If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics.
Stephen T. Warren, 1953-2021
Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more
At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia.
Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
The Emory MVA COVID-19 vaccine induces protective immunity with the platform of modified vaccinia Ankara (MVA), a harmless version of a poxvirus that is well-known for its use in HIV/AIDS vaccines. Like the Moderna and Pfizer COVID-19 vaccines, the Emory MVA COVID-19 vaccine induces strong neutralizing antibodies, which support the immune system’s ability to fight infections. The Emory MVA COVID-19 vaccine also induces killer CD8 T cells, providing a multi-pronged approach to halting SARS-CoV-2.
In addition, the Emory researchers say the vaccine is easily adaptable to address disease variants and can be used in combination with existing vaccines to improve their ability to combat variants and has the potential to be equally effective with a single dose.
Lead researcher Rama Amara, PhD, built the Emory MVA COVID-19 vaccine based on his more than 20 years of experience working with MVA and animal models to develop an HIV/AIDS vaccine. He and his Yerkes-based research team tested two MVA SARS-CoV-2 vaccines in mice. One of them, MVA/S, used the complete spike protein of coronavirus to induce strong neutralizing antibodies and a strong killer CD8 T cell response against SARS-CoV-2.
“Generating neutralizing antibodies is an important component of a successful COVID-19 vaccine because the antibodies can block the virus from entering the body’s cells,” says Amara, Charles Howard Candler professor of microbiology and immunology at Emory University School of Medicine and a researcher in Yerkes’ Division of Microbiology and Immunology and Emory Vaccine Center. “It’s as important to activate CD8 T cells that can clear infected cells, so this allows us to approach halting the virus two ways simultaneously. The CD8 T cells also provide ongoing value because they are key to working against other variants of the virus, especially if antibodies fail.”
Amidst the tumult in the nation’s capital, a quieter reckoning was taking place this week for the Moderna COVID-19 vaccine clinical trial. Lab Land has been hearing from Emory-affiliated study participants that they’re finding out whether they received active vaccine or placebo.
For example, Emory and Grady physician Kimberly Manning, who had written about her participation in the Moderna study in a Lancet essay, posted on Twitter Tuesday. She discovered she had received placebo, and then was offered active vaccine.
“Companies have said that they feel an ethical obligation to deliver vaccine to placebo recipients; the FDA and experts at its advisory panel have debated whether this obligation even exists. Instead, they argue, offering vaccine to volunteers receiving placebo limits the quality of the data about the vaccine’s long-term efficacy and side effects.”
A plan to keep participants in the study under a blinded crossover design was floated, but not implemented. Some participants have said they sensed from the start, based on temporary unpleasant side effects, whether they had received active vaccine or placebo.
For COVID-19, many researchers around the world have tried to repurpose drugs for other indications, often unsuccessfully. New clinical trial results show that baricitinib, developed by Eli Lilly and approved for rheumatoid arthritis, can speed recovery and may reduce mortality in some groups of hospitalized COVID-19 patients.
How did this study, sponsored by the National Institute of Allergy and Infectious Diseases, come together? In part, through decade-long groundwork laid by investigators at Emory, and their collaborations with others.
For several years, drug hunter and virologist Raymond Schinazi and his team had been investigating a class of medications called JAK inhibitors, as an option for tamping down chronic inflammation in HIV infection. Schinazi was one of the first at Emory to investigate the use of anti-inflammatory agents for herpesviruses and HIV in combination with antiviral drugs. He believed that these viruses “hit and run,” leaving behind inflammation, even if they later go into hiding and seem to disappear.
In the race to halt the COVID-19 pandemic, researchers at Yerkes National Primate Research Center of Emory University share two important findings from their latest peer-reviewed, published study in Cell.
Rhesus monkeys are a valid animal model for COVID-19 studies because the way they experience and respond to the virus has comparable similarities to the way the virus affects humans, the researchers say. And baricitinib, an anti-inflammatory medication that is FDA-approved for rheumatoid arthritis, is remarkably effective in reducing the lung inflammation COVID-19 causes when the medication is started early after infection.
The study results have immediate and important implications for treating patients with COVID-19. Baricitinib will be compared against the steroid dexamethasone in a NIAID-sponsored clinical trial called ACTT-4 (Adaptive COVID-19 Treatment Trial), which started in November.
Mirko Paiardini, PhD, a researcher in Yerkes’ Microbiology and Immunology division, and his team selected rhesus macaques as the animal model because they expected the monkeys would mimic the disease course in humans, including the virus traveling to the upper and lower airways, and causing high levels of inflammation in the lungs. The team randomized eight rhesus macaques into two groups – a control and a treatment group; the animals in the treatment group received baricitinib.
“Our results showed the medication reduced inflammation, decreased inflammatory cells in the lungs and, ultimately, limited the virus’ internal path of destruction,” Paiardini says. “Remarkably, the animals we treated with baricitinib rapidly suppressed the processes responsible for inducing lung inflammation, thus elevating baricitinib for consideration as a frontline treatment for COVID-19 and providing insights on the way the drug works and its effectiveness.”
The FDA recently granted baricitinib emergency use authorization in combination with remdesivir based on the results of the ACTT-2 findings. “Our study was under way concurrently and, now, solidifies the importance of baricitinib in treating COVID-19,” Paiardini adds.
Co-senior author Raymond Schinazi, PhD, DSc, inventor of the most commonly used HIV/AIDS drugs to prevent progression of the disease and death, says: “Our study shows the mechanisms of action are consistent across studies with monkeys and clinical trials with humans. This means the nonhuman primate model can provide enough therapeutic insights to properly test anti-inflammatory and other COVID-19 therapies for safety and effectiveness.”
Schinazi is the Frances Winship Walters Professor of Pediatrics at Emory University School of Medicine and is affiliated with Yerkes.
“Ray and his group have been investigating the potential of anti-inflammatory drugs, such as baricitinib, for years in the context of another infection, HIV, in which inflammation is a key cause of sickness and death,” Paiardini says. “Our laboratories have collaborated for years to test therapeutics in the nonhuman primate model of HIV infection, thus placing us in a unique position when COVID-19 hit the U.S. to focus our combined expertise and efforts to halt the virus. It took only a phone call between the two of us to switch gears, begin work to create a reliable and robust monkey model of COVID-19 at Yerkes and test the potential of drugs to block inflammation.”
Tim Hoang, first author and Emory doctoral student in the Immunology and Molecular Pathogenesis Program, says: “It was exciting to be at the forefront of the response to COVID-19 and to be part of this research team that involved collaboration from Yerkes and Emory infectious disease experts, geneticists, chemists, pathologists and veterinarians.”
Co-first author and Emory postdoctoral fellow Maria Pino, PhD, emphasizes: “We knew Yerkes was uniquely suited to conduct this study because of the research and veterinary expertise, specialized facilities and animal colony, and our team’s commitment to providing better treatment options for people who have COVID-19.”
The research team plans to conduct further studies to better understand the inflammation the virus causes and to develop more targeted approached to mitigate the damage COVID-19 leaves behind.
Steven Bosinger, PhD, co-senior author, and his research team conducted the genomic analyses that helped unravel the process by which baricitinib reduces inflammation. “One of the most exciting aspects of this project was the speed genomics brought to the collaborative research,” says Bosinger. “Eight months ago, we began using genomics to accelerate the drug screening process in order to identify treatable, molecular signatures of disease between humans and model organisms, such as the monkeys in this study, In addition to determining the effectiveness of baricitinib, this study highlights Emory researchers’ commitment to improving human health and, in this case, saving human lives.”
Bosinger is assistant professor, Department of Pathology & Laboratory Medicine, Emory School of Medicine (SOM) and Emory Vaccine Center (EVC); director, Yerkes Nonhuman Primate Genomics Core and a researcher in Yerkes’ Division of Microbiology and Immunology.
Some of the others on the Emory research team include: Arun Boddapati (co-first author), Elise Viox, Thomas Vanderford, PhD, Rebecca Levit, MD, Rafick Sékaly, PhD, Susan Ribeiro, PhD, Guido Silvestri, MD, Anne Piantadosi, MD, PhD, Sanjeev Gumber, BVSc, MVSc, PhD, DACVP, Sherrie Jean, DVM, DACLAM, and Jenny Wood, DVM, DACLAM. Jacob Estes, PhD, at Oregon Health & Science University also collaborated.
Paiardini says, “So many colleagues had a key role in this study. First authors Tim and Maria as well as Yerkes veterinary and animal care personnel who worked non-stop for months on this project. This truly has been a collaborative effort at Emory University to help improve lives worldwide.”
This study was funded by the National Institutes of Health, Emory University’s COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, Yerkes’ base grant, which included support for the center’s Coronavirus Pilot Research Project grants, and Fast Grants.
Grant amounts (direct + indirect) are:
NIH R37AI141258, $836,452/yr (2018-23)
NIH R01AI116379, $783,714/yr (2015-20 + 2021 NCE)
NIH P51 OD011132, $10,540,602/yr (2016-20)
U24 AI120134 $681,214/yr (2020-2025)
S10OD026799 $985,030/yr (2019-2020)
Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, $150,000/1 yr
Fast Grants #2144, $100,000/1 yr
Note: Only a portion of the NIH grant funding was applied to the study reported in this news release.
Post-acute is a confusing term, because it includes both people who were hospitalized with COVID-19, sometimes spending weeks on a ventilator or in an intensive care unit, as well as members of the long COVID group, who often were not hospitalized and did not seem to have a severe infection to begin with.
COVID-19 infection can leave behind lung or cardiac damage that could explain why someone would have fatigue and shortness of breath. But there are also signs that viral infection can perturb other systems of the body, leading to symptoms such as “brain fog” (cognitive/memory problems), persistent pain and/or loss of smell and taste.
One goal for the workshop was to have experts discuss how to design future studies, or how to take advantage of existing studies to gain insights. A major clue on what to look for comes from Emory immunologist Ignacio Sanz, who spoke at the conference.
Sanz’s research has shown similarities between immune activation in people hospitalized at Emory with severe COVID-19 and in people with the autoimmune disease lupus. In lupus, the checks and balances constraining the immune system break down. A characteristic element of lupus are autoantibodies: antibodies that recognize parts of the body itself. Their presence in COVID-19 may be an explanation for the fatigue, joint pain and other persistent symptoms experienced by some people after their acute infections have passed.
For details on Sanz’s research, please see our write-up from October, their Nature Immunology paper, and first author Matthew Woodruff’s explainer. The Nature Immunology paper’s results didn’t include measurement of autoantibodies, but a more recent follow-up did (medRxiv preprint). More than half of the 52 COVID-19 patients tested positive for autoantibodies at levels comparable to those in lupus. In those with the highest amounts of the inflammatory marker CRP, the proportion was greater.
“It could be that severe viral illness routinely results in the production of autoantibodies with little consequence; this could just be the first time we’re seeing it,” Woodruff writes in a second explainer. “We also don’t know how long the autoantibodies last. Our data suggest that they are relatively stable over a few weeks. But, we need follow-up studies to understand if they are persisting routinely beyond infection recovery.”
Sanz’s group was looking at patients’ immune systems when both infection and inflammation were at their peaks. They don’t yet know whether autoantibodies persist for weeks or months after someone leaves the hospital. In addition, this result doesn’t say what is happening in the long COVID group, many of whom were not hospitalized.
It makes sense that multiple mechanisms could explain post-COVID impairments, including persistent inflammation, damage to blood vessels or various organs, and blood clots/mini-strokes.
Anthony Komaroff from Harvard, who chaired a breakout group on neurology/psychiatry, said the consensus was that so far, direct evidence of viral infection in the brain is thin. Komaroff said that neuro/psych effects are more likely to come from the immune response to the virus.
There were breakout groups for different areas of investigation, such as cardiovascular, and gastrointestinal. Emory Vaccine Center director Rafi Ahmed co-chaired a session for immunologists and rheumatologists, together with Fred Hutch’s Julie McElrath.
Reports from the breakout groups Friday emphasized the need to design prospective studies, which would include people before they became sick and take baseline samples. Some suggestions came for taking advantage of samples from the placebo groups in recent COVID-19 vaccine studies.
As the Atlanta area recovers from Zeta, we’d like to highlight this Journal of Clinical Microbiology paper about saliva-based SARS-CoV-2 antibody testing. It was a collaboration between the Hope Clinic and investigators at Johns Hopkins, led by epidemiologist Christopher Heaney.
Infectious disease specialists Matthew Collins, Nadine Rouphael and several colleagues from Emory are co-authors. They organized the collection of saliva and blood samples from Emory COVID-19 patients at several stages: being tested, hospitalized, and recovered. Saliva samples were collected by having participants brush their gum line with a sponge-like collection device. More convenient than obtaining blood or sticking a swab up the nose!
The paper shows that antiviral antibody levels in saliva parallel what’s happening in patients’ blood. However, some forms of antibodies (IgM) appear less in saliva because of their greater molecular size. People who test positive do so by 10 days after symptom onset.
The authors conclude: “Saliva-based assays can be used to detect prior SARS-CoV-2 infection with excellent sensitivity and specificity and represent a practical, non-invasive alternative to blood for COVID-19 antibody testing… A logical next step would be to perform a head-to-head comparison of this novel saliva assay with other antibody tests approved for clinical use.”
In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of B cells, resembling acute flares in systemic lupus erythematosus (SLE), an autoimmune disease.
The findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. It also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.
The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers – looking similar to what they had observed in SLE.
Update: check out first author Matthew Woodruff’s commentary in The Conversation: “The autoimmune-like inflammatory responses my team discovered could simply reflect a ‘normal’ response to a viral infection already out of hand. However, even if this kind of response is ‘normal,’ it doesn’t mean that it’s not dangerous.”
Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz and his lab were focused on studying SLE and how the disease perturbs the development of B cells.
“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”
In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.
How many people out there have been exposed to SARS-CoV-2? It’s a tricky question, once you think about all the people who have experienced COVID-19 symptoms over the last several months, but didn’t go to the hospital. And there’s a murkier penumbra of people who may have fended off the virus with a minor immune skirmish.
A recent Emerging Infectious Diseases paper from Emory investigators includes antibody tests on a group of more than 100 adults in the Atlanta area who experienced mild flu-like symptoms this spring, but couldn’t get tested for SARS-CoV-2 itself.
A sizable fraction (22 to 48 percent, depending on when they provided blood samples) had elevated levels of IgM against the coronavirus. IgM is the “rookie” antibody produced when the immune system is first encountering something, as opposed to the more seasoned IgG, which appears later in an immune response and tended to rise only in people who were hospitalized. The Emory authors came to a conclusion that others are also reaching:
“Examining IgM and IgG against multiple SARS-CoV-2–related antigens may thus better inform natural history and vaccine studies than any one antibody.”
To answer these kinds of questions more comprehensively, investigators will need to go broader. For example, this week the American Red Cross published data on what proportion of its blood donors have antibodies against SARS-CoV-2. About 3 percent of first-time donors did, using their criteria.
Measuring blood antibody levels against SARS-CoV-2 may distinguish children with multisystem inflammatory syndrome (MIS-C), which appears to be a serious but rare complication of viral infection, say researchers at Emory University School of Medicine and Children’s Healthcare of Atlanta.
Children with MIS-C had significantly higher levels of antiviral antibodies – more than 10 times higher — compared to children with milder symptoms of COVID-19, the research team found.
The results, published in the journal Pediatrics, could help doctors establish the diagnosis of MIS-C and figure out which children are likely to need extra anti-inflammatory treatments. Children with MIS-C often develop cardiac problems and low blood pressure requiring intensive care.
Visionary immunologist Charlie Janeway was known for calling adjuvants – vaccine additives that enhance the immune response – a “dirty little secret.”
Charlie Janeway, MD, in a hat he wore often
Janeway’s point was that foreign antigens, by themselves, were unable to stimulate the components of the adaptive immune system (T and B cells) without signals from the innate immune system. Adjuvants facilitate that help.
By now, adjuvants are hardly a secret, looking at some of the research that has been coming out of Emory Vaccine Center. This week, an analysis by Ali Ellebedy, now at Washington University St Louis, and colleagues showed that in healthy volunteers, the AS03 adjuvant boosted otherwise poor immune responses to a limited dose of the exotic avian flu H5N1, recruiting both memory and naïve B cells. More on that here.
A question we’ve seen many people asking, and discussed on Twitter etc is this: how long does the immunity induced by a SARS-CoV-2 vaccine last? How can we make the immune cells induced by a vaccine stick around for a long time? Read more