Tag Archives: #antibodies

COVID-19 Monoclonal Antibody Therapy Can Reduce Hospitalizations, Healthcare System Stress (Medicine)

A study by the University of South Florida Health and Tampa General Hospital is among the first to assess effectiveness of monoclonal antibodies in a practical setting when given early to patients at high risk for severe COVID-19

A newly published study by the University of South Florida Health (USF Health) and Tampa General Hospital (TGH) shows that monoclonal antibodies (MABs) work well in reducing COVID-19 related emergency department visits and hospitalizations when given early to high-risk patients. If used under FDA guidelines, the researchers suggest, this treatment can ease the pandemic’s continuing burden on patients and on limited health care resources.

The collaborative study was published June 4 in Open Forum Infectious Diseases.

Investigational monoclonal antibody therapies, administered intravenously, are specifically designed to block infection by SARS-CoV-2, the virus that causes COVID-19. The FDA has granted emergency use authorization (EUA) of MABs in outpatients with mild-to-moderate COVID-19 at increased risk of developing severe disease. Such high-risk patients are prone to hospitalizations, mechanical ventilation and other complications, including death from coronavirus.

“While the emphasis now is rightfully on getting more vaccines in arms, thousands of people in the U.S. are still infected with COVID-19 every day and a significant number suffer serious complications,” said the study’s senior author Asa Oxner, MD, associate professor and vice chair of the Department of Internal Medicine, USF Health Morsani College of Medicine.

“Unfortunately, only a fraction of those outpatients eligible for monoclonal antibodies receive them,” Dr. Oxner said. “We hope results like ours reinforce to the public and health care providers the importance of targeting timely monoclonal antibody treatment to this high-risk patient population to help minimize stress on health care systems during the COVID-19 pandemic.”

Limited clinical trials previously indicated that MABs work best when given soon after diagnosis. But this USF Health-TGH collaborative study was one of the first to evaluate the practical effectiveness of MABs when administered exclusively to patients deemed at high risk for progression to severe COVID-19. The FDA defines medical conditions and factors that place adults and children age 12 or older at higher risk for COVID-19, including older age (65 plus), obesity, diabetes, immunosuppressive disorders or treatment, chronic lung disease and cardiovascular disease, to name a few.

The academic medical center’s retrospective study, conducted Nov 18, 2020, to Jan. 5, 2021, included high-risk outpatients with a confirmed COVID-19 diagnosis, all experiencing mild-to-moderate symptoms for 10 days or less. A group of 200 patients received one of two MAB therapies (a single infusion) – either casirivimab/imdevimab, a combination drug made by Regeneron, or the medication bamlanivimab made by Eli Lilly. This treatment group was compared against a control group of 200 randomly selected outpatients who declined or were not referred for MABs during the same period.

Among the findings:

  • Overall, patients treated with the MABs were significantly less likely to be hospitalized or visit the emergency department (13.5%) than the control patients (40.5%). These results remained significant when comparing the individual monoclonal antibody therapies against the control group.
  • No deaths were reported in the MABs-treated group, compared to 3.5% in the control group.
  • Patients treated with MABs within six days of symptom onset were significantly less likely to be hospitalized or visit the emergency department (7.7%) than those treated after six days (28.1%). The study data indicated MABs are best given within seven days of initial symptoms to reduce the odds of hospitalization within 29 days of infusion.

“Reflecting on our findings, it would be prudent to consider decreasing the FDA eligibility window for MABs to within seven days of symptom onset,” the study authors write. “These medications are a relatively scarce resource, and it would be practical to administer them to patients who are likely to see the most benefit.”

COVID-19 has strained financial and personnel resources across all health systems, with the Florida Hospital Association estimating total losses of $7.4 billion from the beginning of the pandemic through August 2020. The study authors conclude that maximizing the use of monoclonal antibody therapies under EUA guidance has the potential to “keep high-risk COVID-19 patients out of the hospital and reduce the negative impact on the health care system.”

The study co-lead authors were Nicholas Piccicacco, PharmD, and Kristen Zeitler, PharmD, of the TGH Department of Pharmacy.

Reference: Nicholas Piccicacco, Pharm.D, Kristen Zeitler, Pharm.D, Jose Montero, M.D, Ambuj Kumar, M.D, Seetha Lakshmi, M.D, Kami Kim, M.D, David Wein, M.D, Tiffany Vasey, M.S.N, Matthew Vasey, M.D, Asa Oxner, M.D, Effectiveness of SARS-CoV-2 Monoclonal Antibody Infusions in High-Risk Outpatients, Open Forum Infectious Diseases, 2021;, ofab292, https://doi.org/10.1093/ofid/ofab292

Provided by USF Health

Elucidating How the Production Of Antibodies is Regulated, One Cell At A Time (Medicine)

A study coordinated by Luís Graça, principal investigator at the Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal) and Professor at the Faculty of Medicine of the University of Lisbon (FMUL) used lymph nodes, tonsils and blood, to show how the cells that control production of antibodies are formed and act. The results published now in the scientific journal Science Immunology* unveiled key aspects about the regulation of antibody production, with significant importance for diseases where antibody production is dysregulated such as autoimmune diseases or allergies.

In the last few months we witnessed the importance of vaccine-induced antibody protection against infections like COVID-19. However, it has been very difficult to study the human cells involved in the production of antibodies after vaccination, as this process takes place in the lymph nodes and not in the blood. To study this process, it was necessary to use emerging technologies for the sequencing and identification of genes in each individual cell. “To understand the power of this technology, we must note that all of our cells have the same genes. However, a cell like a lymphocyte uses a different combination of genes compared to a neuron. Thus, after vaccination, when a lymphocyte starts the process of controlling the production of antibodies, it will turn on some genes and turn off others. This is what we studied for hundreds of cells simultaneously”, explains Luís Graça.

The difficulty of the process can be appreciated if we remember that about 20 years ago the sequencing of the human genome required a large group of laboratories in several countries benefiting from a series of further developments for over 10 years. Now, this sequenced genome is available for scientists to study the activity of genes in hundreds of independent cells. Something that would have been impossible a few years ago. Saumya Kumar, the first author of the work, says: “When the study started four years ago, we did not have the experimental tools needed and the advances in technology have been extraordinary. Using omics technology offered an incredible solution to this problem and we ended up using it”.

The information thus obtained allowed the researchers to study, in great detail, the genes and molecules involved in regulating the production of antibodies. In this way, a wide range of opportunities open up to attempt the manipulation of some of these molecules for enhanced production of antibodies in vaccines, or to decrease the production of antibodies in diseases caused by them (such as autoimmunity or allergy).

In the words of Luís Graça: “When the biological systems of our organism are not properly regulated, disease arises. It is the knowledge of the organism’s regulation that allows to correct these pathological situations restoring the healthy balance of a well regulated system”.

This study also demonstrates that science has no boundaries: the group at iMM includes scientists from different nationalities, with different skills, from clinicians to bioinformaticians.

Translation results

The work was developed at iMM, in collaboration with the Gulbenkian Institute of Science, BioISI- Biosystems & Integrative Sciences, Faculty of Sciences, University of Lisbon, the Sanger Institute and the University of Cambridge (UK) and the Institut Curie ( France).

The study was funded by the ENLIGHT-TEN / H2020 network, co-funded by the ERDF through POR Lisboa 2020 – Lisbon Regional Operational Program, from PORTUGAL 2020, and by the Fundação para a Ciência e a Tecnologia

Featured image: Each circle represents a different cell. Different colors are cells with different characteristics. The proximity between the circles represents similarity between the genes that these cells are using. This figure shows that the cells divide into two large groups: the most mature (on the bottom right) and the most immature (on the left side) © Saumya Kumar (iMM)

Reference: Saumya Kumar, Válter R. Fonseca et al., “Developmental bifurcation of human T follicular regulatory cells”, Science Immunology  28 May 2021: Vol. 6, Issue 59, eabd8411 DOI: 10.1126/sciimmunol.abd8411

Provided by Instituto De Medicina Molecular

Rogue Antibodies Wreak Havoc in Severe COVID-19 Cases (Medicine)

The development of antibodies in response to the COVID-19 virus has been the great long-term hope for ending the pandemic. However, immune system turncoats are also major culprits in severe cases of COVID-19, Yale scientists report in the journal Nature.

These autoantibodies target and react with a person’s tissues or organs similar to ones that cause autoimmune diseases such as lupus or rheumatoid arthritis. In COVID-19 cases they can attack healthy tissue in brain, blood vessels, platelets, liver, and the gastrointestinal tract, researchers report. The more autoantibodies detected, the greater the disease severity experienced by patients.

And the autoantibodies paradoxically also target and interfere with many immune system proteins that are designed to fend off infections, the study found.

“It’s a two-edge sword,” said Aaron Ring, assistant professor of immunobiology at Yale and senior author of the paper. “Antibodies are crucial to fend off infection, but some COVID-19 patients also develop antibodies that damage their own cells and tissues.”

It is clear that in many cases the presence of coronavirus drove the creation of the damaging autoantibodies, Ring said. But it is also likely that some COVID-19 patients had pre-existing autoantibodies that made them more susceptible to infection, he said. Mice with these same autoantibodies were more susceptible to infection by the COVID-19 virus and more likely to die, the authors report.

The existence of these long-lived rogue autoantibodies could also help explain why some people infected with COVID-19 can later develop lasting medical symptoms, so-called long COVID cases. “This could be the unfortunate legacy of the virus,” Ring said.

“Our findings reinforce the importance of getting vaccinated,” added co-corresponding author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology at Yale. “The fact that even mild infections are associated with autoantibody production underscores the potential for long-term health consequences of COVID-19.”

For the study, Ring’s lab worked with Iwasaki’s lab and members of the Yale IMPACT team — a group of scientists, scholars, and physicians developing research and clinical efforts to combat COVID-19 — to screen blood samples from 194 patients who had contracted the virus, with varying degrees of severity, for the presence of autoantibodies. Specifically, they used a novel technology developed by Ring’s lab called Rapid Extracellular Antigen Profiling (REAP) to identify autoantibody interactions with nearly 3,000 human proteins.

Ring said the findings may lead to strategies to treat or prevent the damaging effects of autoantibodies in COVID-19 patients. In addition, the new REAP technology could be used to pinpoint important antibody responses for many other disease conditions beyond COVID-19. Ring’s lab has found a host of novel autoantibodies in patients with autoimmune disease and is now searching for autoantibodies in patients with cancer and neurological illnesses.

The work was led by co-first authors Eric Wang, a Yale College undergraduate, Jon Klein, a Yale M.D./Ph.D. student, and Yale Immunobiology graduate students Tianyang Mao and Yile Dai. Funding for the project was provided by the Mathers Family Foundation and the Ludwig Family Foundation.

Ring, Wang, and Dai are inventors of a patent describing the REAP technology used in the study and Ring is the founder of Seranova Bio, which seeks to market the technology.

Featured image credit: stock.adobe.com

Reference: Wang, E.Y., Mao, T., Klein, J. et al. Diverse Functional Autoantibodies in Patients with COVID-19. Nature (2021). https://doi.org/10.1038/s41586-021-03631-y

Provided by Yale

Spacing Pfizer COVID-19 Jabs Increases Antibodies in Older People (Medicine)

The second dose of the Pfizer COVID-19 vaccine produced a 3.5-times greater antibody response when given at 12 weeks, compared to three weeks, in people over 80.

The new study is supported by the UK Coronavirus Immunology Consortium. It was jointly funded by UK Research and Innovation and the National Institute for Health Research and supported by the British Society for Immunology.

To provide real-time information in the pandemic, these preliminary results will be posted on the medRxiv preprint server and submitted to a journal to undergo peer review.

175 people aged over 80

The study was led by the University of Birmingham in collaboration with Public Health England (PHE) and involved 175 people who were aged over 80 and living independently.

It is the first direct comparison of the immune response in any age group between those given the second Pfizer vaccine at a three-week interval and those at a 12-week interval.

The Pfizer vaccine was originally authorised for a three-week interval between doses. However several countries, including the UK, chose to expand this to a 12-week interval to allow a higher percentage of the population to receive one vaccine dose quicker.

Increased antibody response

The research found that extending the second dose interval to 12 weeks increased the peak SARS-CoV-2 spike specific antibody response 3.5-fold. This is compared to those who had the second vaccine at three weeks.

Although the peak cellular immune responses were lower after the delayed second vaccine, responses were comparable between the groups when measured at a similar time point following the first dose.

The team concluded that extending administration of the second Pfizer vaccine to 12 weeks potentially enhances and extends antibody immunity. This is believed to be important in virus neutralisation and prevention of infection.

Large-scale protection

First author Dr Helen Parry, at the University of Birmingham, said:

SARS-CoV-2 vaccines have been remarkably effective in providing large-scale protection against infection and symptomatic disease – but many questions remain regarding their optimal delivery for provision of effective and sustained immunity.

This is the first time antibody and cellular responses have been studied when the second vaccine is given after an extended interval. Our study demonstrates that peak antibody responses after the second Pfizer vaccine are markedly enhanced in older people when this is delayed to 12 weeks.

This research is crucial, particularly in older people, as immune responses to vaccination deteriorate with age. Understanding how to optimise COVID-19 vaccine schedules and maximise immune responses within this age group is vitally important.

Corresponding author Professor Paul Moss, at the University of Birmingham and principal investigator of the UK Coronavirus Immunology Consortium, added:

The enhanced antibody responses seen after an extended interval may help to sustain immunity against COVID-19 over the longer term and further improve the clinical efficacy of this powerful vaccine platform.

Our research findings may be important in the development of global vaccination strategy as extension of interval of the second vaccine dose in older people may potentially reduce the need for subsequent booster vaccines.

Blood samples for analysis

The research saw the team taking blood samples for analysis in the lab after participants’ first vaccine and then again two to three weeks after participants had received their second vaccine.

Of the cohort:

  • 99 participants had the second vaccine at three weeks
  • 73 had the second dose at 12 weeks.

Participants who had previous infection (10 in the three-week interval group and five in the 12-week interval group) were excluded from the analysis. Previous infection has been shown to have a major impact on the immune response to vaccination (University of Birmingham website).

After their second vaccine, spike-specific antibodies were detected in all participants no matter how far apart their doses were. However, after the second vaccine the average concentration of antibodies was 3.5 times higher in the 12-week interval group (4,030 U/ml) compared to the three-week interval group (1,138 U/ml).

Cellular immune response

The cellular (or T cell) immune response plays an important role in supporting and maintaining antibody production.

The team found that within the three-week interval group, 60% had a confirmed cellular response at two to three weeks following the second vaccine. Although this fell to only 15% eight to nine weeks later.

The proportion of participants showing a cellular response in the 12-week interval group was only 8% at five to six weeks after the first vaccine. This rose to 31% two to three weeks after the second vaccine.  Research is required to further explore these variations in responses.

Supportive evidence

Dr Gayatri Amirthalingam, Consultant Epidemiologist at PHE, said:

The higher antibody responses in people receiving two doses of the Pfizer vaccine using an extended 12-week interval provides further supportive evidence of the benefits of the UK approach to prioritise the first dose of vaccine. This analysis shows better antibody responses in those receiving their second dose at 12 weeks compared to the standard three-week schedule.

It is vital that you take up the offer of vaccination as it is the best way to protect yourself and your community and to help us out of the pandemic.

Professor Moss added:

Taking a collaborative approach to research through the UK Coronavirus Immunology Consortium and National Core Studies has allowed us to drive forward our knowledge at an incredible pace and build our understanding of how different components of the immune system respond to COVID vaccines. This knowledge will allow us to optimise vaccination protocols and maximise protection against SARS-CoV-2 within our population.

Top image: Credit: triloks/GettyImages

Provided by UKRI

Our Immune Systems Blanket the SARS-CoV-2 Spike Protein With Antibodies (Medicine)

The most complete picture yet is coming into focus of how antibodies produced in people who effectively fight off SARS-CoV-2 work to neutralize the part of the virus responsible for causing infection. In the journal Science, researchers at The University of Texas at Austin describe the finding, which represents good news for designing the next generation of vaccines to protect against variants of the virus or future emerging coronaviruses.

Previous research focused on one group of antibodies that target the most obvious part of the coronavirus’s spike protein, called the receptor-binding domain (RBD). Because the RBD is the part of the spike that attaches directly to human cells and enables the virus to infect them, it was rightly assumed to be a primary target of the immune system. But, testing blood plasma samples from four people who recovered from SARS-CoV-2 infections, the researchers found that most of the antibodies circulating in the blood — on average, about 84% — target areas of the viral spike protein outside the RBD — and, apparently, for good reason.

“We found these antibodies are painting the entire spike, both the arc and the stalk of the spike protein, which looks a bit like an umbrella,” said co-corresponding author Greg Ippolito, who is a research associate professor in UT Austin’s Department of Molecular Biosciences and an assistant professor of oncology at the university’s Dell Medical School. “The immune system sees the entire spike and tries to neutralize it.”

Many of these non-RBD-directed antibodies the team identified act as a potent weapon against the virus by targeting a region in a part of the spike protein located in what would be the umbrella’s canopy called the N-terminal domain (NTD). These antibodies neutralize the virus in cell cultures and were shown to prevent a lethal mouse-adapted version of the virus from infecting mice.

The NTD is also a part of the viral spike protein that mutates frequently, especially in several variants of concern. This suggests that one reason these variants are so effective at evading our immune systems is that they can mutate around one of the most common and potent types of antibody in our arsenals.

“There’s an evolutionary arms race going on between the virus and our immune systems,” said Jason Lavinder, research associate in the McKetta Department of Chemical Engineering and co-corresponding author of the new study. “We’re all developing a standard immune response to this virus that includes targeting this one spot and that’s exerting selective pressure on the virus. But then the virus is also exerting its evolutionary strength by trying to change around our selective immune pressures.”

Despite these maneuvers by SARS-CoV-2, the researchers said about 40% of the circulating antibodies target the stalk of the spike protein, called the S2 subunit, which is also a part that the virus does not seem able to change easily.

“That’s reassuring,” Ippolito said. “That’s an advantage our immune system has. It also means our current vaccines are eliciting antibodies targeting that S2 subunit, which are likely providing another layer of protection against the virus.”

That’s also good news for designing vaccine boosters or next-generation vaccines against variants of concern, and even for developing a vaccine that can protect against future pandemics from other strains of the coronavirus.

“It means we have a strong rationale for developing next-generation SARS-CoV-2 vaccines or even a pan-coronavirus vaccine that targets every strain,” Ippolito said.

UT Austin researchers are among several in the world now aiming to develop a single coronavirus vaccine to fight infection from all coronaviruses, not just SARS-CoV-2.

The first author of the study is William Voss, a graduate student at UT Austin. In addition to Lavinder and Ippolito, senior authors from UT Austin are Jimmy Gollihar, Ilya Finkelstein, Brent Iverson, Jason McLellan and George Georgiou. Georgiou and Ippolito are also affiliated with UT Austin’s Dell Medical School. Gollihar is also affiliated with the Army Research Laboratory South.

Collaborating institutions are the University of North Carolina at Chapel Hill, the U.S. Army Medical Research Institute of Infectious Diseases and the Centers for Disease Control and Prevention.

This research was funded in part by the National Institutes of Health, the Clayton Foundation and the Welch Foundation.

Featured image: An analysis of blood plasma samples from four people who recovered from SARS-CoV-2 infectionsshows that most of the antibodies circulating in the blood — on average, about 84% — target areas of the viral spike protein outside the receptor binding domain (RBD). © University of Texas at Austin

Reference: William N. Voss, Yixuan J. Hou, Nicole V. Johnson, George Delidakis, Jin Eyun Kim, Kamyab Javanmardi, Andrew P. Horton, Foteini Bartzoka, Chelsea J. Paresi, Yuri Tanno, Chia-Wei Chou, Shawn A. Abbasi, Whitney Pickens, Katia George, Daniel R. Boutz, Dalton M. Towers, Jonathan R. McDaniel, Daniel Billick, Jule Goike, Lori Rowe, Dhwani Batra, Jan Pohl, Justin Lee, Shivaprakash Gangappa, Suryaprakash Sambhara, Michelle Gadush, Nianshuang Wang, Maria D. Person, Brent L. Iverson, Jimmy D. Gollihar, John Dye, Andrew Herbert, Ilya J. Finkelstein, Ralph S. Baric, Jason S. McLellan, George Georgiou, Jason J. Lavinder, Gregory C. Ippolito, “Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes”, Science  04 May 2021:
eabg5268 DOI: 10.1126/science.abg5268

Provided by University of Texas at Austin

Simulations Reveal How Dominant SARS-CoV-2 Strain Binds to Host, Succumbs to Antibodies (Biology)

Dominant G-form Spike protein ‘puts its head up’ more frequently to latch on to receptors, but that makes it more vulnerable to neutralization

We found that the interactions among the basic building blocks of the Spike protein become more symmetrical in the G form, and that gives it more opportunities to bind to the receptors in the host — in us.- Gnana Gnanakaran

Large-scale supercomputer simulations at the atomic level show that the dominant G form variant of the COVID-19-causing virus is more infectious partly because of its greater ability to readily bind to its target host receptor in the body, compared to other variants. These research results from a Los Alamos National Laboratory–led team illuminate the mechanism of both infection by the G form and antibody resistance against it, which could help in future vaccine development.

“We found that the interactions among the basic building blocks of the Spike protein become more symmetrical in the G form, and that gives it more opportunities to bind to the receptors in the host — in us,” said Gnana Gnanakaran, corresponding author of the paper published today in Science Advances. “But at the same time, that means antibodies can more easily neutralize it. In essence, the variant puts its head up to bind to the receptor, which gives antibodies the chance to attack it.”

Researchers knew that the variant, also known as D614G, was more infectious and could be neutralized by antibodies, but they didn’t know how. Simulating more than a million individual atoms and requiring about 24 million CPU hours of supercomputer time, the new work provides molecular-level detail about the behavior of this variant’s Spike.

Current vaccines for SARS-CoV-2, the virus that causes COVID-19, are based on the original D614 form of the virus. This new understanding of the G variant — the most extensive supercomputer simulations of the G form at the atomic level — could mean it offers a backbone for future vaccines.

The team discovered the D614G variant in early 2020, as the COVID-19 pandemic caused by the SARS-CoV-2 virus was ramping up. These findings were published in CellScientists had observed a mutation in the Spike protein. (In all variants, it is the Spike protein that gives the virus its characteristic corona.) This D614G mutation, named for the amino acid at position 614 on the SARS-CoV-2 genome that underwent a substitution from aspartic acid, prevailed globally within a matter of weeks.

The Spike proteins bind to a specific receptor found in many of our cells through the Spike’s receptor binding domain, ultimately leading to infection. That binding requires the receptor binding domain to transition structurally from a closed conformation, which cannot bind, to an open conformation, which can.

The simulations in this new research demonstrate that interactions among the building blocks of the Spike are more symmetrical in the new G-form variant than those in the original D-form strain. That symmetry leads to more viral Spikes in the open conformation, so it can more readily infect a person.

A team of postdoctoral fellows from Los Alamos — Rachael A. Mansbach (now assistant professor of Physics at Concordia University), Srirupa Chakraborty, and Kien Nguyen — led the study by running multiple microsecond-scale simulations of the two variants in both conformations of the receptor binding domain to illuminate how the Spike protein interacts with both the host receptor and with the neutralizing antibodies that can help protect the host from infection. The members of the research team also included Bette Korber of Los Alamos National Laboratory, and David C. Montefiori, of Duke Human Vaccine Institute.

The team thanks Paul Weber, head of Institutional Computing at Los Alamos, for providing access to the supercomputers at the Laboratory for this research.

The Funding: The project was supported by Los Alamos Laboratory Directed Research and Development project 20200706ER, Director’s Postdoctoral fellowship, and the Center of Nonlinear Studies Postdoctoral Program at Los Alamos.

Featured image: Supercomputer simulations at Los Alamos National Laboratory demonstrated that the G form of SARS-CoV-2, the dominant strain of the virus causing COVID-19, mutated to a conformation that allows it to more easily attach to host receptors, while also being more susceptible to antibodies than the original D form. © LANL

The Paper: “The SARS-CoV-2 Spike variant D614G favors an open conformational state,” Science Advances.  Rachael A. Mansbach, Srirupa Chakraborty, Kien Nguyen, David C. Montefiori, Bette Korber, S. Gnanakaran.  DOI: 10.1126/sciadv.abf3671

Provided by Los Alamos National Laboratory

Study Reveals How Some Antibodies Can Broadly Neutralize Ebolaviruses (Medicine)

The results are an important step towards the development of a broader-acting treatment for Ebola and related viruses.

Some survivors of ebolavirus outbreaks make antibodies that can broadly neutralize these viruses—and now, scientists at Scripps Research have illuminated how these antibodies can disable the viruses so effectively. The insights may be helpful for developing effective therapies.

Ebolavirus is a family of often-deadly viruses that includes Ebola virus and many lesser-known viruses such as Bundibugyo virus, Sudan virus and Reston virus.

Structural biologists at Scripps Research used electron microscopy techniques to visualize a set of antibodies that target a key site on these viruses called the “glycan cap.” Their research showed that the antibodies work against ebolaviruses using the same three mechanisms to prevent the virus from infecting host cells.

The research, published in Cell Reports, is a step toward the creation of an antibody-based treatment that will be useful against a broad range of ebolaviruses.  

“We now understand the molecular basis for these antibodies’ abilities to neutralize ebolviruses with broad reactivity against different viral species,” says the study’s first author Daniel Murin, PhD, a staff scientist in the laboratory of Andrew Ward, PhD.

Ward, a professor in the Department of Integrative Structural and Computational Biology at Scripps Research, says he hopes the work will contribute the development of a “cocktail” of therapeutic antibodies that can save lives by treating many forms of the Ebola virus.

“The goal is to provide doctors in Ebola-prone regions their best weapon yet against these deadly outbreaks,” Ward says. “The insights we have gained through our structural studies of the virus show how this may be possible.” 

Ever-emergent Ebola

The first known ebolavirus, now called Zaire ebolavirus or simply Ebola virus, was identified in 1976, named for the site of an outbreak that year near the Ebola river in what was then Zaire and is now the Democratic Republic of Congo.

Other species have since been added to this family of viruses, including Sudan ebolavirus and Bundibugyo ebolavirus. Ebola viruses colonize African fruit bats, often cause disease in chimpanzees and other non-human primates, and trigger outbreaks in humans every few years, on average. Infected people develop a hemorrhagic syndrome that is fatal in roughly half of untreated cases.

Vaccines against Ebola have been developed recently but have not yet been widely used. And although antibody-based treatments also have been developed, none has been shown effective against a broad range of ebolavirus species.

Nevertheless, studies in recent years have shown that some survivors of Ebola infections carry antibodies that, in lab-dish tests, can neutralize multiple ebolavirus species. A surprisingly high proportion of these broadly neutralizing antibodies target the glycan cap, a sugar-slathered site on a stalk-like protein—called the glycoprotein—that enables Ebola viruses to enter host cells.

In the new study, Murin and Ward, along with their colleagues in the James Crowe Lab at Vanderbilt University where the antibodies were isolated, used electron microscopy to analyze a set of glycan cap-targeting antibodies from survivors of various ebolaviruses. Their aim was to understand better how these antibodies target the virus so effectively.

Three ways to defeat the virus

Their analysis suggested that the most broadly effective of these glycan cap-targeting antibodies hit the same vulnerable site on the glycan cap, allowing them to thwart viral infectivity in three ways.

First, the antibody displaces a long viral structure near the glycan cap in a way that destabilizes the entire viral glycoprotein structure, sometimes causing it to fall apart.

Second, the glycan cap antibody—when it binds to its target site—can block a key event in the infection process, in which an enzyme called a cathepsin cleaves off the glycan cap. Blocking this cleavage event blocks the glycoprotein’s ability to enter host cells.

Finally, the glycan cap antibody, by displacing the loose structure near the glycan cap, enables another type of neutralizing antibody to bind to a separate vulnerable site on the virus. Thus, a glycan cap antibody can “synergize” with another antibody to hit the virus significantly harder than either antibody does alone.

The scientists also determined the key genetic elements that allow glycan-cap antibodies to thwart ebolaviruses in these three ways.

Now that they have illuminated how these broadly neutralizing antibodies work, Ward, Murin and colleagues are testing them as parts of a next-generation antibody cocktail that they hope will be able to treat the Zaire, Sudan and Bundibugyo ebolaviruses.

The study, “Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies” was authored by Daniel Murin, Pavlo Gilchuk, Philipp Ilinykh, Kai Huang, Natalia Kuzmina, Xiaoli Shen, Jessica Bruhn, Aubrey Bryan, Edgar Davidson, Benjamin Doranz, Lauren Williamson, Jeffrey Copps, Tanwee Alkutkar, Andrew Flyak, Alexander Bukreyev, James Crowe, and Andrew Ward

The research was supported by the National Institutes of Health (U19 AI109762, U19 AI142785)

Featured image: 3-D rendered image of Ebola virus (stock image). Structural biologists at Scripps Research used electron microscopy to learn how certain antibodies are able to keep ebolaviruses from infecting cells. © Scripps

Reference: Charles D. Murin, Pavlo Gilchuk et al., “Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies”, Cell reports, 35(2), 2021. DOI: https://doi.org/10.1016/j.celrep.2021.108984

Provided by Scripps

Covid-19 Vaccines May Not Produce Sufficient Antibody Response in Transplant Recipients (Medicine)

When clinical trials were conducted to determine the immunogenicity — the ability to elicit an immune response — for the first two vaccines marshaled against SARS-CoV-2the virus that causes COVID-19, one group was not among those included: people who have received solid organ transplants and others (such as those with autoimmune disorders) who are immunocompromised.

Now, Johns Hopkins Medicine researchers have tried to rectify that inequity, taking one of the first looks at how people who are immunocompromised respond to their first dose of one of the two mRNA vaccines — Moderna and Pfizer-BioNTech — currently being administered worldwide. Their findings, as published March 15, 2021, in a research letter in the Journal of the American Medical Association, disappointingly show that only 17% produced detectable antibodies against the SARS-CoV-2 virus.

“This is in stark contrast to people with healthy immune systems who are vaccinated, nearly all of whom mount a sufficient antibody defense against COVID-19,” says study lead author Brian Boyarsky, M.D., a surgery resident at the Johns Hopkins University School of Medicine.

The study evaluated the vaccine immunogenic response for 436 transplant recipients, none of whom had a prior diagnosis of COVID-19 or tested positively for SARS-CoV-2 antibodies. The median age was 55.9 years and 61% were women. Fifty-two percent were administered a single dose of the Pfizer-BioNTech vaccine and 48% received one shot of the Moderna vaccine. The median time since transplant for the participants was 6.2 years.

At a median time of 20 days after the first dose of vaccine, the researchers report that only 76 of the 436 participants (17%) had detectable antibodies to the SARS-CoV-2 virus. The researchers also found that among the 76 transplant recipients, the most likely to develop an antibody response were those younger than age 60 who did not take anti-metabolites for immunosuppression and who received the Moderna vaccine.

“Given these observations, we feel that the U.S. Centers for Disease Control and Prevention should update their new guidelines for vaccinated individuals to warn immunocompromised people that they still may be susceptible to COVID-19 after vaccination,” says study senior author Dorry Segev, M.D., Ph.D., the Marjory K. and Thomas Pozefsky Professor of Surgery and Epidemiology and director of the Epidemiology Research Group in Organ Transplantation at the Johns Hopkins University School of Medicine. “As the guidelines are currently written, people assume that vaccination means immunity.”

Segev says that upcoming studies will define the immunogenic response of organ transplant recipients and other immunocompromised patients after a second vaccine dose. Other studies will look at the impact of more extensive immune system profiling — including characterizing the immune cells that remember SARS-CoV-2 after vaccination and produce antibodies, or directly attack the virus in response to the presence of the virus — to help guide vaccination strategies for this population.

Featured image: A medical assistant prepares a dose of a COVID-19 vaccine to be administered to a patient. Johns Hopkins Medicine researchers recently showed that after one dose of the vaccine, organ transplant patients and other immunocompromised people may not produce high levels of antibodies against SARS-CoV-2, the virus that causes COVID-19. Credit: Public domain image courtesy of Lisa Ferdinando, U.S. Department of Defense

Reference: Brian J. Boyarsky, William A. Werbel, Robin K. Avery, Aaron A. R. Tobian, Allan B. Massie, Dorry L. Segev, Jacqueline M. Garonzik-Wang, “Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients”, JAMA. Published online March 15, 2021. doi: 10.1001/jama.2021.4385

Provided by Johns Hopkins Medicine

Monoclonal Antibodies Against MERS Coronavirus Show Promise in Phase 1 NIH-sponsored Trial (Medicine)

A randomized, placebo-controlled Phase 1 clinical trial of two monoclonal antibodies (mAbs) directed against the coronavirus that causes Middle East respiratory syndrome (MERS) found that they were well tolerated and generally safe when administered simultaneously to healthy adults. The experimental mAbs, REGN3048 and REGN3051, target the MERS coronavirus (MERS CoV) spike protein used by the virus to attach to and infect target cells. The mAbs were discovered and developed by scientists at the biopharmaceutical company Regeneron, located in Tarrytown, New York. The trial was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The trial was the first to test the experimental antibodies Hyperlink Code in people. Conducted at WCCT Global, a clinical trial site in California, the study enrolled 48 healthy adults, 36 of whom received the mAbs. All volunteers were followed for 121 days after receiving mAbs (or placebo) by intravenous infusion. No serious adverse events occurred.

In preclinical studies, investigators at Regeneron and the University of Maryland, College Park, also administered REGN3048 and REGN3051 sequentially and in combination to genetically modified mice that, unlike wild-type mice, can be infected with MERS CoV. When administered one day prior to coronavirus exposure, both REGN3048 and REGN3051 reduced the levels of virus later detected in the lungs, with co-administration providing more potent protective effects than either mAb alone. Similarly, co-administering the mAbs one day after MERS CoV exposure provided a therapeutic benefit in mice by lowering viral levels and lessening tissue damage in the lungs as compared to mice that received placebo.

Together, the findings from the clinical trial and the preclinical mouse studies “demonstrate the potential efficacy and utility of monoclonal antibody therapy for the prevention or treatment of MERS-CoV and lays the groundwork for the development of spike-targeted mAb therapies for other infectious disease threats, including SARS-CoV-2,” which causes COVID-19, the authors conclude.

Featured image: MERS-CoV particles on camel epithelial cells. © NIAID and Colorado State University

Reference: S Sivapalasingam et al. Human monoclonal antibody cocktail for the treatment or prophylaxis of Middle East respiratory syndrome coronavirus (MERS-CoV). The Journal of Infectious Diseases DOI: 10.1093/infdis/jiab036 (2021).

Provided by NIAID/NIH