-medical.net/news/20201 ... virus.aspx


Scientists at Fred Hutchinson Cancer Research Center in Seattle have shown that a potent antibody from a COVID-19 survivor interferes with a key feature on the surface of the coronavirus's distinctive spikes and induces critical pieces of those spikes to break off in the process.

The antibody -- a tiny, Y-shaped protein that is one of the body's premier weapons against pathogens including viruses -- was isolated by the Fred Hutch team from a blood sample received from a Washington state patient in the early days of the pandemic.

The team led by Drs. Leo Stamatatos, Andrew McGuire and Marie Pancera previously reported that, among dozens of different antibodies generated naturally by the patient, this one -- dubbed CV30 -- was 530 times more potent than any of its competitors.

Using tools derived from high-energy physics, Hutch structural biologist Pancera and her postdoctoral fellow Dr. Nicholas Hurlburt have now mapped the molecular structure of CV30. They and their colleagues published their results online today in the journal Nature Communications.

The product of their research is a set of computer-generated 3D images that look to the untrained eye as an unruly mass of noodles.

But to scientists they show the precise shapes of proteins comprising critical surface structures of antibodies, the coronavirus spike and the spike's binding site on human cells. The models depict how these structures can fit together like pieces of a 3D puzzle.


" Our study shows that this antibody neutralizes the virus with two mechanisms. One is that it overlaps the virus's target site on human cells, the other is that it induces shedding or dissociation of part of the spike from the rest."

- Marie Pancera, Fred Hutchinson Cancer Research Center

On the surface of the complex structure of the antibody is a spot on the tips of each of its floppy, Y-shaped arms. This infinitesimally small patch of molecules can neatly stretch across a spot on the coronavirus spike, a site that otherwise works like a grappling hook to grab onto a docking site on human cells.

The target for those hooks is the ACE2 receptor, a protein found on the surfaces of cells that line human lung tissues and blood vessels. But if CV30 antibodies cover those hooks, the coronavirus cannot dock easily with the ACE2 receptor. Its ability to infect cells is blunted.

This very effective antibody not only jams the business end of the coronavirus spike, it apparently causes a section of that spike, known as S1, to shear off.

Hutch researcher McGuire and his laboratory team performed an experiment showing that, in the presence of this antibody, there is reduction of antibody binding over time, suggesting the S1 section was shed from the spike surface.

The S1 protein plays a crucial role in helping the coronavirus to enter cells. Research indicates that after the spike makes initial contact with the ACE2 receptor, the S1 protein swings like a gate to help the virus fuse with the captured cell surface and slip inside.

Once within a cell, the virus hijacks components of its gene and protein-making machinery to make multiple copies of itself that are ultimately released to infect other target cells.

The incredibly small size of antibodies is difficult to comprehend. These proteins are so small they would appear to swarm like mosquitos around a virus whose structure can only be seen using the most powerful of microscopes. The tiny molecular features Pancera's team focused on the tips of the antibody protein are measured in nanometers -- billionths of a meter.

Yet structural biologists equipped with the right tools can now build accurate 3D images of these proteins, deduce how parts of these structures fit like puzzle pieces, and even animate their interactions.

Fred Hutch structural biologists developed 3D images of an antibody fished from the blood of an early COVID-19 survivor that efficiently neutralized the coronavirus.

Dr. Nicholas Hurlburt, who helped develop the images, narrates this short video showing how that antibody interacts with the notorious spikes of the coronavirus, blocking their ability to bind to a receptor on human cells that otherwise presents a doorway to infection.

Key to building models of these nanoscale proteins is the use of X-ray crystallography. Structural biologists determine the shapes of proteins by illuminating frozen, crystalized samples of these molecules with extremely powerful X-rays.

The most powerful X-rays come from a gigantic instrument known as a synchrotron light source. Born from atom-smashing experiments dating back to the 1930s, a synchrotron is a ring of massively powerful magnets that are used to accelerate a stream of electrons around a circular track at close to the speed of light. Synchrotrons are so costly that only governments can build and operate them. There are only 40 of them in the world.

Pancera's work used the Advanced Photon Source, a synchrotron at Argonne National Laboratory near Chicago, which is run by the University of Chicago and the U.S. Department of Energy. Argonne's ring is 1,200 feet in diameter and sits on an 80-acre site.

As the electrons whiz around the synchrotron ring, they give off enormously powerful X-rays -- far brighter than the sun but delivered in flashes of beams smaller than a pinpoint.

Structural biologists from around the world rely on these brilliant X-ray beamlines to illuminate frozen crystals of proteins.

They reveal their structure in the way these bright beams are bent as they pass though the molecules. It takes powerful computers to translate the data readout from these synchrotron experiments into the images of proteins that are eventually completed by structural biologists.

The Fred Hutch team's work on CV30 builds on that of other structural biologists who are studying a growing family of potent neutralizing antibodies against the coronavirus.

The goal of most coronavirus vaccine candidates is to stimulate and train the immune system to make similar neutralizing antibodies, which can recognize the virus as an invader and stop COVID-19 infections before they can take hold.

Neutralizing antibodies from the blood of recovered COVID-19 patients may also be infused into infected patients -- an experimental approach known as convalescent plasma therapy.

The donated plasma contains a wide variety of different antibodies of varying potency. Although once thought promising, recent studies have cast doubt on its effectiveness.

However, pharmaceutical companies are experimenting with combinations of potent neutralizing antibodies that can be grown in a laboratory.

These "monoclonal antibody cocktails" can be produced at industrial scale for delivery by infusion to infected patients or given as prophylactic drugs to prevent infection.

After coming down with COVID-19, President Trump received an experimental monoclonal antibody drug being tested in clinical trials by the biotech company Regeneron, and he attributes his apparently quick recovery to the advanced medical treatment he received.

The Fred Hutch research team holds out hope that the protein they discovered, CV30, may prove to be useful in the prevention or treatment of COVID-19. To find out, this antibody, along with other candidate proteins their team is studying, need to be tested preclinically and then in human trials.

"It is too early to tell how good they might be," Pancera said.

Source:

Fred Hutchinson Cancer Research Center

Journal reference:

Hurlburt, N. K., et al. (2020) Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation. Nature Communications. doi.org/10.1038/s41467-020-19231-9.
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Re: How long is antibody duration in Covid 19 ? / Antibodies

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Majority of people infected with mild-to-moderate COVID 19 mount robust antibody response

10/29/20


https://www.news-medical.net/news/20201 ... ponse.aspx


The vast majority of individuals infected with mild-to-moderate COVID 19 mount a robust antibody response that is relatively stable for at least five months, according to research conducted at the Icahn School of Medicine at Mount Sinai and published October 28, in the journal Science.

Additionally, the research team found that this antibody response correlates with the body's ability to neutralize (kill) SARS-CoV-2, the virus that causes COVID-19.

" While some reports have come out saying antibodies to this virus go away quickly, we have found just the opposite – that more than 90 percent 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. Uncovering the robustness of the antibody response to SARS-CoV-2, including its longevity and neutralizing effects, is 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. This is essential for effective vaccine development."

- Florian Krammer, PhD, Study Senior Author and Professor of Vaccinology, Icahn School of Medicine, Mount Sinai

Study findings are based on a dataset of 30,082 individuals, who were screened within the Mount Sinai Health System between March and October, 2020. The antibody test used in this research-;an enzyme-linked immunosorbent assay (ELISA)-;is based on the virus's telltale spike protein that contains the machinery that enables it to attach and gain entry into our cells.

The ELISA assay was developed, validated, and launched at Mount Sinai by a team of internationally renowned researchers and clinicians. The Mount Sinai antibody test detects the presence or absence of antibodies to SARS-CoV-2 and, importantly, is capable of measuring the titer (level) of antibodies an individual has.

The high sensitivity and specificity of this test-;meaning that a false negative or false positive is highly unlikely-;allowed it to be among the first to receive emergency use authorization from New York State and the U.S. Food and Drug Administration.

In late March, Mount Sinai began to screen individuals for antibodies to SARS-CoV-2 in order to recruit volunteer donors for its convalescent plasma therapy program-;one of the first such programs in the nation.

The Clinical Laboratories of The Mount Sinai Hospital set up antibody test results using distinct dilutions set at 1:80, 1:160, 1:320, 1:960 or ≥1:2880. The antibody titer score is generated by the number of times the scientist can dilute a patient's serum and still be able to detect the presence of antibodies. Titers of 1:80 and 1:160 were categorized as low titers; 1:320 moderate; and 1:960 or ≥ 1:2880 were high.

By early October, Mount Sinai had screened 72,401 individuals with a total of 30,082 being positive (defined as detectible antibodies to the spike protein at a titer of 1:80 or higher). Of the 30,082 positive samples, 690 (2.29 percent) had a titer of 1:80; 1453 (4.83 percent) of 1:160; 6765 (22.49 percent) of 1:320; 9564 (31.79 percent) of 1:960; and 11610 (38.60 percent) of 1:2880. Thus, the vast majority of positive individuals had moderate-to-high titers of anti-spike antibodies.

"Our microbiology colleagues generated great science and tools that were brought from the research lab into the clinical laboratory, where we were able to implement robust and compliant diagnostic tests at an unprecedented pace," said Carlos Cordon-Cardo, MD, PhD, Irene Heinz Given and John LaPorte Given Professor and Chair of Pathology, Molecular and Cell-Based Medicine and last author of the paper. "The tireless efforts of so many have enabled us to uncover knowledge that can help inform COVID-19 policy and aid in vaccine development."

Determining the neutralizing effects of SARS-CoV-2 is critical to understanding the possible protective effects of the immune response.

The research team performed a well-established, quantitative microneutralization assay based on authentic SARS-CoV-2 with 120 samples of known ELISA titers ranging from "negative" to ≥1:2880.

They found that approximately 50 percent of sera in the1:80-1:160 titer range had neutralizing activity; 90 percent in the 1:320 range had neutralizing activity; and all sera in the 1:960 to ≥1:2880 range had neutralizing activity.

Another important and outstanding question in the scientific community is the longevity of the antibody response to the spike protein. To answer that question, the team recalled 121 plasma donors at a variety of titer levels for repeat antibody testing at approximately 3 months and 5 months post-symptom onset.

When comparing overall titers, they saw a slight drop from a geometric mean titer (GMT) of 764 to a GMT of 690 from the first to second testing time point and another drop to a GMT of 404 for the last testing time point, indicating that a moderate level of antibody is retained by most people 5 months after symptom-onset.

In the higher titer range, they observed a slow decline in titer over time. Interestingly, they saw an initial increase in titer for individuals who had originally tested as having low to moderate titer levels. This is in agreement with earlier observations from their study group that indicate seroconversion in mild COVID-19 cases might take a longer time to mount.

"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," said Ania Wajnberg, MD, Director of Clinical Antibody Testing at the Mount Sinai Hospital and first author of the paper.

"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."

The Mount Sinai data reveals antibody binding titers to the spike protein correlate significantly with neutralization of SARS-CoV-2 and that the vast majority of individuals with antibody titers of 320 or higher show neutralizing activity in their serum that are stable over a period of at least 3 months with only modest declines at the 5-month time point.

Correlates of protection have been established for many different viral infections including influenza, measles, hepatitis A, hepatitis B. These correlates are usually based on a specific level of antibody acquired through vaccination or natural infection that significantly reduces the risk of reinfection. The team will continue following this study cohort over longer intervals of time.

Although this cannot provide conclusive evidence that these antibody responses protect from reinfection, the team believes it is very likely that the antibodies will decrease the odds of getting reinfected and may attenuate disease in the case of breakthrough infection.

To inform policy for the COVID-19 pandemic and for the benefit of vaccine development, it is imperative to swiftly perform studies to investigate and establish a correlate of protection to SARS-CoV-2. Such investigations are currently being carried out by researchers at the Icahn School of Medicine at Mount Sinai.

This work was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance, the Collaborative Influenza Vaccine Innovation Center, and the generous support of the JPB Foundation, the Open Philanthropy Project, and other philanthropic donations.

Mount Sinai has licensed serological assays to commercial entities and has filed for patent protections for serological assays.

Source:

The Mount Sinai Hospital

Journal reference:

Wajnberg, A., et al. (2020) Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science. doi.org/10.1126/science.abd7728.
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Covid-19: T cell response lasts for at least six months after infection, study shows

Published 02 November 2020


https://www.bmj.com/content/371/bmj.m4257


Robust cellular immunity persists for at least for six months after even mild or asymptomatic SARS-CoV-2 infection, research has shown.1

The study of 100 people showed that all had a cellular immune response against SARS-CoV-2 six months after infection although the size of response was 50% higher in those who had experienced symptomatic disease.

There has been concern that the cellular immune response following covid-19 infection may not be sustained. “This data is reassuring,” lead study author Paul Moss, from the University of Birmingham, told a Science Media Centre briefing on 2 November. “However, it does not mean that people cannot be re-infected. We need to have much larger population studies to show that.” Moss also added that the findings “can’t be taken as confirmation that an ‘immunity passport’ would be feasible.”

The study from the UK Coronavirus Immunology Consortium and Public Health England, which is published as a preprint and has not yet been peer reviewed, is believed to be the first in the world to show that a robust cellular memory against the virus persists for at least for six months.

The researchers collected serum and blood samples from a cohort of more than 2000 clinical and non-clinical healthcare workers, including 100 who tested seropositive for SARS-CoV-2 in March and April 2020. The average age of the donors was 41 (range 22 to 65 years old); 23 were men and 77 were women. None of them were hospitalised with covid-19—56 people had mild or moderate symptoms and 44 were asymptomatic.

Serum samples were collected monthly to measure antibody levels and blood samples were taken after six months to measure the T cell response using an ELISPOT and ICS analysis. The study found that virus specific T cells were detectable in all donors at six months.

The researchers collected serum and blood samples from a cohort of more than 2000 clinical and non-clinical healthcare workers, including 100 who tested seropositive for SARS-CoV-2 in March and April 2020. The average age of the donors was 41 (range 22 to 65 years old); 23 were men and 77 were women. None of them were hospitalised with covid-19—56 people had mild or moderate symptoms and 44 were asymptomatic.

Serum samples were collected monthly to measure antibody levels and blood samples were taken after six months to measure the T cell response using an ELISPOT and ICS analysis. The study found that virus specific T cells were detectable in all donors at six months.

Antibody levels fell by around 50% during the first two months after infection but then plateaued. The magnitude of the T cell response at six months was strongly correlated with the magnitude of the peak antibody response, the study found.

Moss said the finding that the T cell response was 50% higher in those who had experienced symptoms did not necessarily mean that asymptomatic people may be more susceptible to reinfection as they may just be better at fighting off the virus without the need to generate a large immune response.

The findings have implications for vaccine development. The cellular response was directed against a range of proteins from the virus, including the spike protein that is being used as a target in most vaccine studies. The study authors suggested that as T cell responses were also directed against additional nucleoprotein and membrane proteins these could also be valuable targets for future vaccines strategies.

“This is promising news—if natural infection with the virus can elicit a robust T cell response then this may mean that a vaccine could do the same,” said Fiona Watt, executive chair of the Medical Research Council.

Charles Bangham, chair of immunology at Imperial College London, said, “This excellent study provides strong evidence that T cell immunity to SARS-CoV-2 may last longer than antibody immunity.”

He added, “These results provide reassurance that, although the titre of antibody to SARS-CoV-2 can fall below detectable levels within a few months of infection, a degree of immunity to the virus may be maintained. However, the critical question remains: do these persistent T cells provide efficient protection against re-infection?”

References

↵Zuo J, Dowell A, Pearce H, et al. Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection. BioRxiv 2020.11.01.362319v1 [Preprint]. 2 November 2020. www.biorxiv.org/content/10.1101/2020.11.01.362319v1.
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Re: How long is antibody duration in Covid 19 ? / Antibodies

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Study finds a subset of quick COVID-19 healers and antibody 'sustainers'

11/3/20


https://www.news-medical.net/news/20201 ... iners.aspx


One of the pressing questions about COVID-19 remains: How long does immunity last? One key indicator of immunity is the presence of virus-specific antibodies. Previous studies have provided conflicting accounts about whether people who have recovered from infection can sustain potentially-protective antibodies or not.

A new study led by investigators from Brigham and Women's Hospital examined blood samples and cells from patients who had recovered from mild to moderate COVID-19 and found that while antibodies against the virus declined in most individuals after disease resolution, a subset of patients sustained anti-virus antibody production several months following infection. These antibody "sustainers" had a shorter course of symptoms, suggesting that some individuals who recover from COVID-19 faster may be mounting a more effective and durable immune response to the virus. Results are published in Cell.

" We've found a subset of individuals that heal quickly while sustaining virus-specific antibody levels after COVID-19. The kind of immune response we're seeing in these individuals is a bit like investing in an insurance policy -- it's the immune system's way of adding a potential layer of protection against future encounters with the virus."

- Duane Wesemann, MD, PhD, immunologist and associate physician in the Brigham Division of Allergy and Clinical Immunology and associate professor at Harvard Medical School

The Wesemann lab studies the entire set of antibodies a host's immune system produces and how they learn to recognize pathogens. In the spring of 2020, the team turned its attention to the COVID-19 pandemic and the immune response of people who become infected. They are eager to understand the nature of the antibody response to the virus. To this end, the team recruited and enrolled 92 people in the Boston area who had recovered from COVID-19 between March and June of 2020. Five of the individuals were hospitalized but all others recovered at home.

The team collected and analyzed blood samples monthly, measuring a range of antibodies, including immunoglobulin-G (IgG), against the virus that causes COVID-19. They split the cohort into two groups -- those that sustain virus-specific IgG levels over several weeks, and those that lose them. The team analyzed these groups and potential connections they had to clinical and other immunological data.

The team found that IgG levels against the virus tended to decline substantially in most individuals over the course of three to four months. However, in about 20 percent of individuals, antibody production remained stable or enhanced over the same time period. The team found that these "sustainers" had symptoms for a significantly shorter period of time compared to "decayers" (average of 10 days versus 16 days). Sustainers also had differences in memory T cell populations and B cells, two types of immune cells that can play a key role in immune memory and protection.

"The data point to a type of immune response that's not only adept at handling viral disease by leading to a swift resolution of symptoms, but also better at producing cells that can commit to longer term production of anti-virus IgG antibodies," said Wesemann. "Figuring out how these individuals are able to support longer-term antibody production is relevant to COVID-19, and will also have important implications for our understanding of the immune system in general."

Source:

Brigham and Women's Hospital

Journal reference:

Chen, Y., et al. (2020) Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production. Cell. doi.org/10.1016/j.cell.2020.10.051.
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Evidence of robust and persistent antibodies against SARS-CoV-2

11/3/20


https://www.news-medical.net/news/20201 ... CoV-2.aspx


A team of researchers from the Icahn School of Medicine at Mount Sinai, New York, have worked in collaboration to try and answer one of the most baffling questions surrounding the coronavirus disease 19 (COVID-19) pandemic: do antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) last after a primary infection? And, if the antibodies remain active, for how long can they be relied upon as protection against the infection? Over 47.3 million people worldwide have been infected with the virus in one of the greatest public health problems in modern history. At present, no specific therapies are available for treatment, and no effective vaccines have been marketed to prevent the infection.

The team’s study titled, “Robust neutralizing antibodies to SARS-CoV-2 infection persist for months,” was published in the latest issue of the journal Science.

Background

There have been studies that have shown that antibody responses to severe COVID-19 are well defined. Even mild and asymptomatic cases have shown good antibody responses. Researchers write that since these mild and asymptomatic cases form a majority of the cases, this finding is a vital one.

However, there is a need to determine the robustness of this antibody response and its longevity and functionality in the body, the team explains. Serological surveys (or sero surveys) are being conducted around the world to determine the levels as well as the duration of the antibody titers (or concentration of effective antibodies) in the body that could protect against re-infection with SARS-CoV-2.

Antibodies

Researchers explained that antibodies to SARS-CoV-2 basically develop against one or more of its protein components. These encoding proteins of the virus are both structural and non-structural antigens.

At present, there are two structural proteins that act as antigens and stimulate antibodies which can be detected on sero surveys. These are - nucleoprotein (NP) and spike protein.

The NP is found in adequate amounts within the virus or in infected cells. It is usually protected by the virus membranes and thus antibodies to NP are not commonly detected. Antibodies to NP cannot neutralize the virus.

The spike protein is, on the other hand, a large protein on the viral surface. It is a trimeric glycoprotein that has a region called the “receptor binding domain (RBD).” The RBD binds to the receptor angiotensin-converting enzyme 2 (ACE2) on the cell of the humans that allows the virus to penetrate the cell and cause infection. Antibodies develop to the spike protein and thus can be measured through sero surveys.

Tests for serological surveys

At present the most common and most used test is the Mount Sinai ELISA (enzyme-linked immunosorbent assay) that has a high sensitivity – that is, chances of detecting true positives 92.5 percent - and specificity - chances of detecting true negatives 100 percent. This test has a positive predictive value (PPV) of 100 percent, with a negative predictive value (NPV) of 99.6 percent, making it robust and reliable.

Study design

Screening for antibody response began at the Mount Sinai Health System in March 2020. This was initially done to screen for volunteers would be able to donate plasma for convalescent plasma therapy in patients with, or recovering from, severe COVID-19. These potential donors had been detected earlier with COVID-19 on RT PCR.

A large number of people were screened. Of these, only 5 percent needed hospitalization for COVID-19 earlier. The researchers wrote that from March to October 2020, they had screened 72,401 individuals for antibodies, and of these, 30,082 individuals had detectable levels of antibodies.

The researchers’ definition of detectable antibodies were detectible to the spike protein at a titer of 1:80 or higher. Titers of 1:80, 1:160, 1:320, 1:960, or ≥1:2880 were defined, and those with 1:80 and 1:160 were categorized as low titers. Those with 1:320 were defined as moderate, and those with tites of 1:960 and ≥1:2880 were classified as high titers. Plasma donors were eligible with tires of 1:320 or higher.

Results

Antibody response

From the antibodies screening, the following results were seen among the 30,082 positive samples:

690 (2.29 percent) had a titer of 1:80
1,453 (4.83 percent) had a titer of 1:160
6,765 (22.49 percent) had a titer of 1:320
9,564 (31.79 percent) had a titer of 1:960
11,610 (38.60 percent) had a titer of 1:2880

The researchers found that a “vast majority” of positive individuals had “moderate-to-high titers of anti-spike antibodies.”

The team then analyzed 568 individuals who had been confirmed as COVID-19 positive. Among them, over 99 percent developed anti-spike antibodies. A further 95 percent of 2,347 patients who had reported that they had earlier tested positive for COVID-19 showed positive antibody titers.

Longevity of the antibodies


To assess this the team recalled 121 volunteers who had been eligible earlier as plasma donors. The population was tested approximately 30 days after the onset of symptoms and also again at two additional points in time.

The average interval between the initial measurement and the second was 52 days, but ranged between 33 and 57 days. The second measurement was an average of 82 days after onset of symptoms but ranged between 52 and 104 days after symptoms onset. A third measurement was made at an average of 148 days after symptom onset (but ranged between 113 and 186 days).

Overall results were

The geometric mean titer (GMT) fell from 764 to 690 between first and second measurement
The GMT fell to 404 at third measurement
Those who had high tires of 1:2880 and 1:960 saw a slower decline in titer with time
Those with initial titer of 1:320, 1:160, or 1:80 saw a fall on day 30, which persisted till day 148.
The team found that the half-life of the antibody IgG is approximately 21 days. This sustenance of the antibodies shows that it is possibly due to “long-lived plasma cells in the bone marrow”

Conclusions and implications

Overall, the researchers found that the protective duration from SARS-CoV-2 is not clear from previous studies. Their own study shows that individuals who have recovered from mild COVID-19 have developed robust antibody responses to the spike protein that seems to last. Stable antibody response is seen for at least three months, and only modest declines are seen at five months. A future follow up of the participants would show the longevity and functionality of these antibodies, the team has observed.

They found that “A correlate of protection, combined with a better understanding of antibody kinetics to the spike protein, would inform policy regarding the COVID-19 pandemic and would be beneficial to vaccine development efforts.”

Journal reference:

Wajnberg, A. et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science (28 Oct 2020); DOI: 10.1126/science.abd7728, https://mbio.asm.org/content/11/6/e02707-20
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Re: How long is antibody duration in Covid 19 ? / Antibodies

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Scientists identify neutralizing human monoclonal antibodies against SARS-CoV-2

11/3/20


https://www.news-medical.net/news/20201 ... CoV-2.aspx


University of Pittsburgh School of Medicine scientists have discovered the fastest way to identify potent, neutralizing human monoclonal antibodies against SARS-CoV-2, the virus that causes COVID-19.

The method-;as well as a trio of successful animal studies on an antibody called "Ab1"-;are described today in the Proceedings of the National Academy of Sciences. Ab1 is on track for human clinical trials by early next year.

At any given time, the human body contains up to 10 billion different antibodies. With samples from a few hundred people, senior author Dimiter Dimitrov, Ph.D., director of Pitt's Center for Antibody Therapeutics (CAT), and his team over the last several years built multiple libraries containing a total of 1 trillion human antibodies.

With such a large number, odds are that these libraries contain an effective antibody against any pathogen-;the challenge is in identifying the right antibodies in the libraries, something the Pitt team has mastered.

" Making a diverse antibody library is an art. Not everyone can do it. Dr. Dimitrov and his team not only identified potential therapies in record time, before most Americans were even aware that a pandemic was looming, but by publishing their method, they've also better prepared the world for future emerging diseases."

- John Mellors, M.D., Study Co-Author and Chief Person, Division of Infectious Diseases, Pitt and University of Pittsburgh School of Medicine

In contrast, the major method used this year to identify antibodies that neutralize SARS-CoV-2 was to find patients who have recovered from COVID-19, isolate their cells that produce antibodies against the virus and extract the antibodies from those cells.

Large numbers of antibodies then must be screened to find those that bind most tightly to the virus, which adds more time to the discovery process. So while the Pitt team had identified Ab1 back in February, major companies didn't have their monoclonal antibodies until the end of March or early April.

When Chinese scientists published the genetic sequence for SARS-CoV-2 in January of this year, Dimitrov's team rapidly generated the virus's receptor binding domain-;part of the spike protein that attaches to human cells-;and used it as "bait" to pan their multiple libraries of monoclonal antibodies.

Dimitrov decided to focus only on the receptor binding domain as a bait because his team was the first to identify it during the original SARS outbreak in 2003 and show that it is the most important part of the spike protein to attract potent neutralizing antibodies.

Like prospectors trying to find gold in rivers of silt during the California Gold Rush, Dimitrov's team panned their libraries against the spike protein receptor binding domain in February, quickly washing away useless antibodies and homing in on the most promising candidates, which block the virus from binding to the ACE2 receptor. The team struck "gold" in just six days.

Ab1 is a fully human monoclonal antibody that neutralizes SARS-CoV-2 by tightly binding to the virus, preventing it from infecting human cells. In tests on hamsters, regular mice and mice genetically engineered to express the human ACE2 receptor-;the entry point of SARS-CoV-2 into cells-;Ab1 was highly effective at preventing and treating COVID-19 or its animal analogue. Ab1 currently is in production and could be added to Operation Warp Speed or other human clinical trials as early as January 2021.

"The main differences between our rapid 'panning' method and the 'screening' process used by most companies this year to discover antibodies against SARS-CoV-2 is that panning is much quicker than screening, and we don't have to wait for infected patients to recover and make antibodies," Dimitrov said.

"We found our monoclonal antibody in under a week in February, which validated how well our panning methods work. This will save precious time in getting antibody therapy into people the next time a deadly virus emerges."

Last month, Mellors and Dimitrov announced the discovery of Ab8, a smaller-sized but very potent antibody isolated from their antibody libraries by Wei Li, Ph.D., assistant director of the Center for Antibody Therapeutics, who also discovered Ab1.

Ab8 isn't as far along in development as Ab1, but being a smaller molecule, it could potentially be administered subcutaneously or even through inhalation, which might make it more practical for widespread use.

Source:

University of Pittsburgh School of Medicine
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Nanobodies efficiently neutralize SARS-CoV-2 in cells

11/5/20


https://www.news-medical.net/news/20201 ... cells.aspx


Two separate studies have identified nanobodies - which could be produced less expensively than monoclonal antibodies - that bind tightly to the SARS-CoV-2 spike protein and efficiently neutralize SARS-CoV-2 in cells. "The combined stability, potency, and diverse epitope engagement of our ... nanobodies ... provide a unique potential prophylactic and therapeutic strategy to limit the continued toll of the COVID-19 pandemic," write authors on one paper (Michael Schoof et al.)

In the battle against COVID-19, monoclonal antibodies that bind to the spike protein of the SARS-CoV-2 virus are being explored as potential therapeutics. These show promise but must be produced in mammalian cells and need to be delivered intravenously. By contrast, single-domain antibodies called nanobodies can be produced in bacteria or yeast and their stability gives the potential for aerosol delivery. In two separate studies, Michael Schoof et al. and Yufei Xiang et al. describe the identification of nanobodies that efficiently neutralize SARS-CoV-2. Schoof and colleagues screened a yeast surface display of synthetic nanobodies, while Xiang and colleagues screened anti-spike nanobodies produced by a llama.

Both papers describe nanobodies that bind tightly to the spike and efficiently neutralize SARS-CoV-2 in cells. Xiang et al note that thermostable nanobodies they developed can be rapidly produced in bulk from microbes. "We envision that the nanobody technology described here will contribute to curbing the current pandemic and possibly a future event," they say.

Source:

American Association for the Advancement of Science

Journal reference:


Xiang, Y., et al. (2020) Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2. Science. doi.org/10.1126/science.abe4747.
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Re: How long is antibody duration in Covid 19 ? / Antibodies

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Children produce different antibodies in response to infection with new coronavirus

11/5/20


https://www.news-medical.net/news/20201 ... virus.aspx


Children and adults produce different types and amounts of antibodies in response to infection with the new coronavirus, SARS-CoV-2, a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found.

The differences in antibodies suggest the course of the infection and immune response is distinct in children and most children easily clear the virus from their bodies.

"Our study provides an in-depth examination of SARS-CoV-2 antibodies in kids, revealing a stark contrast with adults," says Columbia University immunologist Donna Farber, PhD, the George H. Humphreys II Professor of Surgical Sciences in the Department of Surgery, who led the study with Matteo Porotto, PhD, associate professor of viral molecular pathogenesis in Columbia's Department of Pediatrics. The first authors, Stuart Weisberg, MD, PhD, assistant professor of pathology & cell biology, and Thomas Connors, MD, assistant professor of pediatrics, enrolled patients into the study and conducted the data analysis.

"In kids, the infectious course is much shorter and probably not as disseminated as in adults," Porotto adds. "Kids may clear this virus more efficiently than adults and they may not need a strong antibody immune response to get rid of it."

Children less affected by SARS-CoV-2

One of the striking manifestations of the COVID-19 pandemic is that the majority of children cope well with the virus while older people struggle.

" This is a new infection for everybody, but children are uniquely adapted to see pathogens for the first time. That's what their immune system is designed to do. Children have a lot of naive T cells that are able to recognize all sorts of new pathogens, whereas older people depend more on our immunological memories. We're not as able to respond to a new pathogen like children can."

- Donna Farber, Ph.D., Columbia University Immunologist

Children make fewer SARS-CoV-2 neutralizing antibodies

Among the 47 children in the study, 16 were treated at Columbia University Irving Medical Center for MIS-C and 31 children of similar ages had tested positive for the virus after visiting the medical center for the treatment of other conditions. Half of the children without MIS-C had no COVID-19 symptoms. The 32 adults in the study ranged from severely affected patients admitted to the hospital to those with milder disease who recovered at home.

Both groups of children produced the same antibody profile, the study found, which differed from that of adults.

Compared with adults, children produced fewer antibodies against the virus's spike protein--which the virus uses to infect human cells. The children's antibodies had the least neutralizing activity, while all adults, including young adults in their 20s, produced neutralizing antibodies. The sickest adults had the most neutralizing activity.

Though it may seem counterintuitive that the sickest patients produce antibodies with the greatest neutralizing activity, Farber says that likely reflects the amount of time the virus is present in the sickest patients.

"There is a connection between the magnitude of your immune response and the magnitude of the infection: The more severe the infection, the more robust the immune response, because you need to have more immune cells and immune reactions to clear a higher dose of a pathogen."

Other antibody differences show children's infections are limited


In contrast to adults, children also produced very few antibodies against a viral protein that is only visible to the immune system after the virus infects human cells.

"That suggests that in kids, the infection doesn't really spread a lot and doesn't kill a lot of their cells," Farber says.

"Because children clear the natural virus rapidly, they do not have a widespread infection and they do not need a strong antibody response," Porotto says.

The reduced course of infection in children may signify that they are infectious for a shorter period of time compared with adults and therefore less likely to spread the virus, although the researchers did not measure viral load in the children.

"Current studies in other countries indicate that younger school-age children are not vectors for the new coronavirus, so our data are consistent with those findings," Farber says.

Children should respond well to vaccine

The antibody responses found in children do not suggest that children will have a weaker response to a vaccine, the researchers say.

Vaccines under development for SARS-CoV-2 contain pieces of the virus and do not mimic the normal route of infection.

"Even though children don't produce neutralizing antibodies in response to a natural infection with SARS-CoV-2, vaccines are designed to generate a protective immune response in the absence of an infection," Farber says. "Children respond very well to vaccines, and I think they will develop good neutralizing antibody responses to a SARS-CoV-2 vaccine, and they'll probably be better protected than the adults.

"That said, very few vaccine studies are currently enrolling children and we will need this data to really understand how well the vaccines work in children."

What does the adult immune system lack?

Though the findings suggest the course of infection in children and adults is different, it's still not known how the children are able to clear the virus more easily--and what the adult immune system lacks.

Farber, Porotto, and their colleagues at Columbia are now looking for differences in T-cell response (antibodies are produced by the immune system's B cells), especially T cells that reside in the lung. [Previous research from Farber's lab has shown these "stay-at-home" T cells are more important in fighting lung infections than T cells that travel through the body via the bloodstream].

Children infected with SARS-CoV-2 also may generate a stronger response from the innate immune system, which deploys interferon and cells called macrophages to indiscriminately attack cells infected by pathogens. Earlier studies suggest that the innate immune response may be delayed in adults infected with SARS-CoV-2.

"If the innate response is really strong, that can reduce the viral load in the lungs, and the antibodies and T cells of the adaptive response have less to clear up," Farber says.

It's also possible that the virus is less able to infect children's cells, possibly because children's cells express fewer proteins the virus needs to infect human cells.

The Columbia researchers are now testing these possibilities with cells from children versus adults.

"There are still all these issues that we have very little information about," Porotto says. "The interaction between the virus and the host is the reason why we see so much diversity in responses to this virus, but we don't understand enough about this virus yet to really determine what leads to severe disease and what leads to mild disease."

Source:

Columbia University Irving Medical Center

Journal reference:

Weisberg, S.P., et al. (2020) Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum. Nature Immunology. doi.org/10.1038/s41590-020-00826-9.
Other antibody differences show children's infections are limited
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